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Keibel F. and Mall FP. Manual of Human Embryology II. (1912) J. B. Lippincott Company, Philadelphia.

XVIII. Development of Blood, Vascular System and Spleen: Introduction | Origin of the Angioblast and Development of the Blood | Development of the Heart | The Development of the Vascular System | General | Special Development of the Blood-vessels | Origin of the Blood-vascular System | Blood-vascular System in Series of Human Embryos | Arteries | Veins | Development of the Lymphatic System | Development of the Spleen
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Minot CS. The origin of the angioblast and the development of the blood. (1912)Sect. I, chapt. 18, vol. 2, in Keibel F. and Mall FP. Manual of Human Embryology II. (1912) J. B. Lippincott Company, Philadelphia..

I. The Origin of the Angioblast and the Development of the Blood

Charles Sedgwick Minot (1852–1914)

By Charles Sedgwick Minot.[1]


The number of papers upon the development of the blood is large, but the majority of them have been written from the clinical standpoint and they often leave much to be wished for the scientific interpretation of the theme. To these clinical writings we owe a confusing nomenclature of the bloodcorpuscles which, unfortunately, has become current in medical works, although it sins against every morphological principle. It unites forms which are morphologically different and separates forms which genetically and morphologically belong together, as is explained more fully in the note, p. 503, and in connection with the discussion of the development of leucocytes. Under these conditions it becomes unavoidable to discard almost entirely the current nomenclature and to replace it by 'a new one. The new nomenclature is in part taken over from others, in part proposed by myself. It at least corresponds to the morphological demands.

The following exposition is based chiefly on the investigations of four morphologists, — W. His, 0. van der Stricht, J. Jolly, and F. Weidenreich, — to whom we are indebted for the greater part of our present comprehension of the problem of the blood. Of further importance is the just-published (March, 1909) memoir of Maximow (Arch. f. mikr. Anat., vol. lxxiii, p. 444), who studied the development of blood especially in rabbit einbryos. Ruckert and Mollier,[2] in Hertwig's " Handbuck," have given a detailed account of the early development of the angioblast in all classes of vertebrates. The value of this work is very high, and for that reason we regret very much that they have not included the eytomorphosis of the blood-corpuscles within the limits of their account. Although I am unable in many cases to adopt the point of view of the clinicians as my own, yet I have collected from their writings many data.

1. The Angioblast

Comparative embryology teaches us that the first blood vessels appear upon the yolk-sac collectively and at one time. They form a unit anlage, which we call briefly the angioblast, according to the suggestion of His. It must, however, be immediately mentioned that several investigators, like Maximow in his latest paper, derive the blood-vessels directly from the mesoderm of the embryo. In fact, we can assert the complete precocious independence of the angioblast from the mesoderm proper only as highly probable. The angioblast lies originally immediately upon the yolk and forms a network that can be recognized just after the first appearance of the anlage. The mesoderm, sensu strictu, forms a continuous layer which lies above the anlagen of the vessels and comes into direct contact with the yolk only in the gaps of the vascular network. According to the majority of observations the angioblast appears to be split off, in all vertebrates, directly from the yolk. It is very difficult to decide whether the angioblast is to be interpreted as belonging genetically to the middle germ layer or as a derivative of the entoderm. the views as to these interpretations are very divergent, but the fact remains tbat the angioblast becomes independent very early and is the first tissue of the embryo to exbibit an unquestionable differentiation and sbarp limitation. It must be especially empbasized tbat the vascular anlagen do not develop in common witb the mesoderm, or, if one prefers, witb the remaining mesoderm. I incline strongly to the opinion tbat the mesoderm is formed first and that the angioblast, added later, forms itself, not through transposition and transformation of mesodermic cells already present, but from cells which separate from the yolk, or from the layer of yolk cells, and form a reticulate grouping of themselves between the middle and lower germ layers.

The angioblast probably maintains its complete independence throughout life. In other words, it is probable that the endothelium of the blood-vessels (and of the lymph-vessels) and the blood-cells at every age are all direct descendants of the primitive angioblast. Unfortunately, our present knowledge does not allow us to express an opinion on this point with absolute confidence. Thus, we find that Maximow (Arch. f. mikr. Anat., vol. lxxiii, p. 511-515) attributes the formation of new vessels and of new mesamoeboids, not to the angioblast, but to the mesoderm proper. The most recent American observations speak against Maximow's view.

The differentiation of the angioblast in amniota may be summarized as follows : The network consists originally of cell cords, which soon become hollow. According to many observations the cavity may be bounded at first on its under side only by yolk. The angioblast cells transform themselves in part into endothelial cells, in part into new blood-cells. The endothelium arises from the peripheral layer of the cords; blood elements, on the contrary, from the more centrally placed cells. Only the endothelium forms an uninterrupted network; the blood-cells form scattered clusters, the so-called blood-islands. These consist of cells which are not separated by cell walls either from one another or from the neighboring endothelium. Very often, perhaps always, one finds the lumen of the vessel below (entad) the blood-islands, the cells of which hang down in a cluster from the upper surface of the vessel. In the majority of amniota, the blood-vessels arise in a limited space, which surrounds the embryo and covers only the upper surface of the yolk. This space is the area vasculosa. In man, however, the area covers the whole yolk from the start. The area vasculosa, studied in fresh specimens, can be recognized in many amniota by the red color of the bloodislands. This color corresponds to the beginning of the development of haemoglobin. Soon the cells of the islands separate from one another and become free. They are the primary blood-cells, or, better, the primitive mesamoeboids. Very often the first-formed cells are quite large ; nevertheless, they possess the ability to wander out from the vessels, giving rise in this way to the giant wandering cells which one can observe in very young embryos, as, for example, those of the chick. The large primary cells become gradually smaller by repeated division until they reach the condition which I regard as the rejuvenated stage of the blood-cells, with which the cytomorpbosis proper begins. The mesamoeboids are round cells with relatively large nuclei, which are approximately round. The nucleus is surrounded by a thin layer of protoplasm which, on account of its slight thickness, has often been overlooked. The nucleus has a distinct reticulum, the nodes of which are thickened in part, forming so-called plasmasomes. The protoplasm is finely granular. Cells with these distinct characteristics occur in all vertebrates, but are restricted to early embryonic stages, and have not, up to the present time, been observed in adults. The cells in question multiply in the blood by mitotic division. Their bodies soon become larger, and thus arise colorless cells which continue to divide. Their descendants develop in different ways, in part retaining the embryonic habitus, and in part transforming themselves into red cells — erythrocytes. It must be further noted that in relatively late embryonic life the undifferentiated mesamoeboids in part develop into genuine leucocytes.

The primitive mesamoeboids are the ancestors not only of all blood-cells, but also, as Maximow has demonstrated, of other cell forms which occur in the connective tissue of the adult. Recent morphological investigators of the blood consider the conclusion secure that red and white blood-corpuscles have the same origin, or, in other words, that they arise monophyletically. Especially illuminating are the investigations of Maximow[3] and Frau Dantschakoff[4] on this question.

The majority of embryologists are of the opinion that the colorless mesamoeboids remain throughout life in order to serve as a permanent source of both red and white blood-cells. Since they can move freely, they can alter their distribution in the body. In mammals the multiplication of the primitive mesamoeboids during the earliest development occurs only in the yolk-sack; later it takes place in the circulating blood; still later in the fetal liver and lymphoid organs; and, finally, in the marrow of bones, which serves as the permanent site of blood formation. Up to the present time no conclusive proof has been brought that the cells in question arise autochthonously in the liver or lymphoid organs or bone-marrow. Therefore, embryologists incline to the opinion that we have to deal merely with the accumulation of immigrant cells. In other words, according to the present view all the cellular blood elements are direct descendants of the primitive mesamoeboids. That this view is secure beyond all doubt cannot, however, be asserted.

The development of human blood still awaits a thorough investigation. The observations at present available are in great part — though not exclusively — more or less incidental to other researches. We find data, first, in descriptions of the development of certain organs, especially the yolk-sack, the liver, and the bone-marrow; secondly, in more extended articles on blood development. The number of such articles is very large, but they are chiefly occupied with the phenomena as observed in various animals. Schridde has studied the blood development in nine young human embryos and has reached conclusions which cannot easily be brought into agreement with other apparently reliable observations. Unfortunately, his research is known to me only through his preliminary notice of 1907 (Verh. deutsch. pathol. Ges. fur 1907, p. 360-365). Therefore a critical discussion of his work is excluded.

We possess at present two comprehensive memoirs, in which the previous literature — so far as it concerns the red blood-corpuscles of vertebrates — is extensively considered and critically discussed. The memoir of Weidenreich[5] appeared in two parts, of which the first deals with the form and structure of red corpuscles, while the second describes the immature forms and the origin and transformation of the colored corpuscles. Weidenreich strives to give a unified summary of the results already obtained. The memoir by Jolly[6] offers us not only the results of an excellent comprehensive investigation of the cytomorphosis of the blood-cells, but also valuable discussions of previous investigations. The views defined by Jolly deserve special attention because they have been worked out very conscientiously. Since an exhaustive consideration of the development of the phenomena in animals lies outside the limits of our present undertaking, it seems suitable to recommend the memoirs of Weidenreich and Jolly as excellent sources for the reader who seeks exact literary data.

2. Origin of the Human Angioblast

Our knowledge of the actual facts is here very defective. We do not yet know, by actual observation, how the earliest vessels arise in man. We know merely that the angioblast appears first on the yolk-sack, and that in almost the earliest stage known to us it already occupies the whole surface of the sack. The angioblast has genuine bloodislands and grows later into the embryo presumably by the formation of sprouts. The precocious development of the human angioblast is, in all probability, closely connected with the precocious independent development of the yolk-sack. A few of the more exact data may be presented. Graf von Spee 7 observed a few islands in the wall of the yolk-sack in an ovum of 9 mm. diameter, with an embryonic shield of 0.37 mm. The yolk-sack had a diameter of 1.84 mm. Its mesoblastic covering formed irregular bunches and projections, which were especially noticeable around the pole of the sack farthest from the embryonic shield. Each of these eminences corresponded to a blood-island situated between the mesoderm and the entoderm. Keibel 8 observed similar relations in an embryo of 6 mm. X 8.5 mm. (including villi). The vascular anlagen do not occur in the immediate neighborhood of the embryo, but begin at a line somewhat removed from it. The yolk-sack of an embryo of 1 mm. (Harvard Embryol. Coll., No. 825) comprises two territories : one of these I regard as the area pellucida, because it possesses a very thin entoderm and occupies the embryonic half of the sack; the other territory, which I regard as the area opaca, has a thicker entoderm and lies opposite the embryonic shield. It is to be noted, moreover, that the vascular formation is restricted to this second territory. This case, which up to the present is unique, renders it probable that in man also the formation of the angioblast begins in a true area opaca and then spreads out toward the embryo, as occurs typically in other amniota.

It is well known that in many amniota the earliest mesamoeboids are relatively large. They probably arise directly by pinching off from the yolk (entoderm), and soon thereafter they are separated from the yolk, or entoderm, by the growth of the vascular endothelium around them, by which they become enclosed in a definitive vascular space. The large primitive mesamoeboids, isolated in the manner described, multiply quite rapidly and become smaller. Meanwhile the circulation has begun, and at least a part of the mesamcoboids leave their place of origin. The history of the cells has not by any means become clear to us, for it still remains uncertain whether they all pass through the same transf omiations ; but it is certain that many transform themselves into cells of very small size, with nuclei much smaller than those of the cells in the neighboring germ layers. Their protoplasm is minimum in man, so that the cell bodies form merely thin coverings for the nuclei. This process — multiplication of the nuclei and the retarded growth of protoplasm — is a general phenomenon in the earliest development of metozoa, and I have regarded it " as the rejuvenating process with which ontogeny must begin. If we accept this view, we may say that the mesamoeboids rejuvenate much more rapidly than the other cells of the germ layers.

  • Graf von Spee: Arch. f. Anat. u. Entwicklungs Ges., 1896, p. 8. "Franz Keibel: Arch. f. Anat. u. Entwicklungs Ges., 1S90. p. 255.

While we must admit that our knowledge of the earliest development of the blood in vertebrates is but little satisfactory, because it does not touch many essential points, we must add that the corresponding processes in man are, properly speaking, unknown to us.

The growth of the vessels into the embryo occurs very early. In embryo Klb. 10 (1.8 mm., 5-6 segments) the vessels have already passed into the embryonic body and lie between the visceral mesoderm and the entoderm. The same pathway between the germinal layers is followed, in all vertebrates, by the first vessels as they grow into the embryonic body. Schridde (I.e., p. 362) found in an embryo of 2.5 mm. a similar net of vessels. In human embryos of 8-10 segments the chief primitive vessels are present. They are of merely endothelial tubes.

Keibel Mall 2 354.jpg

Fig. 354. — Three primitive mesamoeboids from the yolk-sac of a human embryo of about 1 mm. Harvard Emb. Coll., series 825. X 1500.

3. The Primitive Mesamosboids of Man

The cells in question have not yet been investigated accurately. 11 In the yolk-sack of the embryo mentioned above (H. E. C, No. 825) there occur cells which I regard as primitive mesamoeboids, three of which are represented in Fig. 354. They are characterized by the largeness of their nuclei and the small amount of their protoplasm. The nuclei possess about the same dimensions as the nuclei in the neighboring mesoderm and entoderm. The karyoplasma forms a dense superficial layer and a very wide meshed net of fine threads in the interior, with a few thickenings of varying sizes and irregular distribution. Not infrequently, however, there is a single main thickening centrally placed. The nuclei scarcely differ in structure from those of the neighboring tissues. The cell body is finely granulated, irregular in form, without a membrane, and is more deeply colored than the nuclei. I consider it probable that the cells are amoeboid. Maximow 12 gives a detailed description of the primitive rnesamoeboids in the rabbit, to which the reader is referred because the author goes more into detail than is at present possible for the cells in man.

Minot: The Problem of Age, Growth, and Death, New* York, 1908. 'Keibel: Normentafeln, Heft viii, p. 20. Compare Schridde; Verhand. dentsch. pathol. Ges., 1907, p. 360.

4. Cytomorphosis of the Erythrocytes

The erythrocvtes arise from the primitive rnesamoeboids, the cell bodies of which become laden with haemoglobin and at the same time acquire a homogeneous appearance. Meanwhile the nuclei also undergo important alterations.

The development of the erythrocytes has been much studied. In the majority of the published papers one feels the lack of a scientific morphological interpretation of the observations, many authors being interested chiefly in clinical applications.

We can confidently distinguish four chief stages in the cytomorphosis of the red corpuscles, for which I propose the following designations:

1. The mesamoeboids, the primitive or earliest colorless cells, which appear at first in the blood-spaces and arise chiefly, perhaps exclusively, by the breaking up of the blood-islands.

2. The Erythrocytes. — This term includes all red blood-cells which arise, probably exclusively, from rnesamoeboids. They are characterized by their content of haemoglobin and the homogeneous appearance of their protoplasm. We can distinguish three stages in the genesis of the erythrocytes of mammals: A. The ichthyoid blood-cells, the first form of the genuine erythrocyte, which occurs in all vertebrates and constitutes the permanent form in ichthyopsida. In the amniota, on the contrary, they represent a transitory stage of development. The cells in this stage are characterized by their content of haemoglobin, their homogeneous appearance, and their granular nuclei.

B. The sauroid blood-cells, the second form of the genuine erythrocytes, which may be observed as the second stage in the developmental differentiation of the ichthyoids in all amniota. The cells in this stage differ from the iehthyoids by their smaller average diameter, and especially by their smaller, darkly staining (pyknotie) nuclei. The sauroids are atrophying cells. They represent the permanent form in sauropsida, the temporary form in mammals.

C. Blood-plastids. — These are erythrocytes which have lost their nuclei, and occur only in mammals.

Note. — " mesamoeboid " was originally proposed by me to designate the wandering cells which occur in the middle germ layer. The mesamoeboid cells, which serve as the parent cells of the red blood-corpuscles, have been often confused with genuine leucocytes, and this has hindered the progress of hematology. The expressions " ichthyoid " and " sauroid " are in themselves not new, but the proposed application of them is new. The term " erythroblasts " has often been used in the sense of our ichthyoid cells, although in these we have to do with red blood-cells already differentiated. Current usage frequently restricts the term to the embryonic forms of the corpuscles in mammals. The mature red corpuscles of amphibia, for example, no one ventures to designate as erythroblasts, although they are homologous with the so-ealled erythroblasts of mammals. " Erythroblast " was introduced by Lowit to designate the colorless cells which, as the preliminary stage of red cells, are appropriately so called. For the regrettable misuse of the word the clinicians are alone responsible. " Normoblast " corresponds to the sauroid cell, but is not always applied with exactly the same meaning. The choice of the term is unfortunate : first, because it seems meaningless from the comparative standpoint, and therefore unavailable; and second, because even from the present clinical point of view it is without significance. The special stage of the " normoblast " is neither more nor less normal than the earlier and later stages. Further, since the stage in question is the permanent one in reptiles, the use of " blast " is unsuitable. " Erythrocyte " is a fitting name for all red blood-corpuscles whether they are nucleated or not, whether their nuclei are pyknotic or not. The effort of the clinicians to restrict this name to the non-nucleated blood-cells of mammals can hardly be justified. At the present day one would hardly expect that red cells with nuclei should not be recognized as erythrocytes but that they should change into erythrocytes by the loss of their nuclei. It does not appear scientific to call a cell Kvrog only after it has become non-nucleated. Similar considerations apply against the use of the expressions " megaloblast " and "microblast." It may be pointed out that in all tissues variations in the size of cells are encountered, and if all these variations are to be specially named the result will be an unlimited confusion in biological nomenclature. I proposed, in 1890, to call the non-nucleated blood-corpuscles of mammals " plastids." At that time I was influenced by the hypothesis proposed by Ranvier, Sehaefer, and others, of the intracellular origin of the red blood-corpuscles. In spite of the fact that the progress of our knowledge has compelled us to give up this hypothesis, we may still term the nonnucleated corpuscles plastids, since the word refers to the fact that they consist of cytoplasm. This renders it possible to ultilize " erythrocyte " as a collective term for any and all red cells, as is done in the present chapter.

  • Maximow: Arch. f. mikr. Anat., vol. lxxiii, 1909, p. 464.

The essential characteristic of erythrocytes is haemoglobin, the formation of which may be initiated earlier or later during the development of the single cell. It has long been known that the deposit of haemoglobin may begin in the blood-islands of the area opaca. This phenomenon appears clearly in the sauropsida and has also been recognized in various mammals. In man, on the contrary, if red blood-islands occur at all, they must break up very early; as indeed, according to Maximow,[7] occurs typically in mammals, which in that respect differ from the sauropsida. In the youngest stage yet observed, the free human mesamoeboids do not have any haemoglobin.

We must assume that in man also the primitive mesamoeboids multiply, and that a part of them retain the primitive habitus. While this goes on, one observes the gradual disappearance of the forms with minimal protoplasm. At the end of the first month, and from then on to birth, we find colorless mesamoeboid cells of the most varying sizes in the blood-spaces and in the blood-forming organs (Figs. 357 and 359).

Note. — The genetic relations of these cells to one another have still to be accurately determined. In the sauropsida there arise at first very large cells. On the other hand, we learn that the youngest cells multiply and at the same time enlarge. Further, the question arises, Are the large cells in vertebrate embryos all ancestors of the smaller cells or not? We may assume that at least a part of the cells are such ancestors.

Now, while the embryonic blood formation is going on, we may observe, especially in younger embryos, that the erythrocytes differ much in size. In later stages, as in the adult, we find that the developing erythrocytes are much more uniform. From these relations we draw the conclusion that during the developmental period both larger and smaller mesamoeboids transform themselves directly into colored corpuscles. But in this connection we must not forget that deductions are less conclusive than direct observations.

The appearance of haemoglobin causes a diffuse coloration of the protoplasm, which at the same time loses its granular appearance and becomes optically homogeneous. Since cells may be observed with varying intensities of coloration, we conclude that there is a gradually increased haemoglobin content of the cell.

Note. — Giglio-Tos maintains that in all vertebrates the haemoglobin arises from special granules. Weidenreich (1. c, p. 406) declares that these granules are artefacts. According to his opinion, we must assume that the haemoglobin appears diffusely in uniform concentration, without being demonstrable in the body of the cell by any special morphological structure. We cannot yet decide whether the haemoglobin is an exclusive or partial product of nuclear activity, as some have supposed, or not.

The cell membrane is probably developed at the same time as the haemoglobin. At least we observe that as soon as the coloration is recognizable the periphery of the protoplasm is bordered by a distinct line. How the membrane is developed is unknown. The nuclei undergo definite alterations during the formation of the haemoglobin, in consequence of which the cells pass to the ichthyoid type. Unfortunately, these alterations have not yet been carefully investigated.

The accompanying pictures represent some of the corpuscles from the blood, — A, of an embryo of 4 mm. (Fig. 355) ; B, of 7.5 mm. (Fig. 356) ; and C, of 9.4 mm. (Fig. 357). In comparison with the earlier stage (Fig. 354) the diminution of the nucleus at once attracts attention.

The more intense nuclear coloration of the older cells is very noticeable. The wide, clear meshes of the nuclear reticulum can no longer be seen. On the other hand, the granules are more numerous, are more deeply colored, and more rounded than before. It is further to be pointed out that there is a striking increase of the cortical layer of the nucleus. These observations may easily be repeated on other embryos. It seems probable that, together with the diminution of the nuclei, increase of the chromatin occurs. This fundamental question, however, cannot be decided on the basis of our present knowledge.

Keibel Mall 2 355.jpg

Fig. 355. — Two blood-corpuscles of a human embryo of 4 mm. X 1500. colored with alum-cochineal and orange G. Harvard Emb. Coll., No. 714.

Keibel Mall 2 356.jpg

Fig. 356. — Three blood-corpuscles of a human embryo of 7.5 mm. X 1500. Zenker's fluid, carmine coloration. Harvard Emb. Coll., No. 256.

In consequence of the changes above described, the cells reach the ichthyoid stage of their development. We have to deal not with the metamorphosis of single cells, but with a genuine cytomorphosis, since the cells continually multiply by division not only during the transformation of the mesamoeboids, but also while in the ichthyoid stage. Evidently the cytomorphosis goes on through successive generations of cells.

Keibel Mall 2 357.jpg

Fig. 357. — Three blood-corpuscles from a human embryo of 9.4 mm. X 1500. Miiller's fluid, alum-cochineal and safranine. Harvard Emb. Coll., No. 259. Li. nucleus of liver-cell for comparison.

The multiplication of young blood-cells by division was ascertained by Eemak in 1850, and since then has often been observed in many different vertebrates. 14 Mitoses of the ichthyic blood cells in the blood-vessels may be observed easily in well-preserved young human embryos. In embryos of 12 mm the formation of the blood in the liver has begun, and after this one finds either no or only exceptional mitotic red corpuscles in the blood-vessels of the body. The blood mitoses of man have not yet been studied in detail.

  • J. Jolly has published an important paper on the division of blood corpuscles in amphibia (Arch. d'Anat. microsc, vol. vi, 1904, p. 455). Jolly gives exhaustive consideration to the literature of the subject.

Bizzozero,[8] after repeatedly studying the multiplication of young erythrocytes, came to the conclusion that after very early embryonic stages the multiplication is accomplished exclusively by the division of cells already containing haemoglobin, and in accordance with this view he denied the continued transformation of colorless cells (Lo wit's erythroblasts) into colored cells. We cannot at present admit that Bizzozero was right.

The sauroid blood-cells arise by the transformation of single ichthyoids. Since, so far as is known at present, they do not multiply by division, they can increase in number only by the metamorphosis of the younger cells. The ichthyoid cells contain hasmoglobin and have a membrane, hence the further visible multiplications concern chiefly the nucleus. There occurs a steady diminution of the volume of the nucleus, and at the same time the framework of chromatin condenses and thickens ; the granules or so-called nucleoli — of which the typical ichthyoid cell has several — become larger and merge with the condensed reticulum so as to become no longer observable (Weidenreich, I.e., p. 407), Fig. 358. The nucleus meanwhile becomes smoothly round, as in other mammals. In this condition it absorbs the usual coloring fluids so intensely that little or nothing can be seen of its structure (Fig. 358). Since the cell does not shrink with the nucleus, the haemoglobin gains the space which the nucleus loses. In brief, the ichthyoid cell changes into the sauroid by pyknosis of the nucleus.

The " normoblasts " of Ehrlich are sauroid cells, but the sauroids vary much in size, a fact which Ehrlich has already pointed out (compare note, p. 504). He directed special attention to the larger and smaller forms, and was of the opinion that the extreme forms were genetically distinct. Weidenreich expresses himself positively against this opinion, justly, it seems to me. In fact, the mesamoeboids in young embryos vary much in size (compare Fig. 354) and a similar unevenness prevails also among the ichthyoid cells (Fig. 357). It is further probable that the large mesamoeboids, of which the majority form small cells by continual division, in small part at least develop haemoglobin precociously and thus produce the so-called megaloblasts.

Variation of the erythrocytes is especially pronounced in quite young embryos (Kolliker, 1846) and diminishes rapidly with age. At the close of fetal life it is comparatively slight. A statistical investigation of the variations in man is much to be desired.

An observation which I have occasionally made may be interpolated here. Now and again one finds a human embryo in which the erythrocytes contain from one to three small rounded granules, which are yellowish brown and vary in size and form. They are highly refractile and have no resemblance to nuclear fragments.

These cells are especially numerous in an embryo of 6 mm. (No. 241 of Professor Mall's collection). Their significance is unknown to me.

Under pathological conditions granules may occur in the cytoplasm of erythrocytes which differ both from nuclear fragments and from the granules just described. They are unevenly fine granules, which take a basophile color. Naegeli 16 asserts that similar granules occur normally in the embryonic erythrocytes of several mammals (and also of man). I have been unable to confirm his statements.

The sauroid blood-cell changes into a blood-plastid by the loss of its nucleus. Since the change is imperfectly known in man, the following description is applicable rather to mammals in general than specifically to Homo. According to the original view of Kolliker[9] the nucleus was dissolved within the cell. According to the view of Rindfleisch[10] the nucleus is expelled. Both views have had many subsequent defenders. Jolly, I.e., gives an excellent exposition of the whole discussion. A more condensed review is given by van der Stricht.[11] Jolly reaches the conclusion that karyolysis may occasionally occur in young embryos, and is very rare, or does not occur at all, in older embyros and after birth. On the other hand, the expulsion of the nucleus is to be regarded as a normal process. The erythrocyte does not usually expel the whole nucleus at once, but in the form of single pieces which are driven out in succession. 20 Maximow, 21 however, reports that in young rabbit embryos the nucleus is expelled while still intact. It may happen that the part of the nucleus first expelled is larger than the part left behind. The expulsion may be easily observed in various phases; the phenomenon does not begin until the formation of blood has commenced in the liver. It occurs abundantly later in the bone medulla, but is rare in the blood-vessels of other parts of the body. Occasionally a pyknotic nucleus forms buds, which lead to the fragmentation of the nucleus and prepare for the expulsion. The expelled nuclei and nuclear fragments are, for the most part, eaten by phagocytes s and therefore almost never appear in the circulating blood. In passing, it may be mentioned that according to Afanassiew 23 the expelled nucleus becomes a blood-plate, an assumption which it has not been possible to affirm.

Keibel Mall 2 358.jpg

Fig. 358. — Four blood-corpuscles from a human embryo of 15.5 mm. X 1500. Coll. F. P. Mall, No. 390. Li., nucleus of liver-cell for comparison of sizes.

  • Naegeli: Ueber basophile Granulationen der Erythrozyten bei Embryonen. Folia haematol., vol. v, 1908, p. 525.

In young human embryos the blood plastids vary greatly; on the average they are larger than in later stages or in the adult. Maximow, 24 studying the rabbit, distinguishes the first erythrocytes as "primitive erythroblasts " and emphasizes the differences in their structure and that of later forms.

The early human plastids do not have the characteristic form of the definitive corpuscles, but retain a spherical shape. Gradually the cells of this type disappear, and at the same time appear the small cup- shaped corpuscles (Fig. 359) which increase steadily in number. Meanwhile the nucleated erythrocytes gradually disappear from the blood, so that a little time after birth only the cupshaped corpuscles are found in circulation.

Keibel Mall 2 359.jpg

Fig. 359. — Blood-corpuscles from a blood-vessel of a human embryo of eight months. X 1500.

We can observe, very early, disintegration of the erythrocytes, even of the primitive mesamoeboids. Three sorts of disintegration are to be considered: 1, dissolving of the haemoglobin and bursting of the corpuscle ; 2, fragmentation ; 3, vacuolization, with subsequent plasmolysis. Cells of the blood may die off in the most various stages of development. Their cytomorphosis closes with death. How far the death phenomena differ in the two cases is unknown. If the haemoglobin is dissolved out, the ervthrocvte remains as a round vesicle with or without a nucleus, as the case may be, with otherwise colorless contents and with a distinct membrane. In the case of a plastid, the corpuscle swells by imbibition and assumes a round form. Although erythrocytes which have lost their haemoglobin occur frequently in embryonic blood, yet, as might be expected, it is very rare to get sight of one in the moment of bursting. The fragmentation of the red corpuscles in the adult has long been known. It occurs also in fetal life, but has as yet been little studied in embryos. The disintegration by vacuolization has, so far as known to me, not been described hitherto, 25 and consequently may be treated somewhat more fully. So far as my observations go, this form of disintegration occurs only outside of the vessels.

  • 10. van der Stricht : Arch, de Biol., vol. xii, 1892, p. 251. Afanassiew: Deutsch. Arch. f. klin. Med., 1884, p. 217. 'A. Maximow: Arch. f. mikr. Anat., vol. Ixxiii. 1009. p. 471.

Keibel Mall 2 360.jpg

Fig. 360. — An erythrocyte lying free in the mesenchyma. > 1800.

Any embryologist can easily convince himself that all forms of blood-cells occur in the mesenchyma of young embryos. I have observed this distribution not only in man, but also in the pig, sheep, rabbit, cat, etc. There are no exceptions. Generally speaking, the forms of the corpuscles in the mesenchyma are identical with those in the vessels of the same embryo. Fig. 360 represents an erythrocyte lying free in the mesenchyma in the neighborhood of the forebrain of a human embryo of 6 mm. The red cells are widely scattered, but occur most frequently near the vessels. Sometimes they lie singly, and sometimes there are several together. The primitive colorless cells show a similar distribution in the mesenchyma. They are the so-called "primitive wandering cells" to which attention has been directed by several investigators, and especially by Saxer. 26 In my opinion, the conditions can be interpreted only on the assumption that all the free cells have wandered from the blood-vessels into the mesenchyma. I recognize no basis for assuming that we have to do with a progressive development in the mesenchyma, but this assertion is not equivalent to an absolute denial of such a possibility. It must be added that I have not yet been able to find evidence of the metamorphosis of mesenchymal cells into wandering cells. This metamorphosis has been especially emphasized by Maximow 27 and others, as a main part of their theories of the development of blood.

  • 28 We repeatedly find in the literature mention of wandering cells with vacuolated protoplasm, but they seem not to have been recognized as degenerating cells.

In older uninjured embryos we find that there are still mesamoeboids, by no erythrocytes. How do the latter disappear? "We can answer that in part, at least, by degenerative vacuolization (compare below). The majority, according to an hypothesis I have formed, are removed by the lymph-vessels. This hypothesis is merely the application to mammals of a discovery made by Eliot R. Clark. Clark 28 observed, in living tadpoles, that erythrocytes which had passed out from the blood-vessels were overgrown by sprouts developing from the lymph-vessels, and thus brought into the cavity of the vessel, in which they then moved along centripetally. In support of this hypothesis may be mentioned the fact that in the placental chorion of man — which, as is well known, has no lymph-vessels — erythrocytes occur in the connective tissue up to the time of birth.

It has long been known that strikingly large free cells appear in the mesenchyma of the chorion. They are pictured in my ' ' Human Embryology. ' ' 29 Hofbauer 30 has recently again called attention to them. Grosser 31 mentions these cells — " deren Bedeutung aber noch unklar ist. Renewed investigation has led me to the conclusion that we have to do with erythrocytes which have gotten into the mesenchyma and, remaining there, have swollen by imbibition and are undergoing degeneration by vacuolization of their protoplasm. Fig. 361 represents eight of the cells referred to, from the chorion of an embryo of 15 mm. a is an unquestionable erythrocyte, although it exceeds somewhat in diameter the average red cells in other vessels, b is also an erythrocyte, but distinctly larger. We can explain the appearance of these cells by the assumption of imbibition, in which the nucleus has participated. Cells similar to a and b are easily found, but the majority of the cells in the mesenchyma have the habitus of d and e and exhibit the beginning of vacuolization. /, g, h are three cells which exhibit three stages of disintegration of the protoplasm. Since I have found similar cells in a considerable number of placentas, I draw the conclusion that they are constant and normal. I regard the interpretation of the pictures unattackable as proof of progressive degeneration. The cells g and h deserve special attention, because they look almost as though they were furnished with pseudopodia.

  • Saxer : Anat. Hef te, vol. vi, 1896, p. 347.
  • A. Maximow : Arch, f . mikr. Anat., vol. lxxiii, 1909, p. 502. 28 E. R. Clark: Association of American Anatomists, Baltimore, 1909. See Anatomical Record, vol. iii, 1909, p. 183.
  • 28 Minot : Human Embryology, Fig. 190, p. 330. 30 Hofbauer: Die menschliche Placenta, 1907.
  • Grosser: Eihaute und Placenta. Wien, 1900. p. 224.

Keibel Mall 2 361.jpg

Fig. 361. — Red blood-cells from the placental chorion of a human embryo of 15 mm. Coll. F. P. Mall, No. 350. a, from a blood-vessel; b-h, from the mesenchyma. X 1500.

Now, we find similar denegerative appearances when we study the erythrocytes in the mesenchyma of the embryo. Hence we cannot avoid the conclusion that the corpuscles which have immigrated into the embryonic mesenchyma are subject to autolysis. I believe that I recognize among the degenerating cells the so-called pseudopod-bearing cells which Maximow and others have described. Important, also, is the observation that the mesamoeboid cells may degenerate in a similar way in the mesenchyma.

5. Hypotheses concerning the Formation of Erythrocytes

82 — According to Hay em, 33 the red cells are developed from blood-plates, which he further calls haeinatoblasts. Pouchet (1879), Arndt (1SS1), Poljakoff, and others have defended Hayem's hypothesis.

The intracellular origin of blood-plastids has been asserted by Ranvier, 34 32 A much more extended analysis of the subject is presented by Jolly. Several older and often amusing hypotheses are mentioned by Feuerstack, Zeitschr. f. wiss. Zool., vol. xxxviii, 1S83, p. 136. Schafei', 35 Minot, and others. This conclusion was drawn from the observation of degenerating capillaries, which retain in their cavities blood-corpuscles and fragments of corpuscles after they have lost their connection with the active vessels. Ranvier named the degenerating capillaries " cellules vasoformatives." Vosmaer (1898) 3a made the true nature of these structures clear by his investigation of the embryonic great omentum. His discovery has been continued and extended by Renaut (1901), Pardi (1905), Jolly (1906), and others.

  • 83 Das Hauptwerk Hayem's Du Sang erschein 1889. Darin stellte er die Ergebissne seiner fruheren Untersuchungen zusammen.
  • Ranvier: Du Developpement et de l'accroissement des vaisseaux sanguins, Arch, de Physiol., vol. vi, 1874, p. 429-450.

According to several hypotheses, the blood-plastids arise from the nuclei alone. Retterer 37 thinks they arise from the nuclei of connective-tissue cells. According to Hubrecht (1899), blood-corpuscles are formed in the placenta of Tarsius by the production of a colored mother cell which expels its nucleus, the nucleus becoming a red corpuscle. According to Poljakoff (1901) red disks are formed from the nuclei not only of connective-tissue cells, but also of leucocytes.

Since Neumann discovered (1869) nucleated red cells in the medulla of bones, there have been numerous hypotheses as to the method by which they changed into plastids. Many investigators have sought to recognize remnants of nuclei, or even entire nuclei, in the corpuscles after their transformation. In most of these cases one has to deal with artefacts. 38 Malassez (1881, 1882) lets the plastids arise as buds from the cytoplasm of red cells. According to Engel (1899) the red cell divides itself into a nucleated and a non-nucleated part; the latter is the definitive corpuscle. Janosik's hypothesis resembles that of Malassez. That the nucleus normally disappears by intracellular karyolysis has been a common opinion. 3 * An especially divergent account of the blood development in the yellow medulla of bone is given by Fr. Freytag. 40 He thinks that special cords arise by the degeneration of fat-cells. Into these cords blood-cells wander and there degenerate, their nuclei undergoing repeated fragmentation until they are broken up into small particles. The particles divide further until they become invisible, and these invisible remains of the nuclei he calls " nuclear units." These units gather to form new granules, the granules flow together and form genuine new nuclei, and finally new protoplasm is formed around each nucleus. The final member of the series is a new erythroblast. The author does not state how he has been able to follow the history of his invisible units, and does not show how he distinguishes the phases of evolution from those of involution of the blood-cells. Even if we admit the accuracy of these observations, they would still remain, in my opinion, without demonstrative value for the author's conclusions.

Our list of the hypotheses on the formation of the blood might easily be lengthened. Since, however, the hypotheses for the most part have only a passing interest, it is hardly worth while to go into greater detail. The reader will find further information given by Jolly. 41 6. Cttomorphosis of Leucocytes. — The primitive mesamoeboids (primary wandering cells of Saxer, Maximow, and others) are also parent cells of the leucocytes, according to the conclusion drawn by Jolly and Weidenreich. Both of these authors have not only studied the literature conscientiously, but have also made extensive independent investigations. While I here adopt their conclusion, I must admit that I cannot venture to express a secure judgment in this question, based upon my own experience. In a meritorious memoir Saxer 42 (1896) appeared as a defender of the view that free wandering cells (leucoblasts) arise directly from mesenchymal cells. Since then several authors have expressed their agreement with this view : for example, T. H. Bryee ** in his investigation of the development of the blood of Lepidosiren; and, recently, Maximow 44 in several articles, and also Weidenreich. 15 I have not succeeded in finding cell forms which can be unquestionably interpreted in favor of Maximow's opinion, although I have searched in numerous human and other mammalian embryos; and I must admit that the proofs which Maximow presents do not appear to me convincing. 4 " Therefore I keep, at least for the present, to the conviction that all leucocytes have a unitary origin and develop from the primitive mesamoeboids.

  • 85 Schafer : Note on the Intracellular Development of Blood-corpuscles in Mammals, Proc. Royal Soc, vol. xxii, 1874, p. 243-245.
  • 88 Vosmaer: On the Retrograde Development of the Blood-vessels, etc.. Versl. Akad. Wetensk. Amsterdam, vol. vi, 1898, p. 245.
  • 87 C. R. Retterer: Soc. Biol. Paris, 1901, p. 769.
  • Compare the careful discussion of Jolly, I.e., p. 180-193.
  • 89 See especially Pappenheim, Virchow's Arch., vol. cxlv, 1896, p. 587. and vol. cli, 1898, p. 89; also His's Archiv, 1899, p. 214.
  • 40 Fr. Freytag: Zeitschr. f. allgein. Physiol, vol. vii. 1908. p. 131. 41 Jolly, I.e., p. 180-193. An excellent, clear, conscientious review of the literature on the subject. Vol. II.— 33

A series of authors have defended the thesis that the first true leucocytes develop in the thymus from entodermal cells. Maurer 47 has maintained this thesis for teleosts, and it has been asserted for man and other mammals by Hermann and Tourneux, 48 Prenant, 49 , E. T. Bell, 60 and others. John Beard" has appeared as a specially eager defender. Stohr 52 opposes the thesis. Bryce, 83 Stohr, and Hammar 84 report that the true leucocytes first appear outside of the organ, and only secondarily, by immigration, in the thymus. The small cells which really develop in the thymus are derived, according to Stohr, from the epithelial cells and remain epithelial cells, not being lymphoid elements (leucocytes) at all. The question is of fundamental significance, although a priori it is improbable that leucocytes have a double origin. For the present I am much inclined to agree with Stohr, and we are thus brought back to the statement at the beginning of this section — the leucocytes are derived from the primitive mesamoeboids.

The transformation is manifested by two principal alterations in the microscopic picture, — 1, the formation of special granules in the cytoplasm; 2, modifications in the form and structure of the nuclei.

We have to consider four principal types of leucocytes: 1. The young forms without granules (lymphocytes).

  • 42 Fr. Saxer: Ueber die Entwickelung und den Bau der normalen Lymphdriisen und die Entstehung der rothen und weissen Blutkorperchen, Anat. Hefte, vol. vi, 1896, p. 347-532, Taf. xv-xxii.
  • 48 T. H. Bryce: Histology of the Blood of the Larva of Lepidosiren, etc., Trans. R. Soc. Edinburgh, vol. xli, 1904, p. 435-467.
  • 44 Maximow : l.s.c.
  • 48 Fr. Weidenreich : Arch, f . mikr. Anat., vol. Ixxiii, 1909, p. 849-851, 857-858.
  • I have been able to convince myself that Maximow is a very trustworthy observer, for I have confirmed many of his new observations by comparison with the sections in the extensive embryological collection of the Harvard Medical School.
  • 47 Maurer: Schilddruse und Thymus der Teleostier, Morph. Jahrb., vol. xi, 1886, p. 129.
  • 48 Hermann et Tourneux : Diet, encycl. sci. med., 1887.
  • 48 Prenant : La Cellule, vol. x, 1894, p. 87-184.
  • 60 E. T. Bell: The Development of the Thymus, Amer. Journ. Anat., vol. v, 1905, p. 29.
  • 81 John Beard : Anat. Anz., vol. ix, 1894, p. 476-486 ; also Lancet, 1899.
  • Philipp Stohr: Ueber die Natur der Thymuselemente, Anat. Hefte, vol. xxxi, 1906, p. 407.
  • J. A. Hammar : His' Arch. Anat., vol. Ixxxiii, 1907, p. 83.
  • 84 J. A. Hammar : Zur Kenntniss der Teleostierthymus, Arch. mikr. Anat.. vol. Ixxiii, 1908, p. 1-68, Taf. i-iii.

Keibel Mall 2 362.jpg

Fig. 362. — The older forms with granules — A. The finely granular (neutrophile of Ehrlieh).

B. The coarsely granular (eosinophile of Ehrlieh).

C. The degenerating (basophile of Ehrlieh).

1. The young forms probably arise directly from the primitive mesamoeboids, which have become smaller by repeated divisions. This origin of the lymphocytes was positively asserted in 1891 by 0. van der Stricht 65 and Kostanecki, 68 and is now very generally accepted. The number of leucocytes is also increased by their own proliferation. The lymphocytes vary extremely as to size. The large cells are probably (1) genuine primitive mesamoeboids, which by division produce the small leucocytes; (2) old cells, which have developed out of the small ones. 87 The following description is restricted to the small leucocytes, i.e., to the cells to which exclusively Ehrlieh M applies the term lymphocyte. Our cells have the following characteristics: first, they have very little protoplasm, which takes a basic color and exhibits no special granules; second, the colorable substance of the nucleus forms several little masses, often with distinct corners, which are united by threads and lie, for the most part, near the surface. The centrosome in the lymphocytes of amphibia has been studied by Flemming, Heidenhain, and Klemensiewicz. Weidenreieh (Arch. f. mikr. Anat., vol. lxxiii, p. 818) found the human centres double and imbedded in a lighter colored oval court situated in the endoplasm close to the nucleus.

Keibel Mall 2 362.jpg

Fig. 362. — Four small lymphocytes from normal human blood. (After Weidenreieh.) The developmental history of these cells is still incompletely known to us. That they multiply by mitotic division of the lymph-glands was first demonstrated by W. Flemming. 68 Whence they come and how they or their mother cells get into the lymph-glands is still to be determined. It is also unknown how the highly characteristic nucleus is formed.

That the lymphocytes are preliminary stages of the granular leucocytes is positively asserted by Weidenreieh. 80 As it is probable that he is right, lymphocytes are here regarded as the representatives of the young stage in the cytoruorphosis of white blood-corpuscles. Unfortunately, the further development of these " young " cells is hardly better known to us than their origin.

  • 66 0. Van der Stricht : Le developpement du sang dans le foie embryonaire, Arch, de Biol., vol. xi, 1891, p. 19-113.
  • 68 K. von Kostanecki: Anat. Hefte, vol. i, 1892, p. 313.
  • 61 As concerns the nomenclature, see Weidenreieh, Arch f. mikr. Anat., vol. lxxiii, 1909, p. 794.
  • Ehrlich's application of the term " lymphocyt " in this restricted sense cannot be justified. Compare Weidenreieh, Arch. f. mikr. Anat., vol. lxxiii, p. 797 ff.
  • W. Flemming: Arch. f. mikr. Anat., vol. xxiv, 1885, p. 50.
  • 80 And by others before him. Compare W. H. Howell, Journ. of Morph., vol. iv, p. 144; C. Benda, Arch. Anat. Physiol., physiol. Abth., 1896, p. 347; and Weidenreieh, Arch. f. mikr. Anat., vol. lxxiii, 1909, p. 861.

The cells which have been recognized with certainty as becoming granular leucocytes are distinctly larger than the lymphocytes. If, therefore, they develop from the lymphocytes, we must say that during the process the protoplasm and the nucleus have both grown. The protoplasm retains its capacity of basic coloration; the nucleus retains — at least at first — its round form, has in its interior a coarse reticulum with some few thicknesses, and it stains deeply. Very often the centrosome can be seen in an eccentric position alongside the nucleus, and its occurrence is probably constant. Cells of this kind occur throughout life in the medulla of bone, and are well known to histologists under the inappropriate name "myelocytes." Out of such cells the three kinds of granular leucocytes are developed.

2, A. The finely granular leucocytes are much more numerous than the coarsely granular, and they represent the chief developmental series of the white corpuscles. The granules in man are " neutrophile," in the rabbit " pseudoeosinophile," and in the guinea-pig " aruphophile." According to Ehrlich, the coloration of the granules changes with the age or maturity of the cells. The clinicians, for diagnostic purposes, have occupied themselves industriously with the question of the coloration of granules and have founded a doctrine of the specific quality of the granules of leucocytes based on the coloration. Up to the present, however, the proof is entirely lacking that the coloration in this case has morphological meaning, or even that it allows a deduction as to the chemical specificity of the granules.' 1 The alterations in the nuclei during the cytomorphosis of the finely granular leucocytes are very striking. The alterations begin with an elongation of the nucleus (Fig. 363), which, however, remains a unitary structure while assuming a kidney-like shape and at the same time moving into a decidedly eccentric position. The convexity of the nucleus is directed to the exterior; the concavity is turned toward the centre of the cell. In the central part of the cell lies the centrosome. By the deepening of its concavity, the nucleus becomes sausage or horse-shoe shaped and at the same time grows more slender and longer, so that the two poles of the nucleus move toward the non-nucleated side of the cell and approach one another. In the next stage the nucleus appears divided into several small pieces, which are connected by thin short or long threads. The number of pieces is usually three or four, seldom five. The form and size of the pieces is extraordinarily variable. Uniting threads may start from any point on the surface of the pieces. During this transformation of form the nucleus elongates and becomes more bent, always curving around the centrosome. The nucleus further undergoes a pronounced pyknosis, so that when it reaches the lobate condition it exhibits no recognizable structure, but stains intensely and more or less uniformly. The alterations in shape are permanent and are not transitory consequences of amoeboid movement of the nucleus. We have to deal with a genuine cytomorphosis : the nucleus never turns back in its course of development. The centrosome 62 has usually two centrioles which are round or oval and usually of the same size. A single centriole occurs rarely, and probably arises by the fusion of the two normal centrioles. The centrioles are surrounded by a small clear court of apparently homogeneous material, but which sometimes shows a radiate structure. When the disintegration of the cells begins, the centrosome can no longer be seen.

  • 81 Compare Fr. Weidenreich : Arch, f . mikr. Anat, vol. lxxii, 1908, p. 308-319.

The formation of the fine granules in the protoplasm may begin either as soon as the nucleus assumes its eccentric position or not until it has reached the lobate form. The granules are small, more or less uniform, and of apparently round shape, and arise endogenously. The general attention of hsematologists and clinicians has been directed to them by the invention by Ehrlich of a method of demonstrating them easily. They appear first at one or several points in the cytoplasm, and increase gradually in number until they occupy the whole body of the cells, with the exception of the immediate neighborhood of the centrosome. Meanwhile the colorability of the intergranular substance diminishes. In a human embryo of three and one-half months the majority of "leucoblasts" in the bone medulla are without granules, but both neutrophile and eosinophile cells are present. During the fourth and fifth months the finely granular cells become more numerous.

Keibel Mall 2 363.jpg

Fig. 363. — Finely granular (neutrophile) leucocyte with compact nucleus, a so-called myelocyte. From the circulating blood of a healthy adult. (After Weidenreich.)

2, B. The coarsely granular leucocytes (eosinophiles) develop at the same time as the finely granular, but are morphologically wholly different. The original round nucleus becomes eccentric and kidney-shaped, then more slender and longer, and bends around the centrosome, which takes a central position. Up to this point of its development it can scarcely be distinguished from the nucleus of the finely granular cell, but finally it assumes its permanent shape by forming two lobes (Fig. 364), which are united by a strand varying in width and length. As a rule, the lobes are of unequal size, but the inequality is seldom striking. The lobes are in general round or oval and occasionally pear-shaped. They usually have very regular contours, but occasionally one sees a small projecting hump. The length of the uniting strand is very variable. Nuclei occur with shapes which do not exactly fit with this description, but they are extremely rare. The centrioles are similar to those of the finely granular leucocytes, and are also situated in a clear court of material, which, however, in the case of the coarsely granular cells, is surrounded by a darker, broader zone, which appears nearly homogeneous. The darker zone is often extremely distinct.

  • 82 The fine research of M. Heidenhain upon the leucocytes of Salamandra (Festschr. f. Kolliker, 1892, p. 138) must be regarded as the starting-point of our knowledge of the centrosome of leucocytes.

The eosinophile granules, according to Weidenreich, 63 are not endogenous structures, but are fragments of erythrocytes which have been eaten by the cells. He found that the erythrocytes break up into fragments in the haemolymph glands of sheep and other mammals, and that the fragments break up into still finer granules, which retain their characteristic color reaction, and are taken up by the lymphocytes, in which they appear as the eosinophile granules. In the measure that the number of granules in the single cells increases, the nucleus passes through its metamorphosis. In the finely granular leucocytes, on the contrary, the granules arise sometimes earlier, sometimes later. A renewed investigation of the eosinophiles in man is very desirable.

Keibel Mall 2 364.jpg

Fig. 364. — A coarsely granular leucocyte (eosinophile) with a bilobate nucleus. Highly magnified. From the blood of a healthy adult. (After Weidenreich.)

2, C. The degenerating leucocytes correspond to the " basophils" of Ehrlich's nomenclature. They are designated by Maximow 64 as "Mastleucocyten." 65 An apposite name for these cells is still lacking. As Maximow has demonstrated, we must distinguish strictly, morphologically and genetically, between "Mastzellen" and " Mastleucocyten." The Mastleucocyten make up a very small percentage of the leucocytes in normal human blood, but occur abundantly in many cases of pathological blood. The nucleus becomes first kidney-shaped and then of an irregular contour, as may be seen in Fig. 365. As the alteration continues, pieces of the nucleus pinch themselves off from the main mass, or else the nucleus assumes a highly irregular form and breaks up into single pieces. These alterations may be easily observed in leukaemic blood. No distinct internal structure can be recognized in the nuclei. The amount of chromatin must be increased, for the coloration of the nucleus is more intense than in other leucocytes. There is no centrosome. The granules are extremely variable in number, size, and form ; in some cells there are only a few present, in others they are abundant. The size varies also within a single cell. The form of the granules is often strikingly irregular; it may be angular, rounded, or elongated, or, in another case, the granules may be more uniformly rounded. They stain a dark blue violet with the Griemsa solution. The protoplasm loses its basophile reaction and appears vacuolated, especially in cells the nuclei of which have become irregular.

  • 63 Fr. Weidenreich: Anat. Anzeiger, vol. xx, 1902, p. 196; also Verhandl. Anat. Ges., vol. xix, 1905, p. 79, and Arch. f. mikr. Anat., vol. lxxxii, p. 282 and 286 (extended discussion). The explanation adopted hy Weidenreich had been previously proposed by Hoyer, Klein (Cbl. inn. Med., 1899), and Fuchs (ditto). Weidenreich's observations have been confirmed by Warthin and Th. Lewis. Zietschmann joins in the opinion of these authors.

Keibel Mall 2 365.jpg

Fig. 365. — Degenerating human leucocytes (Mastleucocyten of Maximow). (After Weidenreich.)

Note. — So far as known to me, Blumenthal " was the first to interpret these cells as degenerative, a view to which Pappenheim ** and Weidenreich w have agreed. That this interpretation is correct is rendered probable by the above-given history of the cells.

  • Maximow: Ueber die 3ellforaien des lockeren Bindegewebes, Arch. f. mikr. Anat., vol. lxvii, 1906, p. 706.
  • 65 Die " Mastleucocyten " des Meerschweinchens und anderer Rodenten sind morphologische vollkommen verschieden von der hier zu beriicksichtigenden menschMcJien Zellen.
  • 98 R. Blumenthal : Ann. Soc. R. Sci. Med. et Nat. Bruxelles, vol. xiv, 1905.
  • 47 Pappenheim : Atlas der mensehlichen Blutzellen, 1 Lief., 1905.
  • 88 Fr. Weidenreich: Folia haematologica, vol. v, 1908, p. 135; also Arch. f. mikr. Anat., vol. lxxii, 1908, p. 252.

The multiplication of leucocytes is effected, as above stated, p. 515, by mitotic division, 69 which may often be seen in the young forms. As the cytomorphosis progresses, the mitoses become rarer. Blumenthal 70 and Benaut 71 have shown that the mitoses continue in the finely granular and eosinophile cells up to the stage of the kidney-shaped nucleus. In cells with lobate nuclei, mitoses have not been observed.

Amitosis of leucocytes has been described by several investigators. H. Pollitzer 72 has given a compilation of the recorded statements. Since the process has been observed only in nuclei which have become pyknotic, it is probable that we have to deal with a degenerative process which accompanies the downfall of the cells and plays no role in their normal multiplication. Yet authorities are not lacking to defend the hypothesis that the normal multiplication of leucocytes is by amitosis. Lowit 73 goes very far in this direction, for he asserts that the multiplication of leucocytes in the liver is effected only by amitosis, a view which Kostanecki 74 has shown to be completely untenable.

Disintegration of Leucocytes. — We may assume that leucocytes at the close of their cytomorphosis die and disappear. Death may befall a cell at any time, but accidental death is by no means comparable with the death which ensues at the close of the cytomorphosis of the cell. Our knowledge is still so incomplete that the following exposition can be regarded as tentative only. So far as the nuclei are concerned, we see that they break down by fragmentation, which begins with the rupture of the threads uniting the single lobes. Thus the cell becomes apparently multinucleated. After this the cells are often devoured by phagocytes ; but if they remain free, the splitting up of the nucleus continues until some ten or fifteen fragments are produced, which possess a rounded form and lie irregularly scattered in the protoplasm. The nuclear fragments, or lumps of chromatin, are homogeneous and disappear by dissolution. During the degeneration of the nucleus the granular cytoplasm gradually disappears. Finally, the remnant of the cell breaks down and the fragments are eaten by phagocytes, or perhaps in part dissolved.

  • 68 Discovered by W. Fleming, Arch, f . mikr. Anat., vol. xxiv, 1885, p. 50-91. Compare also 0. van der Stricht, Verh. Anat. Ges. Gottingen, vol. vii, 1893, p. 81; and Jolly, Arch. d'Anat. rnicr., vol. iii, 1900, p. 168-228. 'Ihe latter gives a detailed analysis of the previous literature.
  • 70 Blumenthal : Travaux Lab. physiol. Inst. Solway, vol. vi, 1904.
  • 71 J. Renaut : Arch. d'Anat. micr., vol. ix, 1907, p. 495.
  • 72 H. Pollitzer : Beitrage zur Morphologie und Biologie der neutrophilen Leueocyten, Zeitschr. Heilk. Abth. path. Anat., vol. xxviii, 1907, p. 277.
  • 73 Lowit: Sitz.-ber. Akad. Wiss., Wien, vol. xcii, 1S85, 3 Abth. 74 Yon. Kostanecki, Anat. Hefte, vol. i, 1S92, p. 312.

The disintegration of leucocytes occurs in connective tissue, in exudates, and especially in the spleen and other lymphoid organs. Disintegration of the leucocytes also occurs in normal blood, but is rare.

7. Origin of the Blood-plates

75 — We are indebted to the investigations of James H. Wright 76 for the recognition .of the actual development of the blood-plates. He succeeded in making the process clear by the application of a new method of coloration. 77 According to Wright, the plates arise by the pinching off of the ends of slender processes of uninucleate giant cells (the megakaryocytes of Howell). After the application of Wright's stain, one can see in both the blood-plates and in the giant cells a narrow hyaline-blue border (ectoplasm) the edge of which is either smooth or finely dentate. The breadth of the border varies, yet is the same in the two structures. Its peripheral layer is capable of amoeboid motion. The central portion of the blood-plate — as also the inner and by far larger portion of the cytoplasm of the giant cell — appears, after the same coloration, to be filled with more or less crowded granules of a red or violet tint. The majority of the giant cells — these observations refer chiefly to the bone medulla of various mammals — have a rounded form, while the minority exhibit forms of great diversity, which arise by the formation of pseudopod-like processes of variable length, width, and shape. In some cells almost the entire cytoplasm is absorbed in the formation of processes. We can observe, in these giant cells of a changed shape, that the red or violet granules of the internal substance of the cytoplasm extend into the processes and form in them an axial cord, which remains surrounded by a hyaline ectoplasm (Fig. 366). Occasionally a process extends into the cavitv of a blood-vessel. Some of them lose the connection with the parent cell, and such free pseudopods have been observed by Wright not only in the blood-vessels of the medulla of bone and in the spleen, but also in the capillaries of the lungs. Now in some of these processes, the width of which corresponds to the diameter of the blood-plates, we can see that the granular internal substance exhibits constrictions. At other points the subdivision of the middle substance is complete, and we encounter a series of rounded segments having the diameter and other characteristics of the internal substance of the blood-plates. Each segment of the internal substance has a clear peripheral zone. A process thus modified is regarded by Wright as a chain of blood-plates which become free by the breaking np of the chain. Other processes occur which are so small that they probably produce only a single plate. That the giant cells really lose their protoplasm is proved by the occurrence of degenerating nuclei which are surrounded by little or no protoplasm.

  • Professor J. H. Wright has laid me under great obligations by reading the MS. of this section, and the value of the exposition has been much increased by his advice and additions.

76 James Homer Wright : Die Entstehung der Blutplattchen, Virchow's Arch., vol. elxxxvi, 1906, p. 55-63; see also Journ. Morphol., vol. xxi, 1910, p. 263.

77 Pathological Technique, by Mallory and Wright, 4th edition, 190S. p. 374.

Keibel Mall 2 366.jpg

Fig. 366. — Giant cells with processes from which blood-plates arise. Alongside are blood-plates and a few leucocytes. A, from the spleen of a kitten; B, from the bone-marrow of a cat. Original drawings by J. H. Wright.

Two further facts deserve especial attention in discussing "Wright's conclusions: first, that genuine blood-plates and genuine giant cells occur only in mammals; second, that the blood-plates first appear in the embryonic blood after the giant cells have been produced in the blood-forming organs.

Note. — A letter from Professor Wright enables me to add the following: There occur in the blood of mammalian embryos, before the development of blood in the liver has begun, together with a few blood-plates, a small number of cells which in their color reaction and in the structure of their protoplasm resemble the giant cells of later stages, although in size they merely equal the red bloodcorpuscles. Wright has observed the cleavage of these cells into blood-plates. They occur in the embryos of guinea-pigs of 4.5 mm., but were not found in a younger embryo. By his investigations of other mammalian embryos, Wright has convinced himself that the cells in question, which occur free in the blood, are identical with the giant cells of the blood-forming organs. He has found all possible transitions. According to Maximow 78 the giant cells in the rabbit and other mammals arise from the primitive mesamoeboids (primary wandering cells), which would agree with Wright's conclusion.

8. The Composition of the Blood in Relation to Age. 79 — The distribution of the blood-corpuscles after the circulation has begun is probably always very unequal. This depends in part on the fact that the young blood-cells accumulate in special places, particularly those which serve as sites for the production of blood, concerning which see the following section. In the adult the percentage of the various forms of corpuscles differs according to the vessel. In embryos the relations are further complicated by the alterations which occur corresponding to the age.

The circulation of the blood begins extraordinarily early in man. The cytology of the blood at this moment is unknown to me.

In an embryo of 4 mm. I find large ichthyoid cells, as described on p. 505 and pictured in Fig. 355. Older cell forms are entirely lacking. Noteworthy is the extreme rarity of the primitive mesamoeboids, a fact which does not correspond to my a priori expectations.

In an embryo of 7.5 mm. the cells are smaller on the average, but are still ichthyoid, Fig. 356, p. 506. They vary much in size, and may possess nuclei which indicate by their lessening diameter and deeper coloration the further cytomorphosis. In this case also I missed the primitive mesamoeboids in the blood.

In embryos of 8-10 mm. the blood-cells are for the most part unquestionably ichthyoid, although their dimensions are extremely variable (Fig. 367). The younger types of cells are still extremely rare. One sees now and then accumulations of undifferentiated cells (Fig. 368) the protoplasm of which seems fused. Such clusters of cells adhere to the endothelium without being continuous with it.

Maximow 80 has observed similar clusters in the rabbit. According to his interpretation they arise by the proliferation of the endothelium. I am unable to agree with here, because I find that there is no continuity of the protoplasm of the cells either in the rabbit or in man ; also because mitoses of the endothelium in the neighborhood of the clusters are almost invariably lacking; and, finally, because the endothelial nuclei are differentiated while the nuclei of. the cells of the clusters are not differentiated. 81 The clusters may be compared with blood-islands, and I regard the cells composing them as mesamoeboids or primary wandering cells.

  • 70 Alex. Maximow: Arch. f. mikr. Anat., vol. Ixxiii, 1909, p. 491.
  • 78 The principal work on this subject is that of Johann Jost (Arch. f. mikr. Anat., vol. lxi, 1903, p. 668), but he investigated only sheep and cow embryos. On p. 691 he gives curves of the percentages of corpuscles. His Metrocyten I are ichthyoid cells, his Metrocyten II are sauroids, and his Erythrocyten red plastids. Valuable data concerning the relations in rabbit embryos have been published by A. Maximow (Arch. f. mikr. Anat., vol. Ixxiii, 1909, p. 526-532). 'Maximow: Arch. f. mikr. Anat., vol. Ixxiii, 1909, p. 517.

In all human embryos up to 12 mm. which I have had an opportunity of investigating, there occurs an active mitotic division of the red ichthyoid cells. Since the primitive cells are rare, we must conclude that the number of corpuscles increases chiefly by their own division during this period of development.

In embryos of about 12 mm. the blood formation is beginning in the liver, p. 528. At the same time the undifferentiated bloodcells become more numerous in the vessels, and the first cells of the sauroid type appear. From this time on, the sauroid cells become constantly more numerous. The red cells are very variable. It must be further remarked that probably many erythrocytes are destroyed in the blood itself, so that we encounter the following cell forms : First, red cells of the round shape with a distinct membrane, but without haemoglobin ; second, similar cells collapsed; third, nuclei with remnants of a cell body; and fourth, free nuclei. 82 I have not obsc wed expulsion of nuclei in very young embryos.

Keibel Mall 2 367.jpg

Fig. 367. — Outlines of erythrocytes of a human embryo of 8 mm. Harvard Embryol. Coll. No. 817.

  • 81 Compare Minot, " Age, Growth, and Death," Fig. 61, Nos. 5, 6, 7, 8. The nuclei of the cell clusters are all in the second stage in the figure referred to, and this stage immediately precedes the differentiation proper.
  • 82 The possibility remains that in these cases we have to do, in part at least, with the consequences of imperfect preservation. Still, I eonsiJ ov it probable that the break-down occurs normally in the manner indicated in the living blood.

In embryos of two months 83 the blood contains, 1, a minority of ichthyoid cells; 2, a large majority of sauroid cells which may be easily recognized by their pyknotic nuclei; 3, a considerable number of non-nucleated plastids, the formation of which occurs chiefly in the liver ; 4, free erythrocyte nuclei, which are rare ; and 5, mesamoeboid cells of various appearance, some larger, some smaller, the largest equal in diameter the nucleated erythrocytes.

Keibel Mall 2 368.jpg

Fig. 368. — Endothelium and blood-cells from the lower part of the aorta of a human embryo of 9.4 mm. Harvard Embryol. Coll., No. 380. Endo., endothelium; A., collection of cells; E., erythrocyte. X 1500.

Most of the mesamoeboids retain their primitive character. Now and again, however, I found one with a kidney- shaped nucleus which probably was a mature granular leucocyte. Unquestionable "lymphocytes" I did not recognize.

  • 83 1 have investigated seven embryos of about this age. In several the preservation of the tissues is pretty good, but in none is the preservation of the erythrocytes satisfactory. Therefore the statements given in the text possess only a preliminary value.

During the third month the young forms of the erythrocytes become steadily rarer and the ichthyoid cells almost disappear from the blood, while the blood-plastids become steadily more predominant. 84 In a beautifully preserved embryo 85 of about eight months, I have found the following conditions : By far the majority of the corpuscles are thin disks without nuclei, many of them shrunken; the unaltered disks are convex on one side and concave on the other. In Fig. 369 two such are figured in optical section. Nucleated erythrocytes are extremely rare. Free dark nuclei and occasionally fragments of nuclei appear now and again. The colorless cells form distinctly a minority, but may be found everywhere. They are either primitive mesamoeboids or young leucocytes, rarely leucocytes with lobed nuclei. The lymphocytes have the above described structure of the nucleus (p. 515) which is so highly characteristic. The eosinophile leucocytes are very rare; they have for the most part a round or oval nucleus. Only by searching can one find an eosinophile with a kidney-shaped nucleus. The coarsely granular leucocytes are more numerous in the thymus and lymph glands.

Keibel Mall 2 369.jpg

Fig. 369. — Blood-corpuscles from the vessels of a human fetus of eight months.

  • For example, in an embryo of 29 mm. (Harvard Embryol. Coll., No. 914), although nucleated corpuscles are still numerous, the majority of the erythrocytes are without nuclei.
  • 85 I am indebted to Professor W. T. Councilman for this very beautiful material, preserved in Zenker's fluid, for which I here express my thanks.
  • Carstanjen: Jahrb. Kinderheilk., 1900, p. 215 and 684.

It remains for the future to furnish satisfactory data concerning the composition of fetal blood and the changes it undergoes corresponding to age.

The percentage relations of the white corpuscles after birth have been investigated by Carstanjen. 86 I have put his chief conclusions in the form of a table. According to Carstanjen, the number of coarsely granular cells does not depend on the age, and, as far as they are concerned, only individual variations were observed. Very striking is the rapid increase of the young forms in the first days after birth. During the fifth year cells with lobate nuclei reach their maximum.

Percentage of Leucocytes in the Blood.

diately First Second

after Twelve half half Two Three Four Five birth. days.






years L6.0 45.6 50.8 49.2 47.0 38.4 33.2 25.1

Young forms (Lymphocytes) 16.0 Finely granular cells with lobate nuclei 73.4 36.7 34.5 40.8 42.0 48.0 52.6 61.0

9. Sites of Blood Fokmation

Since it is highly probable that all blood-cells are descendants of the primitive mesamoeboids, we must assume that these last seek out at different ages certain localities for their multiplication and transformation.Cite error: Closing </ref> missing for <ref> tag however, in 1846, gave the first definite proof of this important phenomenon, - when he published his discovery that special cells occur in the fetal liver which change into erythrocytes. Although since then there have been many investigations[12] upon the fetal liver, the process of blood formation has not yet been completely cleared up. In these investigations there has been no lack of opinions which have later been recognized as untenable. Such, for example, is the opinion of Neumann, according to which the corpuscles arise endogenously ; or the opinion of Foa and Salvioli, who derived the erythrocytes from hepatic giant cells.

The blood formation in the human liver begins in embryos of about 12 mm. in length.[13] At this time the hepatic cylinders are well developed, but are separated from one another by broad sinusoids. The endothelium of the sinusoids clings everywhere closely to the hepatic cylinders. The broad blood-channels are clearly bounded; they contain blood-cells of varying appearance, but no true leucocytes, only rnesamceboids and young erythrocytes (Fig. 370). Besides these there are also blood-cells so placed that they appear as part of the hepatic cylinders, and these last are the beginning of the development of the blood-producing centres in the liver.

  • 82 R. Remak : Ueber die Entstehung der Blutkorperchen, Med. Zeit., Ver. Heilk. Preussen, vol. x, 1841, p. 127. Compare also Canstatt, Jahresber., 1841, p. 17, and Remak's Untersuch. Entwicklungs Ges. Wirbelthiere, 1851, p. 22.
  • Prevost et Dumas: Developpement du Cceur et formation du Sang, Ann. Sci. Nat., vol. iii, 1824, p. 96—107, p. iv (le foie sanguifactif, p. 105).
  • M E. H. Weber: Zeitschr. f. rat. Med., vol. iv, 1846.

From the stage of 12 mm. on, the number of the blood-cells which apparently are included in the liver cylinders increases rapidly. The blood-cells gather in little groups, which interrupt irregularly the hepatic cylinders. When colored sections are examined, these groups are conspicuous because the cells, in consequence of the progress of their development, possess nuclei of diminished size which stain very deeply. The nuclei of the livercells are much larger and more lightly colored, and their substance is not condensed, but forms a loose network. In earlier stages the sinusoids of the organ are separated from one another only by the cylinders consisting of liver-cells. In the region of the clusters of erythrocytes, an examination of sections of the liver gives one the impression that the structure has remained essentially as before except that the hepatic cylinders now seem to consist in part of erythrocytes. Certainly the clusters of blood-cells lie outside the direct blood-channels through which the blood flows freely. It need hardly be said that the red cells are morphologically never parts of the hepatic cylinders.

Keibel Mall 2 370.jpg

Fig. 370. — Blood-cells from a hepatic vessel of a human embryo of 11 mm. Coll. F. P. Mall, No. 353. o, c, d, primitive rnesamceboids; 6, erythrocyte. X 1500.

The shape of the clusters of blood-cells is very variable. They may be sharply circumscribed, rounded, or elongated, and distinctly separated from one another; but quite as often they are extended into prolongations, by which the neighboring clusters may be united with one another, so that here and there we get a network with ample nodes. The size of the single clusters is very inconstant. In the third month it is not rare to find clusters in a section of which one can count fifty or more cells.

As regards the constitution of the cells in the blood clusters, we must distinguish the colorless cells from those colored with haemoglobin. M. B. Schmidt estimated the number of colorless and colored cells to be approximately equal in a human embryo of nine and one-half months, and in his opinion this proportion holds true for mature and nearly mature embryos. In earlier stages the colored corpuscles predominate.

The orginally colorless cells must be classed as mesamoeboids, which must not be confused with true leucocytes. Nevertheless, they have been quite frequently loaded with this name. They can easily be distinguished from true leucocytes, although they are the parent cells of white corpuscles as well as of the red. Figure 369 represents some cells in the open blood-channels of the liver of an embryo of 11 mm. Such cells are numerous in the hepatic vessels at this time, although rare in the vessels elsewhere. Kostanecki[14] calls attention to the fact that the colorless cells lie usually, if not always, against the wall of the vessels. mesamoeboids with two nuclei alike in size are not rare.

Keibel Mall 2 371.jpg

Fig. 371. — Hepatic cylinders of a human embryo of 11 mm. Coll. F. P. Mali, No. 353. The blood-cells with small nuclei lie apparently in the substance of the liver-cells, -which have large nuclei.

The two chief forms of cells in the blood clusters are irregularly distributed. Often one sees in a single cluster nucleated elements, colored with varying intensity by haemoglobin, alongside of uncolored corpuscles. Now and again a group consists of only colorless corpuscles, which usually lie so closely pressed together that they flatten one another and appear like a mosaic pattern.

Again, the boundaries between the cells disappear and the relatively large nuclei then lie closely crowded in a common protoplasmic mass. Such groups resemble those which occur in the blood-vessels of young embryos (Fig. 368). They are to be regarded as developing mesamoeboids.

The colored cells differ much from one another. They vary within wide limits of size, in this respect contrasting with the nonnucleated plastids. There occur many cells which are so large that the nucleus alone equals the average volume of the plastids. Others, on the contrary, are less in diameter than a plastid. The content of haemoglobin must be independent of the size of the cell and the amount of protoplasm; it now appears in the somewhat saturated color, as in the plastids, and again as a just-recognizable shade of vellow. Every intermediate condition occurs between these extremes. The cells containing the least haemoglobin may display a light, granular protoplasm which, as the cells become more strongly colored, can no longer be seen. The optical homogeneity of the mature erythrocyte is generally known. The nuclei vary in their structure: first occur those of the ichthyoid type, which by their structure are clearly related to the nuclei of the colorless cells ; second, nuclei of the sauroid type, which are smaller, and the substance of which appears darker and more homogeneous, allowing only a few indistinct granules and threads to be recognized in it. Every possible transition between these two nuclear types may be observed. The small sauroid nuclei belong to the cells richest in haemoglobin. One may say that the higher the content of the cell in haemoglobin, the smaller is the nucleus and the more condensed its chromatin framework.

"We come now to the question of the relation of the above described cells to the open sinusoids on the one hand, and, on the other, to the hepatic cylinders. Two opposing views are to be considered, since some defend the opinion that the clusters all lie in the vessels or in diverticula of the vessels, while others assert that a part of the cells are extravascular in position. Thus, M. B. Schmidt (I.e., p. 203), von Kostanecki," and others assert definitely that the cell clusters are intravascular; 0. van der Stricht, 100 on the other hand, reports that in mammals the young blood-cells lie in part outside of the vessels, between the hepatic cells, and that in older embryos the cells are clearly embedded in the mesenchymatous cells. So far as my observations go they fully confirm van der Stricht, 101 and the excellent observations on rabbit embrvos which Alexander Maximow 102 has recently published appear to me to decide the question. Finally, and in favor of van der Stricht, since the vascular endothelium of young embryos allows the blood corpuscles to pass through, we need feel no surprise that a migration of blood-cells occurs also in the liver.

By the shaking of sections, Schmidt has removed a portion of the blood-cells, and has then observed spaces which were simply enlargements of the sinusoids and which were enclosed on both sides by the cords of liver-cells. The liver-cells are pressed back, especially from the wider cavities, and are thereby reduced sometimes to mere strips of protoplasm ; the endothelium is frequently still recognizable. In other cases, Schmidt saw the blood-cells situated between two liver-cells ; the latter appeared hollowed out and as if eaten by the blood-cells (lacunar corrosion of Neumann). At other times it appeared to him as if the small blood clusters were embedded in a single liver-cell. In both cases he was unable to see the endothelium. Strictly speaking, therefore, the observations of Schmidt agree better with the conclusions of van der Stricht than with his own view.

Origin of the Cells of the Blood Clusters. — According to the prevalent view, as above stated, the clusters arise by the accumulation of cells which circulate in the blood. A fact in favor of this view is that from the first all the forms of cells occur in the blood clusters which at that time can be found in the blood. If we had to do with cells which arose in loco, we should expect that only young cells would appear at first, which later would differentiate themselves. Further investigations are necessary to give a final decision as to the origin of the cells.

M. B. Schmidt[15] has drawn from his observations the conclusion that the proliferation of the endothelium produces new young erythrocytes, which then multiply farther by mitosis. To me his argument is by no means convincing.

Investigations up to the present render it clear that a multiplication of erythrocytes occurs in the embryonic liver during a long period, the end of which is after birth. The cytomorphosis of the red cells in the liver is essentially, or exactly, the same as elsewhere during early stages of the embryo, and also as in the medulla of bone. The clusters yield, at least in part, immature corpuscles which enter the circulating blood, so that we must assume that these complete their cytomorphosis in the blood itself.

0. van der Stricht (I.e.), von Kostanecld (I.e., p. 313), and others report that in the liver of mammals lymphocytes are formed by the metamorphosis of primitive colorless cells.

Neumann was the first to prove that the blood flowing out of the liver contains more young erythrocytes and more mesamoeboids than the inflowing blood. Later M. B. Schmidt found that in a nearly mature embryo the proportion of nucleated to non-nucleated cells was — In the portal vein 1 : 38, In the hepatic vein 1 : 25.

4. Formation of Leucocytes in the Lymphoid Organs

It is well known that the lymphoid glands, tonsils, the thymus, etc., all serve for the multiplication of lymphocytes. It is easy to observe the proliferations of the young leucocytes in the corresponding embryonic organs of man, yet the life history of the lymphocytes during embryonic development is almost unknown.

5. Blood Formation in the Medulla of Bone

The medulla of bone[16] is a vascular, mesenchymatous tissue, which originally is merely a reticulum of branching cells, with relatively wide endothelial blood-vessels. A part of the cells become osteoblasts. In the adult condition the structure remains essentially the same, although the mesenchvma forms connective-tissue fibrils, multinucleated giant cells, and, later, fat-cells; the latter vessels become arteries and veins. Certain investigators assert that the cavities of the blood-vessels are in direct open connection with the spaces of the mesenchyma, but, so far as I know, the conclusive proof of the correctness of this statement is lacking.

The history of the fetal medulla in man has not yet been investigated, probably because fresh material is indispensable for such investigations. Hence it is that we can merely sketch the history in outline, and about as follows : The medulla of bone arises late ontogenetically, since it does not appear until immediately before the commencement of ossification in each piece of cartilage, and therefore appears in different parts of the skeleton at different times.

Soon after its formation, there appear in it cells which we regard as primitive mesamoeboids, and also young erythrocytes, young leucocytes, and young giant cells (megalokaryocytes) ; all three of which, according to the well-founded prevalent view, are developed from mesamoeboids. The mesamoeboids are called, inappropriately, " myelocytes," although as compared with the original medulla (mesenchyma) they must be regarded as foreign elements. Gradually the number of " myelocytes," as well as young red and white cells, increases. The cytomorphosis progresses toward maturity, that is, until the erythrocytes have lost their nuclei and the leucocytes have acquired their granules. When mature, the corpuscles under normal conditions pass into the blood stream, by which they are carried off in order to participate in the circulation until they break down. Probably the lymphocytes also pass in small numbers into the blood stream. Only under pathological conditions do nucleated erythrocytes or so-called myelocytes pass out in noticeable numbers into the circulating blood. This pathological condition has as yet been observed only after birth.

The number of blood-forming cells in the medulla increases slowly until birth, after which it mounts rapidly in the course of a few days. Incidentally occurs a diminution of the blood formation in the liver.

The distribution of the "myelocytes " and developing blood-corpuscles in the medulla has not been rendered clear by the existing investigations. The uncertainty is chiefly due to the fact that neither the course of the smaller vessels nor the structure of their walls is sufficiently known to us. The developing blood elements lie in part in the mesenchyma, in part in wide capillaries, — according to several investigations, made chiefly upon rabbits. 108 I may cite especially the work of 0. van der Stricht and of Brinckerhoff and Tyzzer. The young forms are in excess in the mesenchyma. The young forms include the colorless mesamoeboids, the ichthyoid erythrocytes, and the granular leucocytes with round or kidney-shaped nuclei. The cells in the vessels often cling closely crowded to the vascular wall, almost as if they were glued to it and to one another. In these vascular accumulations the sauroid erythrocytes and the mature granular leucocytes predominate. Since the number of the red plastids outside the active blood stream is never very great, we conclude that the plastids leave the medulla soon after their development.

  1. To Professor Mall I am specially indebted, for he has had the kindness to lend me extremely valuable material from his embryological collection.
  2. Ruckert und Mollier : Die erste Entstehung der Gefasse und des Blutes bei TVirbeltieren, Hertwig's Hdbch. vergi. Entw. "Wirbeltieren, vol. i, p. 1910-1278.
  3. Maximow : Arch, f . mikr. Anat., vol. lxvii, 1906, p. 680-757, and vol. lxxiii, 1909, p. 444-561; Folia Haematol., vol. iv, p. 611-626; Verhandl. Anat. Ges., vol. xxxii, p. 65-72.
  4. Wera Dantschakoff : Entwick. d. Blutes b. Vogeln, Anat. Hef te, vol. xxxvii, p. 471.
  5. Franz Weidenreich : Die rothen Blutkorperchen, I, Ergeb. anat. Entw. Ges., vol. xiii, 1905, p. 1-94; II, ibid., vol. xiv, 1905, p. 345-450.
  6. J. Jolly : Recherches sur la formation des globules rouges des mammiferes, Arch. Anat. microsc, vol. ix, 1907, p. 133-314.
  7. M A. Maximow : Arch, f . mikr. Anat., vol. lxxiii, 1909, p. 461.
  8. G. Bizzozero : Ueber die Entstehung der rothen Blutkb'rperchen wahrend des extra-uterinen Lebens. Moleschott's Untersuchungen zur Naturlehre, vol. xiii, 1888, p. 153-173, 1 pi.
  9. Kolliker: Ueber die Blutkorperchen eines menschlichen Embryo. Zeitschr. f. rationelle Med., vol. iv, 1846, p. 112.
  10. Rindfleisch: Ueber Knochenmark und Blutbildung. Arch. f. mikr. Anat., vol. xvii, 1880, p. 21.
  11. O. van der Stricht : Archives de Biol., vol. xii, 1892, p. 247. 'Man vergleiche Kostanecki, Anat. Hefte, vol. v, 1891, p. 315 and 317. A. Maximow: Arch. f. mikr. Anat., vol. lxxiii, 1909, p. 486.
  12. The following investigations may be mentioned : Fahrner : De Globuli sanguinis, Turici, 1845. Neumann: Berlin, klin. Wochenschr., 1871, p. 58; and Arch. f. Heilk., vol. xv, 1874. Foa e Salvioli: Arch, delle Sci. Med., vol. iv, 1880. M. B. Schmidt: Ziegler's Beitr., vol. xi, 1892, p. 199. The most exact investigations are those of van der Stricht, Archives de Biol., vol. xi, p. 19-113 and vol. xii, p. 235; and Maximow, Arch. f. mikr. Anat., vol. lxxiii, 1909, p. 533-546. Both authors studied chiefly rabbits. Maximow gives a good review of previous results.
  13. This is according to my own observations and the statement of Schridde, Verhandl. deutsch. pathol. Gesellsch., 1907, p. 364.
  14. Von Kostanecki: Anat. Hefte, vol. i, 1891, p. 308.
  15. Maximow: Arch. f. mikr. Anat., vol. lxxiii. 1909, p. 538. M. B. Schmidt : Ziegler's Beitrage, vol. xi, 1892, p. 212, 219.
  16. C. M. Jackson : Zur Histologic und Histogenese des Knochenmarkes, Arch. f. Anat, 1904, p. 33-70.

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Keibel F. and Mall FP. Manual of Human Embryology II. (1912) J. B. Lippincott Company, Philadelphia.

XVIII. Development of Blood, Vascular System and Spleen: Introduction | Origin of the Angioblast and Development of the Blood | Development of the Heart | The Development of the Vascular System | General | Special Development of the Blood-vessels | Origin of the Blood-vascular System | Blood-vascular System in Series of Human Embryos | Arteries | Veins | Development of the Lymphatic System | Development of the Spleen
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