Talk:Cardiovascular System - Blood Development

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Cite this page: Hill, M.A. (2020, May 29) Embryology Cardiovascular System - Blood Development. Retrieved from


The Origin of a New Progenitor Stem Cell Group in Human Development

Adv Anat Embryol Cell Biol. 2019;230:1-70. doi: 10.1007/978-3-030-02050-7_1.

Wartenberg H1, Miething A2, Møllgård K3.


The observation of two precursor groups of the early stem cells (Groups I and II) leads to the realization that a first amount of fetal stem cells (Group I) migrate from the AMG (Aortal-Mesonephric-Gonadal)-region into the aorta and its branching vessels. A second group (Group II) gains quite a new significance during human development. This group presents a specific developmental step which is found only in the human. This continuation of the early development along a different way indicates a general alteration of the stem cell biology. This changed process in the stem cell scene dominates the further development of the human stem cells. It remains unclear where this phylogenetic step first appears. By far not all advanced mammals show this second group of stem cells and their axonal migration. Essentially only primates seem to be involved in this special development. PMID: 30543033 DOI: 10.1007/978-3-030-02050-7_1


The association between AB blood group and neonatal disease

J Neonatal Perinatal Med. 2018 Oct 19. doi: 10.3233/NPM-17115. [Epub ahead of print]

McMahon KE1, Habeeb O2, Bautista GM1, Levin S1, DeChristopher PJ1, Glynn LA3, Jeske W1, Muraskas JK1. Author information Abstract BACKGROUND: Numerous studies have examined the association between ABO blood groups and adult disease states, but very few have studied the neonatal population. The objective of this study was to determine the relationship between AB blood group and the occurrence of common neonatal disorders such as neutropenia at birth, sepsis, respiratory distress syndrome (RDS), intraventricular hemorrhage (IVH), retinopathy of prematurity (ROP), and patent ductus arteriosus (PDA) compared to all other blood groups. METHODS: We performed a retrospective review on 3,981 infants born at 22 0/7 to 42 6/7 weeks' gestational age and compared the relative risk of neonatal diseases in infants with AB blood group to that of infants with all other blood groups (A, B, and O). RESULTS: When compared to all other blood groups, AB infants demonstrated an increased risk for developing negative clinical outcomes. AB blood group was significantly associated with a 14-89% increased risk of neutropenia at birth, sepsis, RDS, and ROP. Risks for IVH and PDA were not significant. CONCLUSION: We hypothesize that the phenotypic expression of A and B antigens, rather than the antigens themselves, in the AB group may reveal an enhanced susceptibility to injury at the endothelial level resulting in an increased risk for disease development. KEYWORDS: ABO antigens; ABO blood group; endothelial injury; neonatal disease; neonatal neutropenia; neonatal sepsis PMID: 30347622 DOI: 10.3233/NPM-17115


Embryonic hematopoiesis under microscopic observation

Dev Biol. 2017 Aug 15;428(2):318-327. doi: 10.1016/j.ydbio.2017.03.008.

Klaus A1, Robin C2.


Hematopoietic stem cells (HSCs) are at the origin of adult hematopoiesis, providing an organism with all blood cell types needed throughout life. During embryonic development a first wave of hematopoiesis (independent of HSCs) allows the survival and growth of the embryo until birth. A second wave of hematopoiesis that will last into adulthood depends on the production of HSCs that begins at mid-gestation in large arteries such as the aorta. HSC production occurs through a hemogenic endothelial to hematopoietic transition (EHT) process and the formation of hematopoietic clusters in most vertebrate species. Advances in understanding EHT, cluster formation and HSC production were triggered by combined progresses made in the development of in vivo assays, microscopy, imaging and fluorescence tools. Here, we review the current knowledge on developmental hematopoiesis with a focus on the first step of HSC production in the aorta and how microscopic approaches have contributed to a better understanding of the vital process of blood cell formation. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

KEYWORDS: Aorta; Embryo; Fluorescence; Hematopoietic clusters; Hematopoietic stem cells; Microscopy; Yolk sac PMID 28728681 DOI: 10.1016/j.ydbio.2017.03.008


A comprehensive study of umbilical cord blood cell developmental changes and reference ranges by gestation, gender and mode of delivery

J Perinatol. 2015 Jul;35(7):469-75. doi: 10.1038/jp.2014.241. Epub 2015 Jan 29.

Glasser L1, Sutton N1, Schmeling M1, Machan JT2. Author information Abstract OBJECTIVE: The purpose of this study was to determine the normal hematological values in cord blood during gestation, the impact of the type of delivery and differences in gender. STUDY DESIGN: The database included 10 287 live births of 30-44 weeks gestation from cesarean or vaginal deliveries. Cord blood was collected into bags containing lyophilized heparin. Specimens were stored for 24 h or less and analyzed using the SysmexXE-2100. Data from cesarean births were used to evaluate developmental hematopoietic changes. RESULT: Increases during maturation occurred in hemoglobin, hematocrit, red blood cell count, and decreases in mean corpuscular volume and mean corpuscular hemoglobin. The number of nucleated red blood cells per 100 white blood cells decreased but absolute counts remained constant. Quantitative counts of white blood cells, neutrophils, monocytes (MON), eosinophils and lymphocytes (LYMP) increased, but percentages of lymphocytes and monocytes decreased. Platelets increased from 30-35 weeks. CONCLUSION: Reference ranges were established for cord blood. Erythroid and myeloid cells show developmental changes. Mode of delivery has a significant effect on hematologic values. Only a rare parameter showed differences based on gender. The cord blood complete blood cell count has the potential for providing relevant clinical information for managing neonatal patients. PMID: 25634517 DOI: 10.1038/jp.2014.241

WBC count progressively increased with gestational age due primarily to an increase in the absolute neutrophil count (Figure 2) with minor contributions from LYMP and MON. However, the increase in the absolute neutrophil count is disproportionally elevated compared with the absolute LYMP count and as a result the %LYMP show a relative decrease that is statistically significant (Figures 3a and b). The data in our report added to the study of Millar et al.7 from 15 to 21 weeks and Forestier et al.4 from 18 to 29 weeks gestation depicts the spectrum of developmental changes in the fetal hematopoietic system. There were no significant differences with regard to gender in any of the absolute or differential leukocyte counts in this study. However, there were significant differences with regard to the type of delivery.

Distinct routes of lineage development reshape the human blood hierarchy across ontogeny

In a classical view of hematopoiesis, the various blood cell lineages arise via a hierarchical scheme starting with multipotent stem cells that become increasingly restricted in their differentiation potential through oligopotent and then unipotent progenitors. We developed a cell-sorting scheme to resolve myeloid (My), erythroid (Er), and megakaryocytic (Mk) fates from single CD34+ cells and then mapped the progenitor hierarchy across human development. Fetal liver contained large numbers of distinct oligopotent progenitors with intermingled My, Er, and Mk fates. However, few oligopotent progenitor intermediates were present in the adult bone marrow. Instead only two progenitor classes predominate, multipotent and unipotent, with Er-Mk lineages emerging from multipotent cells. The developmental shift to an adult “two-tier” hierarchy challenges current dogma and provides a revised framework to understand normal and disease states of human hematopoiesis.


Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors

Nature. 2014 Dec 3. doi: 10.1038/nature13989. [Epub ahead of print]

Perdiguero EG1, Klapproth K2, Schulz C1, Busch K2, Azzoni E3, Crozet L1, Garner H1, Trouillet C1, de Bruijn MF3, Geissmann F1, Rodewald HR2.


Most haematopoietic cells renew from adult haematopoietic stem cells (HSCs), however, macrophages in adult tissues can self-maintain independently of HSCs. Progenitors with macrophage potential in vitro have been described in the yolk sac before emergence of HSCs, and fetal macrophages can develop independently of Myb, a transcription factor required for HSC, and can persist in adult tissues. Nevertheless, the origin of adult macrophages and the qualitative and quantitative contributions of HSC and putative non-HSC-derived progenitors are still unclear. Here we show in mice that the vast majority of adult tissue-resident macrophages in liver (Kupffer cells), brain (microglia), epidermis (Langerhans cells) and lung (alveolar macrophages) originate from a Tie2+ (also known as Tek) cellular pathway generating Csf1r+ erythro-myeloid progenitors (EMPs) distinct from HSCs. EMPs develop in the yolk sac at embryonic day (E) 8.5, migrate and colonize the nascent fetal liver before E10.5, and give rise to fetal erythrocytes, macrophages, granulocytes and monocytes until at least E16.5. Subsequently, HSC-derived cells replace erythrocytes, granulocytes and monocytes. Kupffer cells, microglia and Langerhans cells are only marginally replaced in one-year-old mice, whereas alveolar macrophages may be progressively replaced in ageing mice. Our fate-mapping experiments identify, in the fetal liver, a sequence of yolk sac EMP-derived and HSC-derived haematopoiesis, and identify yolk sac EMPs as a common origin for tissue macrophages.

PMID 25470051

Jam1a-Jam2a interactions regulate haematopoietic stem cell fate through Notch signalling

Nature. 2014 Aug 21;512(7514):319-23. doi: 10.1038/nature13623. Epub 2014 Aug 13.

Kobayashi I1, Kobayashi-Sun J1, Kim AD1, Pouget C1, Fujita N2, Suda T3, Traver D4.


Notch signalling plays a key role in the generation of haematopoietic stem cells (HSCs) during vertebrate development and requires intimate contact between signal-emitting and signal-receiving cells, although little is known regarding when, where and how these intercellular events occur. We previously reported that the somitic Notch ligands, Dlc and Dld, are essential for HSC specification. It has remained unclear, however, how these somitic requirements are connected to the later emergence of HSCs from the dorsal aorta. Here we show in zebrafish that Notch signalling establishes HSC fate as their shared vascular precursors migrate across the ventral face of the somite and that junctional adhesion molecules (JAMs) mediate this required Notch signal transduction. HSC precursors express jam1a (also known as f11r) and migrate axially across the ventral somite, where Jam2a and the Notch ligands Dlc and Dld are expressed. Despite no alteration in the expression of Notch ligand or receptor genes, loss of function of jam1a led to loss of Notch signalling and loss of HSCs. Enforced activation of Notch in shared vascular precursors rescued HSCs in jam1a or jam2a deficient embryos. Together, these results indicate that Jam1a-Jam2a interactions facilitate the transduction of requisite Notch signals from the somite to the precursors of HSCs, and that these events occur well before formation of the dorsal aorta.

PMID 25119047


Embryonic hematopoiesis

Blood Cells Mol Dis. 2013 Dec;51(4):226-31. doi: 10.1016/j.bcmd.2013.08.004. Epub 2013 Sep 13.

Golub R1, Cumano A.


Blood cells are continually produced from a pool of progenitors that derive from hematopoietic stem cells (HSCs). In vertebrates, the hematopoietic system develops from two distinct waves or generation of precursors. The first wave occurs in the yolk sac, in mammals or equivalent embryonic structure, and produces nucleated primitive erythrocytes that provide the embryo with the first oxygen transporter and are, therefore, essential for the viability of the embryo. The yolk sac also produces myeloid cells that migrate to the central nervous system and to the skin to form the microglia and skin specific macrophages, the Langerhans cells. The second wave occurs in the dorsal aorta and produces multipotential hematopoietic progenitors. These cells are generated once in the lifetime from mesoderm derivatives closely related to endothelial cells, during a short period of embryonic development. Newly generated cells do not reconstitute the hematopoietic compartment of conventional recipients; therefore, they are designated as immature or pre-HSCs. They undergo maturation into adult HSCs in the aorta or in the fetal liver accompanied by the expression of MHC class I, CD45, CD150, Sca-1 and the absence of CD48. Differentiation of HSCs first occurs in the fetal liver, giving rise to mature blood cells. HSCs also expand in the fetal liver, and in a short time period (four days in the mouse embryo), they increase over 40-fold. HSCs and progenitor cells exit the fetal liver and colonize the spleen, where differentiation to the myeloid lineage and particular lymphoid subsets is favored. © 2013. KEYWORDS: AGM; BM; CFU-S; DC; E; Embryo; FL; FLOC; FS; FSOC; Fetal liver; Fetal spleen; G-CSF; GFP; HIAC; HSCs; Hematopoiesis; LTR; LTi; M-CSF; NK; Rag; S; Stem cells; YS; aorta gonads mesonephros; bone marrow; colony forming unit-spleen; dendritic cells; embryonic day; fetal liver; fetal liver organ culture; fetal spleen; fetal spleen organ culture; granulocyte colony-stimulating-factor; green fluorescence protein; hematopoietic stem cells; intra aortic hematopoietic clusters; long-term reconstitution; lymphoid tissue inducer; macrophage colony-stimulating-factor; natural killer cells; recombination activation gene; somites; yolk sac

PMID 24041595

Macrophage biology in development, homeostasis and disease

Thomas A. Wynn, Ajay Chawla & Jeffrey W. Pollard AffiliationsContributionsCorresponding authors Nature 496, 445–455 (25 April 2013) doi:10.1038/nature12034

The switch from fetal to adult hemoglobin

Cold Spring Harb Perspect Med. 2013 Jan 1;3(1). pii: a011643. doi: 10.1101/cshperspect.a011643.

Sankaran VG, Orkin SH. Source Division of Hematology/Oncology, Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115.


The fetal-to-adult hemoglobin switch and silencing of fetal hemoglobin (HbF) have been areas of long-standing interest among hematologists, given the fact that clinical induction of HbF production holds tremendous promise to ameliorate the clinical symptoms of sickle cell disease (SCD) and β-thalassemia. In this article, we discuss historic attempts to induce HbF that have resulted in some therapeutic approaches to manage SCD and β-thalassemia. We then go on to discuss how more recent molecular studies that have identified regulators, including BCL11A, MYB, and KLF1, hold great promise to develop targeted and more effective approaches for HbF induction. We go on to discuss strategies by which such approaches may be developed. Older studies in this field can provide important lessons for future studies aimed at developing more effective strategies for HbF induction, and we therefore chronologically cover the work accomplished as this field has evolved over the course of the past four decades.

PMID 23209159



Normal and disordered reticulocyte maturation

Curr Opin Hematol. 2011 May;18(3):152-7. doi: 10.1097/MOH.0b013e328345213e.

Ney PA. Source Department of Biochemistry, St Jude Children's Research Hospital, Memphis, Tennessee, USA.


PURPOSE OF REVIEW: Reticulocyte remodeling has emerged as an important model for the understanding of vesicular trafficking and selective autophagy in mammalian cells. This review covers recent advances in our understanding of these processes in reticulocytes and the role of these processes in erythroid development. RECENT FINDINGS: Enucleation is caused by the coalescence of vesicles at the nuclear-cytoplasmic junction and microfilament contraction. Mitochondrial elimination is achieved through selective autophagy, in which mitochondria are targeted to autophagosomes, and undergo subsequent degradation and exocytosis. The mechanism involves an integral mitochondrial outer membrane protein and general autophagy pathways. Plasma membrane remodeling, and the elimination of certain intracellular organelles occur through the exosomal pathway. SUMMARY: Vesicular trafficking and selective autophagy have emerged as central processes in cellular remodeling. In reticulocytes, this includes enucleation and the elimination of all membrane-bound organelles and ribosomes. Ubiquitin-like conjugation pathways, which are required for autophagy in yeast, are not essential for mitochondrial clearance in reticulocytes. Thus, in higher eukaryotes, there appears to be redundancy between these pathways and other processes, such as vesicular nucleation. Future studies will address the relationship between autophagy and vesicular trafficking, and the significance of both for cellular remodeling.

PMID 21423015


Establishment and regulation of the HSC niche: Roles of osteoblastic and vascular compartments

Birth Defects Res C Embryo Today. 2010 Dec;90(4):229-42.

Coskun S, Hirschi KK. Source Center for Cell and Gene Therapy, Baylor College of Medicine; Houston, Texas, 77030, USA.


Hematopoietic stem cells (HSC) are multi-potent cells that function to generate a lifelong supply of all blood cell types. During mammalian embryogenesis, sites of hematopoiesis change over the course of gestation: from extraembryonic yolk sac and placenta, to embryonic aorta-gonad-mesonephros region, fetal liver, and finally fetal bond marrow where HSC reside postnatally. These tissues provide microenviroments for de novo HSC formation, as well as HSC maturation and expansion. Within adult bone marrow, HSC self-renewal and differentiation are thought to be regulated by two major cellular components within their so-called niche: osteoblasts and vascular endothelial cells. This review focuses on HSC generation within, and migration to, different tissues during development, and also provides a summary of major regulatory factors provided by osteoblasts and vascular endothelial cells within the adult bone marrow niche. 2010 Wiley-Liss, Inc.

PMID 21181885

Fetal and adult hematopoietic stem cells give rise to distinct T cell lineages in humans

Science. 2010 Dec 17;330(6011):1695-9.

Mold JE, Venkatasubrahmanyam S, Burt TD, Michaëlsson J, Rivera JM, Galkina SA, Weinberg K, Stoddart CA, McCune JM.

Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, CA 94143-1234, USA. Erratum in:

Science. 2011 Feb 4;331(6017):534. Comment in:

Science. 2010 Dec 17;330(6011):1635-6.


Although the mammalian immune system is generally thought to develop in a linear fashion, findings in avian and murine species argue instead for the developmentally ordered appearance (or "layering") of distinct hematopoietic stem cells (HSCs) that give rise to distinct lymphocyte lineages at different stages of development. Here we provide evidence of an analogous layered immune system in humans. Our results suggest that fetal and adult T cells are distinct populations that arise from different populations of HSCs that are present at different stages of development. We also provide evidence that the fetal T cell lineage is biased toward immune tolerance. These observations offer a mechanistic explanation for the tolerogenic properties of the developing fetus and for variable degrees of immune responsiveness at birth.

PMID 21164017

Erythropoietin couples hematopoiesis with bone formation

PLoS One. 2010 May 27;5(5):e10853.

Shiozawa Y, Jung Y, Ziegler AM, Pedersen EA, Wang J, Wang Z, Song J, Wang J, Lee CH, Sud S, Pienta KJ, Krebsbach PH, Taichman RS.

Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan, United States of America.

Abstract BACKGROUND: It is well established that bleeding activates the hematopoietic system to regenerate the loss of mature blood elements. We have shown that hematopoietic stem cells (HSCs) isolated from animals challenged with an acute bleed regulate osteoblast differentiation from marrow stromal cells. This suggests that HSCs participate in bone formation where the molecular basis for this activity is the production of BMP2 and BMP6 by HSCs. Yet, what stimulates HSCs to produce BMPs is unclear.

METHODOLOGY/PRINCIPAL FINDINGS: In this study, we demonstrate that erythropoietin (Epo) activates Jak-Stat signaling pathways in HSCs which leads to the production of BMPs. Critically, Epo also directly activates mesenchymal cells to form osteoblasts in vitro, which in vivo leads to bone formation. Importantly, Epo first activates osteoclastogenesis which is later followed by osteoblastogenesis that is induced by either Epo directly or the expression of BMPs by HSCs to form bone.

CONCLUSIONS/SIGNIFICANCE: These data for the first time demonstrate that Epo regulates the formation of bone by both direct and indirect pathways, and further demonstrates the exquisite coupling between hematopoiesis and osteopoiesis in the marrow.

Figure 7. Coupling of hematopoiesis with osteopoiesis by Epo.

PMID 20523730

The origin and fate of yolk sac hematopoiesis: application of chimera analyses to developmental studies

Int J Dev Biol. 2010;54(6-7):1019-31.

Ueno H, Weissman IL.

Institute of Stem Cell Biology and Regenerative Medicine, Department of Pathology, Ludwig Institute at Stanford University, Stanford University, Stanford, CA, USA.

Abstract During mammalian development, as exemplified by mice, hematopoietic cells first appear in the yolk sac blood islands, then in the dorsal aorta of the aorta-gonad-mesonephros (AGM) region and the placenta, eventually seeding into liver, spleen and then bone marrow. The formation of hematopoietic stem cells from mesodermal precursors has finished by mid-fetal life. Once established, the hematopoietic system must supply blood cells to host circulation and tissues for the entire life of the animal. Easy access to hematopoietic cells has enabled a vast number of studies over the last several decades, and much is now understood about the different hematopoietic lineages, how they differentiate, and their derivation from immature progenitors. Yet to be elucidated are the following two intriguing questions: do yolk sac and AGM hematopoietic cells arise from a common precursor or from distinct precursor cells?; and what is the lineage relationship between blood and endothelial cells. In this review, we will survey the state of our current knowledge in these areas, and discuss the potential use of multicolor chimera analyses to elucidate unresolved questions.

PMID 20711980

Fetal liver hepatic progenitors are supportive stromal cells for hematopoietic stem cells

Proc Natl Acad Sci U S A. 2010 Apr 27;107(17):7799-804. Epub 2010 Apr 12.

Chou S, Lodish HF.

Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.

Abstract Previously we showed that the ~2% of fetal liver cells reactive with an anti-CD3epsilon monoclonal antibody support ex vivo expansion of both fetal liver and bone marrow hematopoietic stem cells (HSCs); these cells express two proteins important for HSC ex vivo expansion, IGF2, and angiopoietin-like 3. Here we show that these cells do not express any CD3 protein and are not T cells; rather, we purified these HSC-supportive stromal cells based on the surface phenotype of SCF(+)DLK(+). Competitive repopulating experiments show that SCF(+)DLK(+) cells support the maintenance of HSCs in ex vivo culture. These are the principal fetal liver cells that express not only angiopoietin-like 3 and IGF2, but also SCF and thrombopoietin, two other growth factors important for HSC expansion. They are also the principal fetal liver cells that express CXCL12, a factor required for HSC homing, and also alpha-fetoprotein (AFP), indicating that they are fetal hepatic stem or progenitor cells. Immunocytochemistry shows that >93% of the SCF(+) cells express DLK and Angptl3, and a portion of SCF(+) cells also expresses CXCL12. Thus SCF(+)DLK(+) cells are a highly homogenous population that express a complete set of factors for HSC expansion and are likely the primary stromal cells that support HSC expansion in the fetal liver.

PMID: 20385801


Endochondral ossification is required for haematopoietic stem-cell niche formation

Nature. 2009 Jan 22;457(7228):490-4. Epub 2008 Dec 10.

Chan CK, Chen CC, Luppen CA, Kim JB, DeBoer AT, Wei K, Helms JA, Kuo CJ, Kraft DL, Weissman IL.

Department of Pathology, Developmental Biology and Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, California, USA.

Abstract Little is known about the formation of niches, local micro-environments required for stem-cell maintenance. Here we develop an in vivo assay for adult haematopoietic stem-cell (HSC) niche formation. With this assay, we identified a population of progenitor cells with surface markers CD45(-)Tie2(-)alpha(V)(+)CD105(+)Thy1.1(-) (CD105(+)Thy1(-)) that, when sorted from 15.5 days post-coitum fetal bones and transplanted under the adult mouse kidney capsule, could recruit host-derived blood vessels, produce donor-derived ectopic bones through a cartilage intermediate and generate a marrow cavity populated by host-derived long-term reconstituting HSC (LT-HSC). In contrast, CD45(-)Tie2(-)alpha(V)(+)CD105(+)Thy1(+) (CD105(+)Thy1(+)) fetal bone progenitors form bone that does not contain a marrow cavity. Suppressing expression of factors involved in endochondral ossification, such as osterix and vascular endothelial growth factor (VEGF), inhibited niche generation. CD105(+)Thy1(-) progenitor populations derived from regions of the fetal mandible or calvaria that do not undergo endochondral ossification formed only bone without marrow in our assay. Collectively, our data implicate endochondral ossification, bone formation that proceeds through a cartilage intermediate, as a requirement for adult HSC niche formation.

PMID 19078959

Sonic hedgehog expands diaphyseal trabecular bone altering bone marrow niche and lymphocyte compartment

Mol Ther. 2009 Aug;17(8):1442-52. Epub 2009 May 12.

Kiuru M, Hidaka C, Hubner RH, Solomon J, Krause A, Leopold PL, Crystal RG.

Department of Genetic Medicine, Weill Medical College of Cornell University, New York, New York 10065, USA.


Bone marrow contains distinct microenvironments that regulate hematopoietic stem cells (HSCs). The endosteal HSC niche includes osteoblasts, mineral, and extracellular matrix proteins that interact through various molecular signals to control HSCs. Sonic hedgehog (Shh) is a morphogen involved in the regulation of skeletal development and hematopoiesis, but the effects of Shh on bone in relation to the HSC niche are not well understood. We demonstrate that systemic overexpression of Shh in mice increases osteoblast number with the resultant formation of new trabeculae in the femoral diaphysis. Suggestive of a functional change in the hematopoietic niche, numbers of Lin(-) Sca-1(+) c-Kit(+) cells with hematopoietic progenitor function expand, although cells with in vivo repopulating capacity in the wild-type environment do not increase. Instead, Shh mediates a decrease in number of bone marrow lymphocytes accompanied by a decreased expression of stromal-derived growth factor 1 (SDF-1) and a decrease in Flk2-expressing Lin(-) Sca-1(+) c-Kit(+) cells, indicating a modulation of early lymphopoiesis. This is caused by a microenvironment-induced mechanism as Shh treatment of bone marrow recipients, but not donors, results in a dramatic depletion of lymphocytes. Together, these data suggest that Shh mediates alterations in the bone marrow hematopoietic niche affecting the early lymphoid differentiation.

PMID 19436267


Fate tracing reveals the endothelial origin of hematopoietic stem cells

Cell Stem Cell. 2008 Dec 4;3(6):625-36.

Zovein AC, Hofmann JJ, Lynch M, French WJ, Turlo KA, Yang Y, Becker MS, Zanetta L, Dejana E, Gasson JC, Tallquist MD, Iruela-Arispe ML.

Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, CA 90095, USA.

Abstract Hematopoietic stem cells (HSCs) originate within the aortic-gonado-mesonephros (AGM) region of the midgestation embryo, but the cell type responsible for their emergence is unknown since critical hematopoietic factors are expressed in both the AGM endothelium and its underlying mesenchyme. Here we employ a temporally restricted genetic tracing strategy to selectively label the endothelium, and separately its underlying mesenchyme, during AGM development. Lineage tracing endothelium, via an inducible VE-cadherin Cre line, reveals that the endothelium is capable of HSC emergence. The endothelial progeny migrate to the fetal liver, and later to the bone marrow, and are capable of expansion, self-renewal, and multilineage hematopoietic differentiation. HSC capacity is exclusively endothelial, as ex vivo analyses demonstrate lack of VE-cadherin Cre induction in circulating and fetal liver hematopoietic populations. Moreover, AGM mesenchyme, as selectively traced via a myocardin Cre line, is incapable of hematopoiesis. Our genetic tracing strategy therefore reveals an endothelial origin of HSCs.

PMID 19041779


Cytoskeletal influences on nuclear shape in granulocytic HL-60 cells

BMC Cell Biol. 2004 Aug 19;5:30.

Olins AL, Olins DE.

Department of Biology, Bowdoin College, Brunswick, Maine 04011, USA.


BACKGROUND: During granulopoiesis in the bone marrow, the nucleus differentiates from ovoid to lobulated shape. Addition of retinoic acid (RA) to leukemic HL-60 cells induces development of lobulated nuclei, furnishing a convenient model system for nuclear differentiation during granulopoiesis. Previous studies from our laboratory have implicated nuclear envelope composition as playing important roles in nuclear shape changes. Specifically noted were: 1) a paucity of lamins A/C and B1 in the undifferentiated and RA treated cell forms; 2) an elevation of lamin B receptor (LBR) during induced granulopoiesis.

RESULTS: The present study demonstrates that perturbation of cytoskeletal elements influences nuclear differentiation of HL-60 cells. Because of cytotoxicity from prolonged exposure to cytoskeleton-modifying drugs, most studies were performed with a Bcl-2 overexpressing HL-60 subline. We have found that: 1) nocodazole prevents RA induction of lobulation; 2) taxol induces lobulation and micronuclear formation, even in the absence of RA; 3) cytochalasin D does not inhibit RA induced nuclear lobulation, and prolonged exposure induces nuclear shape changes in the absence of RA.

CONCLUSIONS: The present results, in the context of earlier data and models, suggest a mechanism for granulocytic nuclear lobulation. Our current hypothesis is that the nuclear shape change involves factors that increase the flexibility of the nuclear envelope (reduced lamin content), augment connections to the underlying heterochromatin (increased levels of LBR) and promote distortions imposed by the cytoskeleton (microtubule motors creating tension in the nuclear envelope).

PMID 15317658


Normal blood cell values in the early mid-trimester fetus

Prenat Diagn. 1985 Nov-Dec;5(6):367-73.

Millar DS, Davis LR, Rodeck CH, Nicolaides KH, Mibashan RS. Abstract

Samples of pure fetal blood from 116 fetuses of 15-21 weeks' gestation were obtained by direct vision fetoscopy. Ninety nine of these fetuses, presumed to be haematologically normal, were suitable for analysis. The data obtained show that the erythropoietic system is evolving rapidly in this gestational age range. The myeloid series shows no significant increase or decrease in numbers apart from eosinophils and basophils which increase significantly with gestational age whereas the platelet count remains constant. The growing application of fetoscopic blood sampling to the prenatal diagnosis and management of fetal blood disorders renders mandatory a knowledge of normal fetal blood values.

PMID: 4088972 [Indexed for MEDLINE]


Development of gamma G, gamma A, gamma M, beta IC-beta IA, C 1 esterase inhibitor, ceruloplasmin, transferrin, hemopexin, haptoglobin, fibrinogen, plasminogen, alpha 1-antitrypsin, orosomucoid, beta-lipoprotein, alpha 2-macroglobulin, and prealbumin in the human conceptus

J Clin Invest. 1969 Aug;48(8):1433-46.

Gitlin D, Biasucci A.


The synthesis of gammaG, gammaA, gammaM, beta(1C)/beta(1A), C'1 esterase inhibitor, ceruloplasmin, transferrin, hemopexin, haptoglobin, fibrinogen, alpha(1)-antitrypsin, orosomucoid, beta-lipoprotein, alpha(2)-macroglobulin, and prealbumin was studied in 15 normal human embryos and fetuses of 29 days to 18 wk gestation and in the yolk sacs of four embryos from 5.5 to 11.5 wk gestation using tissue culture in (14)C-labeled amino acids followed by radioimmunoelectrophoresis.

The human embryo as early as 29 day gestation synthesized beta(1C)/beta(1A), C'1 esterase inhibitor, transferrin, hemopexin, alpha(1)-antitrypsin, beta-lipoprotein, alpha(2)-macroglobulin, and prealbumin in culture.

At 32 days gestation ceruloplasmin and orosomucoid were also synthesized, but synthesis of fibrinogen was not observed before 5.5 wk.

Synthesis of gammaM occurred as early as 10.5 wk gestation, and gammaG synthesis was found in cultures as early as 12 wk gestation; gammaA synthesis was not detected in any of the tissue cultures.

With the exception of the gamma-globulins, each of the proteins studied was synthesized by the liver, but additional sites of synthesis for some of these proteins were also found.

Synthesis of gammaG and gammaM occurred primarily in the spleen, but other sites of synthesis were noted as well.

Changes in the concentrations of most of these proteins and plasminogen in embryonic and fetal serum from 5.5 to 41 wk gestation, in amniotic fluid from 6.5 to 38 wk gestation, and in the sera of neonates during the 1st 3 wk postpartum are described. Although gammaA, gammaM, ceruloplasmin, or haptoglobin were not detectable in some of the embryonic and fetal sera, gammaA and ceruloplasmin were both present as early as 6.5 wk gestation, haptoglobin by 9.5 wk gestation, and gammaM by 17 wk gestation. Each of the other proteins were present in all of the sera examined.

PMID 5796355


Erythroblastosis foetalis or haemolytic disease of the newborn

DIAMOND LK. Proc R Soc Med. 1947 Jul;40(9):546-50. No abstract available.

PMID 20344530