Placenta Is a Niche for Hematopoietic Stem Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2671-2671
Author(s):  
Hanna K.A. Mikkola ◽  
Christos Gekas ◽  
Francoise Dieterlen-Lievre ◽  
Stuart H. Orkin
Keyword(s):  
De Novo ◽  
Fetal Liver ◽  
Yolk Sac ◽  
Mouse Development ◽  
Adult Type ◽  
Cell Potential ◽  
Hematopoietic Stem ◽  
Hematopoietic Organ ◽  
Hematopoietic System ◽  
Hematopoietic Organs

Abstract The hematopoietic system in the embryo develops in anatomically distinct sites, facilitating rapid generation of erythroid cells and formation of a pool of pluripotent HSCs. The origin of definitive HSCs is not fully resolved, and little is known about how the different fetal hematopoietic microenvironments direct the genesis, maturation, expansion and differentiation of HSCs. In avians, de novo hematopoiesis occurs not only in the yolk sac and the AGM but also in another mesodermal appendage, the allantois. In mammals, the allantois forms the umbilical cord and fetal placenta upon fusion with the chorion. The placenta has not been recognized as a hematopoietic organ, although Melchers reported fetal B-cell potential in murine placenta 25 years ago (Nature 1979, 277:219). Recently, Alvarez-Silva et al. showed that the placenta is a rich source for multipotential hematopoietic progenitors prior to the fetal liver (Development2003, 130:5437). We have performed spatial and temporal analysis of HSCs during mouse development and for the first time assessed HSC activity in the placenta. Hematopoietic organs from E10.5-18.5 embryos (CD45.1/CD45.2) were treated with collagenase and transplanted in limiting dilutions (3–1/1000 embryo equivalents, ee) into irradiated CD45.2+ adult hosts with CD45.1+ support BM cells. Reconstitution was analyzed by FACS and HSCs were quantified as repopulating units (RUs/ee = ([reconstituted recipients] /[total recipients]) /[transplanted dose]). Our data show that the placenta functions as a hematopoietic organ that during midgestation harbors a large pool of pluripotent HSCs. The onset of HSC activity in the placenta parallels that of the AGM starting at E10.5–11.0. However, the placenta HSC pool expands until E12.5–13.5 (>50 RUs) contrasting lack of HSC expansion in the AGM. The expansion of CD34+c-kit+ HSCs in the placenta occurs prior to and during the initial expansion of HSCs in the fetal liver and is not accompanied with myeloerythroid differentiation. A far greater expansion of placenta HSCs compared to that of clonogenic progenitors (17-fold vs. 2-fold at E11.5–12.5) suggests that the placenta provides a favorable niche for HSCs. Indeed, placenta HSCs possess functional properties of authentic adult-type HSCs by providing high level multilineage reconstitution for >5 months and exhibiting self-renewal capacity upon serial transplantation. Importantly, placenta HSCs are distinct from circulating HSCs that appear in low numbers after E11.5. HSC activity in the placenta declines towards the end of gestation while HSCs in the fetal liver and blood continue to increase, possibly reflecting mobilization of placenta HSCs to the fetal liver and other developing hematopoietic organs. The early onset of HSC activity in the placenta suggests that the allantois and its derivatives may participate in de novo genesis and maturation of HSCs together with the AGM and possibly the yolk sac. As the main blood volume from the dorsal aorta reaches the fetal liver via umbilical vessels and the placenta, placenta may also provide a niche where nascent HSCs, or pre-HSCs, from the AGM colonize for maturation and expansion prior to seeding fetal liver. While further studies are needed to define the precise origin of placenta HSCs and the function of placenta microenvironment as an HSC supportive niche, the unique kinetics and magnitude of HSC activity suggest an important, previously unappreciated role for the placenta in establishing the definitive hematopoietic system.

Hematopoietic Stem Cells Emerge in the Placental Vasculature in the Absence of Circulation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1258-1258
Author(s):  
Katrin E. Rhodes ◽  
Christos Gekas ◽  
Yanling Wang ◽  
Christopher T. Lux ◽  
Cameron S. Francis ◽  
...  
Keyword(s):  
De Novo ◽  
Hematopoietic Cells ◽  
Adult Life ◽  
Yolk Sac ◽  
Lymphoid Cells ◽  
Hematopoietic Stem ◽  
Hematopoietic Organ ◽  
Large Pool ◽  
A Site ◽  
Large Vessels

Abstract The placenta was recently unveiled as an important hematopoietic organ, harboring a large pool of HSCs during midgestation. Yet, it has not been defined whether the placenta can generate HSCs de novo. By using the Runx1-LacZ and Ncx1 knockout mouse models we show that the placenta is a site of HSC generation and identify the cellular niches in which placental HSCs reside. Runx1 is essential for the emergence of definitive HSCs and remains expressed in HSCs throughout fetal development and adult life. Analysis of Runx1LacZ/+ and Runx1LacZ/LacZ placental sections nominated the large vessels of the placenta and the chorioallantoic mesenchyme as putative sites of HSC origin. Once formed, LacZ+ candidate HSCs convened in the labyrinth vessels. Co-staining of Runx1LacZ/+ placentas with an antibody specific for phosphorylated Ser 10 at histone 3, a marker of mitosis, showed mitotically active definitive hematopoietic cells in the labyrinth vessels, suggesting that the labyrinth is a microenvironmental niche capable of stimulating HSC expansion. In wild-type placentas, CD41+ nascent hematopoietic cells were found in the same vascular sites as in the Runx1-LacZ placentas but never in the mesenchyme. Instead, placental stroma was populated by F4/80+CD45+/−CD41- macrophages, suggesting that the placenta harbors two distinct hematopoietic lineages that are supported by different microenvironments. To verify that the CD41+ nascent HSCs were generated de novo in the placenta, we analyzed Ncx1−/− embryos, which lack heartbeat due to lack of the sodium-calcium exchange pump 1. In the absence of circulation, trafficking of hematopoietic cells between tissues is abolished. Strikingly, CD41+ HSCs emerge in the large vessels of the placenta in Ncx1−/− mutants. In some sections CD41+ cells formed clusters that were still connected to the vessels of the placenta and umbilical cord. These findings imply that formation of HSCs extends to a much larger anatomical area than was previously thought, including the placenta. Importantly, the placentas in both Ncx1−/− and control embryos (E8.5–9.5) generated mixed hematopoietic outgrowth including definitive progenitors in OP-9 co-culture, as verified by expression of c-kit, CD41 and CD45. When the differentiation of the definitive progenitors was assessed on methylcellulose, Ncx1−/− tissues demonstrated similar potential as Ncx1+/− hematopoietic organs (yolk sac, aorta gonad mesonephros (AGM) and placenta), yielding erythroid, myeloid and mixed colonies and B220+ lymphoid cells. These studies reveal that definitive hematopoietic cells with both myeloerythroid and lymphoid potential are generated de novo within the placental vasculature. Furthermore, the placental labyrinth provides a unique hematopoietic niche that is conducive for proliferation of hematopoietic cells and, unlike the AGM or the yolk sac, serves as a supportive niche for a large pool of HSCs prior to liver colonization.

scholarly journals Cellular Basis of Embryonic Hematopoiesis and Its Implications in Prenatal Erythropoiesis

2020 ◽  
Vol 21 (24) ◽  
pp. 9346
Author(s):  
Toshiyuki Yamane
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Fetal Liver ◽  
Yolk Sac ◽  
Hematopoietic Progenitors ◽  
Adult Type ◽  
Hematopoietic Stem ◽  
Cellular Origin ◽  
Developmental Switches ◽  
Primitive 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.

scholarly journals First blood: the endothelial origins of hematopoietic progenitors

Angiogenesis ◽  
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.

scholarly journals Epidermal γδ T cells originate from yolk sac hematopoiesis and clonally self-renew in the adult

2018 ◽  
Vol 215 (12) ◽  
pp. 2994-3005 ◽  
Author(s):  
Rebecca Gentek ◽  
Clément Ghigo ◽  
Guillaume Hoeffel ◽  
Audrey Jorquera ◽  
Rasha Msallam ◽  
...  
Keyword(s):  
T Cells ◽  
Immune Cell ◽  
Fetal Liver ◽  
Γδ T Cells ◽  
Yolk Sac ◽  
Lineage Tracing ◽  
Hematopoietic Stem ◽  
Turn Over ◽  
Initial Seeding ◽  
Mapping Systems

The murine epidermis harbors two immune cell lineages, Langerhans cells (LCs) and γδ T cells known as dendritic epidermal T cells (DETCs). LCs develop from both early yolk sac (YS) progenitors and fetal liver monocytes before locally self-renewing in the adult. For DETCs, the mechanisms of homeostatic maintenance and their hematopoietic origin are largely unknown. Here, we exploited multicolor fate mapping systems to reveal that DETCs slowly turn over at steady state. Like for LCs, homeostatic maintenance of DETCs is achieved by clonal expansion of tissue-resident cells assembled in proliferative units. The same mechanism, albeit accelerated, facilitates DETC replenishment upon injury. Hematopoietic lineage tracing uncovered that DETCs are established independently of definitive hematopoietic stem cells and instead originate from YS hematopoiesis, again reminiscent of LCs. DETCs thus resemble LCs concerning their maintenance, replenishment mechanisms, and hematopoietic development, suggesting that the epidermal microenvironment exerts a lineage-independent influence on the initial seeding and homeostatic maintenance of its resident immune cells.

Migratory path of definitive hematopoietic stem/progenitor cells during zebrafish development

Blood ◽  
2007 ◽  
Vol 109 (12) ◽  
pp. 5208-5214 ◽  
Author(s):  
Hao Jin ◽  
Jin Xu ◽  
Zilong Wen
Keyword(s):  
Progenitor Cells ◽  
Fetal Liver ◽  
Embryo Cell ◽  
Migration Route ◽  
Hematopoietic Stem ◽  
Hematopoietic Organ ◽  
Blood Island ◽  
Adult Kidney ◽  
Definitive Hematopoiesis

Abstract The development of vertebrate definitive hematopoiesis is featured by temporally and spatially dynamic distribution of hematopoietic stem/progenitor cells (HSPCs). It is proposed that the migration of definitive HSPCs, at least in part, accounts for this unique characteristic; however, compelling in vivo lineage evidence is still lacking. Here we present an in vivo analysis to delineate the migration route of definitive HSPCs in the early zebrafish embryo. Cell-marking analysis was able to first map definitive HSPCs to the ventral wall of dorsal aorta (DA). These cells were subsequently found to migrate to a previously unappreciated organ, posterior blood island (PBI), located between the caudal artery and caudal vein, and finally populate the kidney, the adult hematopoietic organ. These findings demonstrate that the PBI acts as an intermediate hematopoietic organ in a manner analogous to the mammalian fetal liver to sustain definitive hematopoiesis before adult kidney hematopoiesis occurs. Thus our study unambiguously documents the in vivo trafficking of definitive HSPCs among developmentally successive hematopoietic compartments and underscores the ontogenic conservation of definitive hematopoiesis between zebrafish and mammals.

Expression of CD41 marks the initiation of definitive hematopoiesis in the mouse embryo

Blood ◽  
2003 ◽  
Vol 101 (2) ◽  
pp. 508-516 ◽  
Author(s):  
Hanna K. A. Mikkola ◽  
Yuko Fujiwara ◽  
Thorsten M. Schlaeger ◽  
David Traver ◽  
Stuart H. Orkin
Keyword(s):  
Endothelial Cells ◽  
Mouse Embryo ◽  
Fetal Liver ◽  
Stem Cell Differentiation ◽  
Yolk Sac ◽  
Embryoid Bodies ◽  
Embryonic Stem Cell Differentiation ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Stem ◽  
Definitive Hematopoiesis

Murine hematopoietic stem cells (HSCs) originate from mesoderm in a process that requires the transcription factor SCL/Tal1. To define steps in the commitment to blood cell fate, we compared wild-type and SCL−/− embryonic stem cell differentiation in vitro and identified CD41 (GpIIb) as the earliest surface marker missing from SCL−/− embryoid bodies (EBs). Culture of fluorescence-activated cell sorter (FACS) purified cells from EBs showed that definitive hematopoietic progenitors were highly enriched in the CD41+ fraction, whereas endothelial cells developed from CD41− cells. In the mouse embryo, expression of CD41 was detected in yolk sac blood islands and in fetal liver. In yolk sac and EBs, the panhematopoietic marker CD45 appeared in a subpopulation of CD41+ cells. However, multilineage hematopoietic colonies developed not only from CD45+CD41+ cells but also from CD45−CD41+ cells, suggesting that CD41 rather than CD45 marks the definitive culture colony-forming unit (CFU-C) at the embryonic stage. In contrast, fetal liver CFU-C was CD45+, and only a subfraction expressed CD41, demonstrating down-regulation of CD41 by the fetal liver stage. In yolk sac and EBs, CD41 was coexpressed with embryonic HSC markers c-kit and CD34. Sorting for CD41 and c-kit expression resulted in enrichment of definitive hematopoietic progenitors. Furthermore, the CD41+c-kit+ population was missing from runx1/AML1−/− EBs that lack definitive hematopoiesis. These results suggest that the expression of CD41, a candidate target gene of SCL/Tal1, and c-kit define the divergence of definitive hematopoiesis from endothelial cells during development. Although CD41 is commonly referred to as megakaryocyte–platelet integrin in adult hematopoiesis, these results implicate a wider role for CD41 during murine ontogeny.

scholarly journals Prdm16 is a physiologic regulator of hematopoietic stem cells

Blood ◽  
2011 ◽  
Vol 117 (19) ◽  
pp. 5057-5066 ◽  
Author(s):  
Francesca Aguilo ◽  
Serine Avagyan ◽  
Amy Labar ◽  
Ana Sevilla ◽  
Dung-Fang Lee ◽  
...  
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Fetal Liver ◽  
Feedback Loops ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Number Of Genes ◽  
Adult Bone ◽  
Deficient Mice

Abstract Fetal liver and adult bone marrow hematopoietic stem cells (HSCs) renew or differentiate into committed progenitors to generate all blood cells. PRDM16 is involved in human leukemic translocations and is expressed highly in some karyotypically normal acute myeloblastic leukemias. As many genes involved in leukemogenic fusions play a role in normal hematopoiesis, we analyzed the role of Prdm16 in the biology of HSCs using Prdm16-deficient mice. We show here that, within the hematopoietic system, Prdm16 is expressed very selectively in the earliest stem and progenitor compartments, and, consistent with this expression pattern, is critical for the establishment and maintenance of the HSC pool during development and after transplantation. Prdm16 deletion enhances apoptosis and cycling of HSCs. Expression analysis revealed that Prdm16 regulates a remarkable number of genes that, based on knockout models, both enhance and suppress HSC function, and affect quiescence, cell cycling, renewal, differentiation, and apoptosis to various extents. These data suggest that Prdm16 may be a critical node in a network that contains negative and positive feedback loops and integrates HSC renewal, quiescence, apoptosis, and differentiation.

Role of the WT1 tumor suppressor in murine hematopoiesis

Blood ◽  
2003 ◽  
Vol 101 (7) ◽  
pp. 2570-2574 ◽  
Author(s):  
Julia A. Alberta ◽  
Gregory M. Springett ◽  
Helen Rayburn ◽  
Thomas A. Natoli ◽  
Janet Loring ◽  
...  
Keyword(s):  
Stem Cells ◽  
Tumor Suppressor ◽  
Fetal Liver ◽  
Hematopoietic Cells ◽  
Leukemic Cells ◽  
Hematopoietic Stem ◽  
Hematopoietic System ◽  
Colony Forming Unit ◽  
Organ Systems

The WT1 tumor-suppressor gene is expressed by many forms of acute myeloid leukemia. Inhibition of this expression can lead to the differentiation and reduced growth of leukemia cells and cell lines, suggesting that WT1 participates in regulating the proliferation of leukemic cells. However, the role of WT1 in normal hematopoiesis is not well understood. To investigate this question, we have used murine cells in which the WT1 gene has been inactivated by homologous recombination. We have found that cells lacking WT1 show deficits in hematopoietic stem cell function. Embryonic stem cells lacking WT1, although contributing efficiently to other organ systems, make only a minimal contribution to the hematopoietic system in chimeras, indicating that hematopoietic stem cells lacking WT1 compete poorly with healthy stem cells. In addition, fetal liver cells lacking WT1 have an approximately 75% reduction in erythroid blast-forming unit (BFU-E), erythroid colony-forming unit (CFU-E), and colony-forming unit–granulocyte macrophage–erythroid–megakaryocyte (CFU-GEMM). However, transplantation of fetal liver hematopoietic cells lackingWT1 will repopulate the hematopoietic system of an irradiated adult recipient in the absence of competition. We conclude that the absence of WT1 in hematopoietic cells leads to functional defects in growth potential that may be of consequence to leukemic cells that have alterations in the expression of WT1.

Circulation is established in a stepwise pattern in the mammalian embryo

Blood ◽  
2003 ◽  
Vol 101 (5) ◽  
pp. 1669-1675 ◽  
Author(s):  
Kathleen E. McGrath ◽  
Anne D. Koniski ◽  
Jeffrey Malik ◽  
James Palis
Keyword(s):  
Vascular System ◽  
Fetal Liver ◽  
Yolk Sac ◽  
Red Cells ◽  
Hematopoietic Progenitors ◽  
Mammalian Embryo ◽  
Hematopoietic Organ ◽  
Significant Enrichment ◽  
A Site ◽  
The Relationship

To better understand the relationship between the embryonic hematopoietic and vascular systems, we investigated the establishment of circulation in mouse embryos by examining the redistribution of yolk sac–derived primitive erythroblasts and definitive hematopoietic progenitors. Our studies revealed that small numbers of erythroblasts first enter the embryo proper at 4 to 8 somite pairs (sp) (embryonic day 8.25 [E8.25]), concomitant with the proposed onset of cardiac function. Hours later (E8.5), most red cells remained in the yolk sac. Although the number of red cells expanded rapidly in the embryo proper, a steady state of approximately 40% red cells was not reached until 26 to 30 sp (E10). Additionally, erythroblasts were unevenly distributed within the embryo's vasculature before 35 sp. These data suggest that fully functional circulation is established after E10. This timing correlated with vascular remodeling, suggesting that vessel arborization, smooth muscle recruitment, or both are required. We also examined the distribution of committed hematopoietic progenitors during early embryogenesis. Before E8.0, all progenitors were found in the yolk sac. When normalized to circulating erythroblasts, there was a significant enrichment (20- to 5-fold) of progenitors in the yolk sac compared with the embryo proper from E9.5 to E10.5. These results indicated that the yolk sac vascular network remains a site of progenitor production and preferential adhesion even as the fetal liver becomes a hematopoietic organ. We conclude that a functional vascular system develops gradually and that specialized vascular–hematopoietic environments exist after circulation becomes fully established.

scholarly journals Early events in human T cell ontogeny. Phenotypic characterization and immunohistologic localization of T cell precursors in early human fetal tissues.

1988 ◽  
Vol 168 (3) ◽  
pp. 1061-1080 ◽  
Author(s):  
B F Haynes ◽  
M E Martin ◽  
H H Kay ◽  
J Kurtzberg
Keyword(s):  
T Cells ◽  
T Cell ◽  
Fetal Liver ◽  
Yolk Sac ◽  
Phenotypic Characterization ◽  
Hematopoietic Stem ◽  
Fetal Tissues ◽  
Human T Cell ◽  
Human Fetal Tissues ◽  
Early Human

During early fetal development, T cell precursors home from fetal yolk sac and liver to the epithelial thymic rudiment. From cells that initially colonize the thymus arise mature T cells that populate T cell zones of the peripheral lymphoid system. Whereas colonization of the thymus occurs late in the final third of gestation in the mouse, in birds and humans the thymus is colonized by hematopoietic stem cell precursors during the first third of gestation. Using a large series of early human fetal tissues and a panel of monoclonal antibodies that includes markers of early T cells (CD7, CD45), we have studied the immunohistologic location and differentiation capacity of CD45+, CD7+ cells in human fetal tissues. We found that before T cell precursor colonization of the thymus (7-8 wk of gestation), CD7+ cells were present in yolk sac, neck, upper thorax, and fetal liver, and were concentrated in mesenchyme throughout the upper thorax and neck areas. By 9.5 wk of gestation, CD7+ cells were no longer present in upper thorax mesenchyme but rather were localized in the lymphoid thymus and scattered throughout fetal liver. CD7+, CD2-, CD3-, CD8-, CD4-, WT31- cells in thorax and fetal liver, when stimulated for 10-15 d with T cell-conditioned media and rIL-2, expressed CD2, CD3, CD4, CD8, and WT31 markers of the T cell lineage. Moreover, CD7+ cells isolated from fetal liver contained all cells in this tissue capable of forming CFU-T colonies in vitro. These data demonstrate that T cell precursors in early human fetal tissues can be identified using a mAb against the CD7 antigen. Moreover, the localization of CD7+ T cell precursors to fetal upper thorax and neck areas at 7-8.5 wk of fetal gestation provides strong evidence for a developmentally regulated period in man in which T cell precursors migrate to the epithelial thymic rudiment.

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