Cellular Basis of Embryonic Hematopoiesis and Its Implications in Prenatal Erythropoiesis

Primitive erythrocytes are the first hematopoietic cells observed during ontogeny and are produced specifically in the yolk sac. Primitive erythrocytes express distinct hemoglobins compared with adult erythrocytes and circulate in the blood in the nucleated form. Hematopoietic stem cells produce adult-type (so-called definitive) erythrocytes. However, hematopoietic stem cells do not appear until the late embryonic/early fetal stage. Recent studies have shown that diverse types of hematopoietic progenitors are present in the yolk sac as well as primitive erythroblasts. Multipotent hematopoietic progenitors that arose in the yolk sac before hematopoietic stem cells emerged likely fill the gap between primitive erythropoiesis and hematopoietic stem-cell-originated definitive erythropoiesis and hematopoiesis. In this review, we discuss the cellular origin of primitive erythropoiesis in the yolk sac and definitive hematopoiesis in the fetal liver. We also describe mechanisms for developmental switches that occur during embryonic and fetal erythropoiesis and hematopoiesis, particularly focusing on recent studies performed in mice.

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Angiotensin-converting enzyme (CD143) specifies emerging lympho-hematopoietic progenitors in the human embryo

Blood ◽

10.1182/blood-2010-11-314781 ◽

2012 ◽

Vol 119 (16) ◽

pp. 3712-3723 ◽

Cited By ~ 28

Author(s):

Lidia Sinka ◽

Katia Biasch ◽

Ibrahim Khazaal ◽

Bruno Péault ◽

Manuela Tavian

Keyword(s):

Stem Cells ◽

Angiotensin Converting Enzyme ◽

Hematopoietic Stem Cells ◽

Human Embryo ◽

Fetal Liver ◽

Converting Enzyme ◽

Hematopoietic Progenitors ◽

Adult Type ◽

Hematopoietic Stem ◽

Adult Human

Abstract Adult-type lympho-myeloid hematopoietic progenitors are first generated in the aorta-gonad-mesonephros region between days 27 and 40 of human embryonic development, but an elusive blood forming potential is present earlier in the underlying splanchnopleura. In the present study, we show that angiotensin-converting enzyme (ACE, also known as CD143), a recently identified cell-surface marker of adult human hematopoietic stem cells, is already expressed in all presumptive and developing blood-forming tissues of the human embryo and fetus: para-aortic splanchnopleura, yolk sac, aorta-gonad-mesonephros, liver, and bone marrow (BM). Fetal liver and BM-derived CD34+ACE+ cells, but not CD34+ACE− cells, are endowed with long-term culture-initiating cell potential and sustain multilineage hematopoietic cell engraftment when transplanted into NOD/SCID mice. Furthermore, from 23-26 days of development, ACE expression characterizes rare CD34−CD45− cells concentrated in the hemogenic portion of the para-aortic splanchnopleura. ACE+ cells sorted from the splanchnopleura generated colonies of hematopoietic cells more than 40 times more frequently than ACE− cells. These data suggest that, in addition to being a marker of adult human hematopoietic stem cells, ACE identifies embryonic mesodermal precursors responsible for definitive hematopoiesis, and we propose that this enzyme is involved in the regulation of human blood formation.

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Podocalyxin is a CD34-related marker of murine hematopoietic stem cells and embryonic erythroid cells

Blood ◽

10.1182/blood-2004-10-4077 ◽

2005 ◽

Vol 105 (11) ◽

pp. 4170-4178 ◽

Cited By ~ 75

Author(s):

Regis Doyonnas ◽

Julie S. Nielsen ◽

Shierley Chelliah ◽

Erin Drew ◽

Takahiko Hara ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Hematopoietic Stem Cells ◽

Fetal Liver ◽

Erythroid Cells ◽

Hematopoietic Progenitors ◽

Hematopoietic Stem ◽

Nucleated Red Blood Cells ◽

Erythroid Precursors ◽

Valuable Marker

Abstract Podocalyxin/podocalyxin-like protein 1 [PCLP1]/thrombomucin/MEP21 is a CD34-related sialomucin. We have performed a detailed analysis of its expression during murine development and assessed its utility as a marker of hematopoietic stem cells (HSCs) and their more differentiated progeny. We find that podocalyxin is highly expressed by the first primitive hematopoietic progenitors and nucleated red blood cells to form in the embryonic yolk sac. Likewise, podocalyxin is expressed by definitive multilineage hematopoietic progenitors and erythroid precursors in fetal liver. The level of podocalyxin expression gradually declines with further embryo maturation and reaches near-background levels at birth. This is followed by a postnatal burst of expression that correlates with the seeding of new hematopoietic progenitors to the spleen and bone marrow. Shortly thereafter, podocalyxin expression gradually declines, and by 4 weeks postpartum it is restricted to a rare population of Sca-1+, c-kit+, lineage marker- (Lin-) cells in the bone marrow. These rare podocalyxin-expressing cells are capable of serially reconstituting myeloid and lymphoid lineages in lethally irradiated recipients, suggesting they have HSC activity. In summary, we find that podocalyxin is a marker of embryonic HSCs and erythroid cells and of adult HSCs and that it may be a valuable marker for the purification of these cells for transplantation.

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Yolk sac erythromyeloid progenitors sustain erythropoiesis throughout embryonic life

10.1101/2020.02.27.968230 ◽

2020 ◽

Cited By ~ 1

Author(s):

Francisca Soares-da-Silva ◽

Odile Burlen-Defranoux ◽

Ramy Elsaid ◽

Lorea Iturri ◽

Laina Freyer ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Hematopoietic Stem Cells ◽

Hematopoietic Stem Cell ◽

Fetal Liver ◽

Selective Advantage ◽

Yolk Sac ◽

Lineage Tracing ◽

Hematopoietic Stem ◽

Embryonic Life

AbstractThe first hematopoietic cells are produced in the yolk sac and are thought to be rapidly replaced by the progeny of hematopoietic stem cells. Here we document that hematopoietic stem cells do not contribute significantly to erythrocyte production up until birth. Lineage tracing of yolk sac-derived erythromyeloid progenitors, that also contribute to tissue resident macrophages, shows a progeny of highly proliferative erythroblasts, that after intra embryonic injection, rapidly differentiate. These progenitors, similar to hematopoietic stem cells, are c-Myb dependent and are developmentally restricted as they are not found in the bone marrow. We show that erythrocyte progenitors of yolk sac origin require lower concentrations of erythropoietin than their hematopoietic stem cell-derived counterparts for efficient erythrocyte production. Consequently, fetal liver hematopoietic stem cells fail to generate megakaryocyte and erythrocyte progenitors. We propose that large numbers of yolk sac-derived erythrocyte progenitors have a selective advantage and efficiently outcompete hematopoietic stem cell progeny in an environment with limited availability of erythropoietin.

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Yolk sac, but not hematopoietic stem cell–derived progenitors, sustain erythropoiesis throughout murine embryonic life

Journal of Experimental Medicine ◽

10.1084/jem.20201729 ◽

2021 ◽

Vol 218 (4) ◽

Author(s):

Francisca Soares-da-Silva ◽

Laina Freyer ◽

Ramy Elsaid ◽

Odile Burlen-Defranoux ◽

Lorea Iturri ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Hematopoietic Stem Cells ◽

Hematopoietic Stem Cell ◽

Fetal Liver ◽

Yolk Sac ◽

Lineage Tracing ◽

Erythroid Progenitors ◽

Hematopoietic Stem ◽

Embryonic Life

In the embryo, the first hematopoietic cells derive from the yolk sac and are thought to be rapidly replaced by the progeny of hematopoietic stem cells. We used three lineage-tracing mouse models to show that, contrary to what was previously assumed, hematopoietic stem cells do not contribute significantly to erythrocyte production up until birth. Lineage tracing of yolk sac erythromyeloid progenitors, which generate tissue resident macrophages, identified highly proliferative erythroid progenitors that rapidly differentiate after intra-embryonic injection, persisting as the major contributors to the embryonic erythroid compartment. We show that erythrocyte progenitors of yolk sac origin require 10-fold lower concentrations of erythropoietin than their hematopoietic stem cell–derived counterparts for efficient erythrocyte production. We propose that, in a low erythropoietin environment in the fetal liver, yolk sac–derived erythrocyte progenitors efficiently outcompete hematopoietic stem cell progeny, which fails to generate megakaryocyte and erythrocyte progenitors.

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Hematopoietic Defects in Cited2 Mutant Fetal Liver.

Blood ◽

10.1182/blood.v106.11.2272.2272 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2272-2272

Author(s):

Yu Chen ◽

Yu-Chung Yang

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Fetal Liver ◽

Liver Cells ◽

Hematopoietic Progenitors ◽

Self Renewal ◽

Hematopoietic Stem ◽

Fetal Liver Cells

Abstract Cited2 [cAMP-responsive element-binding protein (CBP)/p300-interacting transactivators with glutamic acid (E) and aspartic acid (D)-rich tail 2] is a newly identified transcriptional modulator. Knockout of Cited2 gene is embryonic lethal because of heart and neural tube defects. Cited2 binds directly to CBP and p300, which have been shown to be crucial for hematopoietic stem cell self-renewal and proper hematopoietic differentiation, respectively. Cited2 also induces the expression of a polycomb-group gene, Bmi-1, which is essential for self-renewal of adult hematopoietic stem cells. These connections provided rationale to study the potential role of Cited2 in hematopoiesis. Mouse fetal liver is the major hematopoietic organ from day 10 postcoitus until right before birth. The smaller sized Cited2−/− fetal liver and significantly decreased fetal liver cellularity strongly suggest the potential defect in hematopoiesis. In vitro colony formation assay in methycellulose-based medium was used to characterize the hematopoietic progenitors. We found that fetal liver cells from E13.5, 14.5 and E15.5 Cited2−/− embryos gave rise to much less colonies, which reflects the decreased number and proliferative ability of hematopoietic progenitors due to Cited2 deficiency. Immunostaining of lineage-specific cell surface markers followed by flow cytometry was performed to characterize different hematopoietic populations in E14.5 and E15.5 fetal liver of wild type and Cited2−/− embryos. Cited2−/− fetal liver cells displayed a significant reduction in numbers throughout the hematopoietic hierarchy including hematopoietic stem cells (Lin− c-Kit+ Sca-1+), progenitor cells (Lin− c-Kit+), and differentiated cells of different lineages (CD45+, Ter119+, Mac-1+, Gr-1+), thus revealing a multi-level hematopoietic deficiency of Cited2−/− embryos. Long-term reconstitution experiment was then carried out to measure the ability of hematopoietic stem cells from Cited2−/− fetal liver cells to engraft and reconstitute hematopoietic system of congenic recipient mice. Mice transplanted with Cited2−/− fetal liver cells showed reconstitution of T cells whereas a 2-fold decrease in the reconstitution of B cell and myeloid lineages was observed, indicating a compromised ability of Cited2−/− fetal liver hematopoietic stem cells to maintain hematopoiesis. The results suggest an important role of Cited2 in hematopoietic differentiation and a selective function of Cited2 in B lymphoid &myeloid induction. The underlying mechanisms responsible for these defects will be pursued by microarray analysis of gene expression profile of Cited2−/− fetal liver cells, followed by more detailed phenotypic analyses of B and myeloid lineage markers plus in vitro and in vivo functional assays.

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Faculty Opinions recommendation of Cultivation of aorta-gonad-mesonephros-derived hematopoietic stem cells in the fetal liver microenvironment amplifies long-term repopulating activity and enhances engraftment to the bone marrow.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1004105.47154 ◽

2002 ◽

Author(s):

Ana Cumano

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Hematopoietic Stem Cells ◽

Fetal Liver ◽

Hematopoietic Stem

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Lyve1 marks yolk sac derived hematopoietic stem cells and nearly half of adult blood

Experimental Hematology ◽

10.1016/j.exphem.2016.06.025 ◽

2016 ◽

Vol 44 (9) ◽

pp. S32

Author(s):

Matthew Inlay ◽

Yasamine Ghorbanian ◽

Lydia Lee ◽

Hanna Mikkola

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Yolk Sac ◽

Hematopoietic Stem

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First blood: the endothelial origins of hematopoietic progenitors

Angiogenesis ◽

10.1007/s10456-021-09783-9 ◽

2021 ◽

Author(s):

Giovanni Canu ◽

Christiana Ruhrberg

Keyword(s):

Stem Cells ◽

Molecular Mechanisms ◽

Vascular Endothelial Cells ◽

Fetal Liver ◽

Cell Types ◽

Yolk Sac ◽

Vascular Endothelial ◽

Hematopoietic Stem ◽

Close Proximity ◽

Clinical Interest

AbstractHematopoiesis in vertebrate embryos occurs in temporally and spatially overlapping waves in close proximity to blood vascular endothelial cells. Initially, yolk sac hematopoiesis produces primitive erythrocytes, megakaryocytes, and macrophages. Thereafter, sequential waves of definitive hematopoiesis arise from yolk sac and intraembryonic hemogenic endothelia through an endothelial-to-hematopoietic transition (EHT). During EHT, the endothelial and hematopoietic transcriptional programs are tightly co-regulated to orchestrate a shift in cell identity. In the yolk sac, EHT generates erythro-myeloid progenitors, which upon migration to the liver differentiate into fetal blood cells, including erythrocytes and tissue-resident macrophages. In the dorsal aorta, EHT produces hematopoietic stem cells, which engraft the fetal liver and then the bone marrow to sustain adult hematopoiesis. Recent studies have defined the relationship between the developing vascular and hematopoietic systems in animal models, including molecular mechanisms that drive the hemato-endothelial transcription program for EHT. Moreover, human pluripotent stem cells have enabled modeling of fetal human hematopoiesis and have begun to generate cell types of clinical interest for regenerative medicine.

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