Talk:Book - Human Embryology (1945) 6

CHAPTER VI THE FATE OF THE GERM LAYERS AND THE FORMATION OF THE ESSENTIAL (PRIMARY) TISSUES INCLUDING THE BLOOD[edit] In the late presomite stages the embr>o consists of an outer ectodermal and an inner endo dermal la^er of cells separated b> an intermediate later composed of the mesoderm and nolo chord (Fig 49) In normal detelopment the cells of these three primary germ layers make specific contributions to the formation of the diflcrcnt tissues and organs Experimental embryology has demonstrated that the specificity of these contributions is not so rigid as ttas formerly believed (Chapter VIII) nevertheless it is important to know what each of these layers normally contributes to the different tissues and organs of the older embryo

FATE OF GERMINAL LAYERS IN NORMAL DEVELOPMENT ECTODERM

The embryonic ectoderm is an epithelial layer which is continuous laterally with the flattened amniotic ectoderm From it m normal development there arise —

1 The epithelium of theskm (thccpidermis) anditsdcnvatives — hair nails the epithelial cells of the sweat and sebaceous glands and of the mammary glands

2 The epithelium of the mucous membrane and glands of the lips, cheeks gums pari of the floor of the mouth and of the palate and that of the nasal cavities and paranasal sinuses

3 The epithelium of the lower part of the anal canal and of the terminal parts of the genital and urinary tracts

4 The primary dental laminae which give rise to the enamel organs of the teeth

5 Rathke s pouch which becomes the anterior (buccal) part of the hypophysis cerebri

6 The lens of the eye the anterior epithelial layer of the cornea and the outer layer of the Xvmpanic membrane

7 The central nervous system including the retina the two epithelial layers of the ciliary process and ins and the optic nerve but excluding the blood vessels and probably, the microglia

8 The peripheral nervous system including the sympathetic nerve cells and fibres the medulla of the suprarenal gland and the neurolemmal sheath cells

9 The sensory cpithelia of the olfactory and auditory organs

10 The musculature of the iris and possibly certain other structures which are usually considered to be of mesodermal ongm c g branchial cartilage meninges and dermal pigment cells (the latter structures are sometimes said to be mes ectodermal in origin for discussion see pages 271 and 366)

In the early stages all the ectodenoal derivatives are cpithelia and they remain essentially epithelial tissues throughout life except m the nervous system where the cells become highly specialized and in the mes ectoderm ® ’

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HUMAN EMBRYOLOGY

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Fig. 94 A scheme to show the differentiation of various cell typei'from the undifferentiated mesenchymal cell

THI FATE OF THE GERNI LAYERS

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transformed into other types e g , fibrocytes in certain circumstances, may acquire osteogenic properties and it is even possible for chondrocytes to become osteocytcs

In some varieties of developing connective tissue the mesenchymal cells take on a fat storing function (Fig 94) The fat is initially stored as small discrete droplets which later increase in size and coalesce so that the cytoplasm of the cell becomes a peripheral nm round the fat Some mesenchyme cells, which appear to be mes ectodermal (Chapter XV) acquire the property of synthetizing melanin, to form melanoblasts (dendritic cells) Other mesenchymal cells show a special affinity For particulate matter and for certain colloidal dyes These are the macrophages which are usually classified as fixed {histuu^les) or wandering {monocytes) In certain regions, e g , luer, spleen, lymphatic system and bone marrow, the macrophages are associated with reticular fibres and arc then classified at belonging to the reticulo endoiheltal yslem Other mesenchymal cells in close proximity to blood vessels, develop granules which stain metachromitically They are called mast celts and they resemble the basophilic Icucocv tes of the blood although they do not appear to be genetically related to them (Fig 94) Other cells of mesenchymal origin are the so called plasma cells and the fixed eosinophils

DEVELOPMENT OF BLOOD

A most important and highly specialized group of the mesenchymal cells is that which gives origin to the blood and the vascular and lymphatic systems Some of these cells remain fixed but become thinned out and so arranged that they enclose a fluid matrix m which another important strain of mesenchymal cell is found The former are the endothelial cells of the blood or lymph vessels (Chapter IX) the latter are the free cellular elements of the blood and lymph the plasma of which is the fluid matrix

The first blood cells and blood vessels arise in the extra embryonic mesoderm in early primitive streak stages Blood vessels arise at about the same time m the splanchnopleunc mesoderm of the yolk sac in the somatopleuric mesoderm of the chonon and in the mesoderm of the connecting stalk (Chapter V) The blood cells however, are restricted in their extra' embryonic development to the wall of the yolk sac and allantoic diverticulum The earliest stages in the development of human blood are unknown but from comparative embryology and from the study of the less advanced areas of blood formation in the yolk sac of presomite human embryos of about eighteen days it seems likely that the first blood cells arise from mesenchymal cells lying between the yolk sac endoderm and the splanchnopleunc mesothchum \\hcthcr these cells are derived from mesoderm or from mesenchyme of endodermal origin* is not finally established, but there is no doubt that they should be regarded as mesenchymal

Haemocytoblasts The first recognizable blood cell is the haemocytoblasl (Fig 94) which IS a sphcncal or slightly polygonal cell with basophilic cytoplasm It resembles closely the large free basophil stem cells (myeloblasts and large lymphocytes) found in all embryonic and adult haematopoietic foci Its nucleus is large with acidophilic nucleoli (Fig 95) Accord ing to one interpretation (the monophylctic theory ) the haemocytoblasl is the stem cell which gives origin to all the cellular elements of the blood The haemocytoblasts proliferate by mitosis so that small groups of them are formed, among which some acquire haemoglobin (pnmitiveerythroblasts) These groups are the so called ‘blood islands (Fig 95), and initially they appear to possess no endothelial covenng Soon however the mesenchymil cells surrounding the blood islands become flattened to form the specialized endothelium

Erytbroblasts and Erythrocytes The haemocytoblasts m the yolk sac wall give origin to a generation of primitive erythroblasts which become transformed into primitiie eiyihrocytes and subsequently to an apparently independent lineage dtjimtxu erythroblasts and erythrocytes The primitive erythroblasts constitute the most numerous group of cells m the

volk WTOdcclb arc initaally formed from the endoderm cells of the secondary

the mole)^ Barlelmez 1940 Gladstone and Hamilton 1941 Mossman unpublished observations m

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HUMAN EMBRYOLOGY

blood islands of the early yolk sac. Initially they are similar to the haemocytoblasts, but they gradually become acidophilic as haemoglobin accumulates in their cytoplasm (Figs. 95 and 96) The early primitive erythroblasts are capable of multiplying by mitosis, but with increasing maturity the nucleus becomes pyknotic and eventually may be extruded or disappear. The resulting non-nucleated acidophilic cell, which at first shows a reticulated remains of the nucleus, is a primitive erythrocyte. After the 35 mm. stage the primitive erythroblasts cease to show mitotic division and they, together with their derivatives, soon disappear.

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- Y Fig 95. — drawing of part of the wall of the yolk sac in the abenabryonic region (of the Shaw embryo) showing the different types of blood cell lying within and in the neighbourhood of a vascular space which IS lined Tvith endothelium. (Modified from Gladstone and Hamilton, 1941 ) X c. 750. (Reproduced by courtesy of the Journal of Anatomy.)

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The definitive erythroblasts, which are distinctly smaller than the primitive erythroblasts, begin to appear at about the 10 mm stage (Gilmour, 1941) and gradually increase in number until, by the 30 mm stage, they and the cells derived from them, exceed the number of primitive erythrolilasts and erythrocytes in the foetal blood. The definitive erythroblasts also arise from the haemocytoblasts and they are first found in the wall of the yolk sac. Soon after their fimt appearance, however, they are found multiplymg in the mesodermal stroma of the hver (page 20 ) and, rather later, in the developing spleen (page 224) and, occasionally, in other mesoderma

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THE FATE OF THE GERM LASERS

foci e g thp vitsonephros Later still hacmatopoieuc activity commences m the developing bone maTToiL (clavicle, 43 mm , humerus, 57 mm femur, 75 mm see Gilraour, 1941) By the end of the third month the bone marrow has become the mayor site for cry throcytopoiesis, although the liver and spleen normallv continue to form new red blood cells until just after birth

The definitive ervthroblasts go through Stages of development comparable with those of the primitive crythroblasts They tend however to retain their basophilic properties for a longer period and the cells resulting from their differentiation— the definitive ervthrocvtes— are smaller and more circular than the primitive erythrocytes In the transition from the definitive erythroblast to the defimtive erythrocyte the nuclei of the cells also show the reticulate appearance ( reticulocytes )

The time of appearance of haemoglobin stamable by cosin in the crythroblasts varies and in general two varieties of erythrocyte formation arc recognized In one variety (megaloblastic eryihropoiesis) haemoglobin appears early in large crythroblasts with large nuclei which preserve their nuclear structure The erythrocyte which develops from such erythro blasts IS called a megalocytc and is larger thvn that (normocyte) found m normal adult blood In the other variety (normoblastic ery'lhropoiesis) haemoglobin appears late m small erythro blasts with pyVnotic nuclei and the resulting cell, a normocyte is vnthm the normal size for adult blood All primitive crythroblasts and the definitive crythroblasts of early foetal life giv e rise both to megalocy tes and normocy ics After the first few w ceks of post natal life normal cry thropoiesis is entirely normoblastic

Foetal Haemoglobin There is much evidence to show that the haemoglobin m foetal blood is not identical with that found post natal)} This statement holds for human blood as well as for that of many other mammals In some of the latter there is evidence to show that the oxygen dissociation curve of foetal haemoglobin differs from that of the mother jn a manner which facilitates the passage of oxygen to the foetus In the human however, foetal haemoglobin does not show this teleological character (For further discussion see Kendrew, » 949 )

Leucocytes, Lymphocytes, Monocytes and Megakaryocytes The haemocytoblasts are also capable of giving origin to granular leucocytes, megakaryocytes, monocles and lymphocytes (Fig 94) In the yolk sac wall of early embryos m addition to the haemo cytoblasts and crythroblasts some megakaryocytes, a few phagocytic cells and possibly, primitive mvclocvtes arc present

LftfoJg/ojtoiexa Within the embryo ufiret found at about the tBmm stage in the mesenchyme of the liver and various connective tissues The cells promyelocytes anse from haemocyto blasts which appear to differentiate in stiu from rounded mesenchymal cells These promyelo cytes can become neutrophilic eosmophibc or basophihe The promvelocytes give ongm by multi plication to myelocytes which become transformed into polymorphonuclear leucoeyts (Fig 94) By the 43 mm stage leucocytopoiesis has commenced m the bone marrow where the promyelocytes undergo changes comparable to those just described Mvelocy’tes and leucocytes first appear in the blood stream at about the 50 mro stage (Gilmour, t94i)

The stem cell in lymphocytopousu is the lymphoblast which apparently, may anse either directly from a mesenchymal cell or from a baemocytoblast Lymphoblasts first appear jn the connective tissue around ly-mph vessels (page 169) at about the 30 mm stage They begin to appear m the lymph glands at about the 50 mm stage by which time the lymphatic vessels contain some Ivmphocytes They are also found dunng embryonic life in the thymus gland and spleen and for a short time in the liver and bone marrow but not in the wall of the yolk sac The lymphoblasts can become transformed either into small or large lymphocytes As h-mphocytes are first found m the blood of 26 mm embrvos they probably also arise directly from haemoev tobUsts in the circuhtmg blood since at this stage there is little lymphocy topoiesis in the connective tissue The haemoev toblasts can also give ongm to monocytes and mega warvocytes and the latter mav abo anse dircctlv from the mcsenchvmal cells (Fig 94)

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THEORIES OF BLOOD FORMATION

Ehrlich, the initiator of modern haematology, considered that the erythroblasts and myeloblasts had an origin different from that of the lymphoblasts This is the so-called dualistic interpretation of the origin of the blood cells and is one of the modifications of the polvphyletic theory which postulates that there are two (or more) varieties of stem cells from which the different hinds of blood corpuscles are derived. Most modern haematologists support the monophyletic theory of Maximow, according to which there is only one haematogenous stem cell — the primitive blood cell or haemocytoblast of Pappenheim There is still, however, a lack of general agreement on the precise relationship of the different varieties of blood cells to each other Most investigators believe that in the early stages of development there is only one haemocytopoietic tissue which gives origin, m several different situations, to myeloid (erythrocytes and granular leucocytes which originate, m post-natal life, from bone marrow) and lymphoid (lymphocytes and probably monocytes which originate, post-natally, in the lymph nodes and splenic tissue) elements It is only later in embryomc life that the lymphoid and myeloid tissues become separated. The original sites of blood cell formation are only temporary and in later development haematopoiesis is taken over by those organs which will form the new blood cells m the adult.

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Fig g6 — A drawing of part of the wall of the yolk sac near its attachment to the embryonic disc A well formed blood island is seen on the right of the drawing (Modified from Gladstone and Hamilton, 1941 ) X c 750 (Reproduced by the courtesy of the Journal of Anatomy )

There is also controversy as to whether or not the intra-embryonic haematogenous foci arise in situ from intra-embryonic mesenchyme (theory of “local origin”) or arise from haemocytoblasts (of yolk sac mesodermal origin) which have migrated into the embryo where they settle dowm to form areas of prohfei ation (theory of “extra-embryonic origin of blood cells J. Most of the evidence supports the view that the intra-embryonic mesodermal cells have the same potency to differentiate into blood cells (or blood vessels, page 136) as the cells of the yolk sac wall How'ever, Irwin (1949), in studying the genetics of antigens intrinsic m the red bloo cells of cattle, has shown that in the case of non-identical twins each calf is born with, an retains throughout life, all the inherited intrinsic erythrocyte antigens of its twin as well as those inherited from its own sire, where the sires can be proven by other characters to be differentSince these antigens are only found within red blood cells, it follows that the primordial ce s from which the red blood cells are derived must have migrated and become established mutua > m each foetus This natural transplantation of embryonic tissue is made possible by t e well-known anastomatic union of the choriomc vessels in fraternal bovine twins

The problem of blood development is yet further complicated by lack of agreement on ti relationship of the differentiating blood cells to the endothelium. Some workers believe t a

THE TATE OF THF GERM LA\ERS 103

the er> ihrocy ics arise intra \ ascularlj and the granulocytes extra v ascularly The earliest y oik sac hacmocytoblasts appear before the endothelium has difTcrcntiated Most of the hacmato poiesis inside the body of the embryo is extra \ascular, the cells secondarily migrating into the blood vessels where they undergo further differentiation In the earlier stages however, erythrocytopoM-sis appears to be largely mlta vascular but later m the liver and marrovv IS mainly extra vascular (Gilmour, 1941)

All modern investigations of the embryonic blood demonstrate that the problem of the development of its cells is onlv part of the wider problem of the developmental potencies of the primitive mesenchymal cell and that it is also closely related to the development of the rcticulo endothelial system (for details of these problems sec Downey 1938 and Bessis 1948)

RLFLRFNCES

Bartelmez G \\ and Fvani H (igsC) Devtlopmcnt of the human embrvo during the p<ncd of somite formation inctuding embryos VMtii 2 to >C pain of somiirs Cent ib Emb’yel Ca negit Insl tliuA 17 1-G7 Besiis M (igtB) Cytologic Sanguine Masson Pam

Bloom \\ (1937) Cellular differentiation and tissue culture Phtiiol Her 17 589-C17

and Barielmez C \\ (lOl®) Haetnainpoiesis in young human embryos Am J -inat 67 "1-54

Downey H (1938) Handbook of Haematology Hoeber Nesv ^ork Fischer \ (>946) Biology of Tissue Cells Cambridge Unis Press London

Gilmour J R (1941) Normal haemopoiesis in intrauterine and neonatal life J Path and Bad 52 25-55 Gladstone R J and Hamilton \\ J (igp) \ presomite human embryo (Shan) with pnmitise streak and chorda canal with special reference to the deselopment of thesascular svstem j inal land 76 (>-44 Gfuenwald P (194a) Common traits in development and structure of ihc organs originating from the ceielomic s all 3 Moffh 70 313-387 Hertwig O (i83i) Die Colomtheone Jena

Irwin M R (1949) Immunological studies in embryologs and geneiica Quad He Bid 24 109-123 Kendrew J C (1949) Foetal Haemoglobin FnJeatou 8 Co-fi>

Maximow \ {1927) Bmdegewebe und blutbildende Ces ebe 7>i llandb d rnikr \nat de Mensclien fv MolIendorfT) 2 Ft I Springer Berlin

Willmer E N (1945) Gros th and I ormm Tissue Cultures /« Fssays on Cro' ih and Form edited bv Clark and Medw ar Clarendon Oxford