Distinct Roles of Integrins α6 and α4 in Fetal Liver Hematopoietic Stem and Progenitor Cell Homing.

Abstract During development and after transplantation, intravenously injected hematopoietic stem and progenitor cells (HSPCs) selectively transmigrate through the sinusoidal walls into the bone marrow (BM) niches to engraft and reconstitute hematopoiesis. The rate of reconstitution following transplantation varies depending on the source of hematopoietic stem cells (HSCs) (To, et al 1992). However, the molecular pathways that control the homing of HSCs, in particular, of fetal HSCs are still not well understood. In the present study we studied the contribution of α6 and α4 integrins in homing of fetal liver HSPCs into adult BM by using function-blocking antibodies and an integrin α6 knockout mouse model. We found an ubiquitous expression of both integrin α6 and α4 receptors on fetal liver Lin−Sca-1+c-kit+ (LSK) HSPCs. Genetic ablation of integrin α6 resulted in reduced homing of fetal liver progenitors (HPCs) to BM of lethally irradiated adult recipients. In agreement with this, the integrin α6 antibody inhibited homing of fetal liver HPCs into BM and spleen. The role of integrin a6 in homing and engraftment of fetal liver HSCs was studied by a competitive repopulation assay by using integrin α6−/− or α6+/+ fetal liver cells. Absence of α6 integrin in fetal liver cells did not cause any engraftment defect or mobilization hypersensitivity as compared to wild-type cells. In agreement with this, anti-integrin α6 antibody did not either inhibit BM homing of short-term or long-term HSCs. In contrast, homing of fetal liver HSCs and HPCs to BM was virtually abrogated after treatment with integrin α4 antibody. Our results show that the α6 integrin receptors are functional during homing of fetal liver HPCs, but not multilineage repopulating HSC in vivo. Furthermore, we show the critical role of integrin α4 receptor for homing of both fetal liver HPCs and multilineage repopulating HSCs to BM, indicating distinct developmentally regulated functions for integrin α6 and α4 receptors during fetal hematopoiesis

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The Role of K-ras Signaling in Erythropoiesis In Vivo.

Blood ◽

10.1182/blood.v106.11.3136.3136 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3136-3136

Author(s):

Jing Zhang ◽

Yangang Liu ◽

Caroline Beard ◽

Rudolf Jaenisch ◽

Tyler Jacks ◽

...

Keyword(s):

Fetal Liver ◽

Erythroid Differentiation ◽

Liver Cells ◽

Ras Signaling ◽

Erythroid Progenitors ◽

Akt Activation ◽

Fetal Liver Cells ◽

Terminal Erythroid Differentiation

Abstract K-ras plays an important role in hematopoiesis. K-ras-deficient mouse embryos die around E12-E13 with severe anemia. In humans, oncogenic mutations in K-ras gene are identified in ~30% of patients with acute myeloid leukemia. We used mouse primary erythroid progenitors as a model system to study the role of K-ras signaling in vivo. Both Epo- and stem cell factor (SCF) - dependent Akt activation are greatly reduced in K-ras-/- fetal liver cells, whereas other cytokine- induced pathways, including Stat5 and p44/p42 MAP kinase, are activated normally. The reduced Akt activation in erythroid progenitors per se leads to delayed erythroid differentiation. Our data identify K-ras as the major regulator for cytokine-dependent Akt activation, which is important for erythroid differentiation in vivo. Overexpression of oncogenic Ras in primary fetal erythroid progenitors led to their continual proliferation and a block in terminal erythroid differentiation. Similarly, we found that primary fetal liver cells expressing oncogenic K-ras from its endogenous locus undergo abnormal proliferation and terminal erythroid differentiation is partially blocked. We are currently investigating the signal transduction pathways activated by this oncogenic K-ras that underlies these cellular phenotypes.

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Cited2 is required for normal hematopoiesis in the murine fetal liver

Blood ◽

10.1182/blood-2007-01-066316 ◽

2007 ◽

Vol 110 (8) ◽

pp. 2889-2898 ◽

Cited By ~ 34

Author(s):

Yu Chen ◽

Peter Haviernik ◽

Kevin D. Bunting ◽

Yu-Chung Yang

Keyword(s):

Fetal Liver ◽

Liver Cells ◽

Cathepsin G ◽

Molecular Regulation ◽

Hematopoietic Stem ◽

Hematopoietic Development ◽

Fetal Liver Cells ◽

B Lymphoid ◽

First Time

Abstract Cited2 (cAMP-responsive elementbinding protein [CBP]/p300-interacting transactivators with glutamic acid [E] and aspartic acid [D]–rich tail 2) is a newly identified transcriptional modulator. Knockout of the Cited2 gene results in embryonic lethality with embryos manifesting heart and neural tube defects. Cited2−/− fetal liver displayed significant reduction in the numbers of Lin−c-Kit+Sca-1+ cells, Lin−c-Kit+ cells, and progenitor cells of different lineages. Fetal liver cells from Cited2−/− embryos gave rise to markedly reduced number of colonies in the colony-forming unit assay. Primary and secondary transplantation studies showed significantly compromised reconstitution of T-lymphoid, B-lymphoid, and myeloid lineages in mice that received a transplant of Cited2−/− fetal liver cells. Competitive reconstitution experiments further showed that fetal liver hematopoietic stem cell (HSC) function is severely impaired due to Cited2 deficiency. Microarray analysis showed decreased expression of Wnt5a and a panel of myeloid molecular markers such as PRTN3, MPO, Neutrophil elastase, Cathepsin G, and Eosinophil peroxidase in Cited2−/− fetal livers. Decreased expression of Bmi-1, Notch1, LEF-1, Mcl-1, and GATA2 was also observed in Cited2−/− Lin−c-Kit+ cells. The present study uncovers for the first time a novel role of Cited2 in the maintenance of hematopoietic homeostasis during embryogenesis and thus provides new insights into the molecular regulation of hematopoietic development.

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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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The Role of Gi Signaling in Hematopoiesis.

Blood ◽

10.1182/blood.v112.11.1402.1402 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1402-1402

Author(s):

Marie Terpager ◽

Hiroshi Kataoka ◽

Ivo Cornelissen ◽

Justin Hamilton ◽

Shaun R Coughlin

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Hematopoietic Stem Cells ◽

Pertussis Toxin ◽

Fetal Liver ◽

Liver Cells ◽

Cytokine Signaling ◽

Hematopoietic Stem ◽

Fetal Liver Cells

Abstract Hematopoiesis implies a number of different cellular events from self-renewal of stem cells and proliferation to differentiation and migration. All these steps require tight regulation by signaling, and many cytokine signaling pathways have been described. However the signaling mechanisms that govern trafficking, proliferation, survival and differentiation of hematopoietic stem cells and other hematopoietic cell types are poorly understood. G-protein coupled receptors (GPCRs) can regulate many of these processes, and the Gi-coupled receptor CXCR4 is known to play a key role. Roles for other Gi-coupled receptors are just beginning to be uncovered, and given the functions of Gi-signaling in regulation of cell homing, proliferation and survival, it seems likely that Gi-coupled GPCR signaling plays an important role in hematopoiesis. By using a genetic approach – knockout of Gi function in hematopoietic lineages – we are probing the role of Gi-coupled GPCR’s in hematopoiesis to determine which receptors are involved. There are 6 sub-types in the Gi family, and it has been difficult to eliminate all Gi function by gene knockout. However, all Gi family members, except for Gz, are sensitive to inhibition by pertussis toxin (PTX). To ablate Gi signaling in specific cell lineages, we utilized a mouse in which the ROSA26 gene was modified to drive expression of pertussis toxin S1 subunit (PTX) after Cre-mediated excision of a floxed stop cassette. To study the effect of inhibition of Gi signaling in hematopoiesis, we crossed mice carrying one allele of the hematopoietic lineage-specific Cre transgene Vav-iCre with the ROSA26PTX/PTX mice. Half the offspring from this cross carry Vav-Cre Tg+/o: ROSA26PTX/+ (Vav-PTX mice), the other half transgene-negative ROSA26PTX/+ (controls). Vav-PTX mice were born at the expected Mendelian rate. Pups were grossly normal but consistenly displayed a smaller thymus. However, all Vav-PTX mice died between day 2 and 14, presumably from pneumococcal pneumonia. Neonatal Vav-PTX mice showed fewer hematopoietic cells in bone marrow, which was also observed in Vav-PTX embryos collected at E18.5. Thus, defective hematopoiesis was not secondary to postnatal infection or general failure to thrive. Competitive transplantation studies using fetal liver cells from Vav-PTX embryos or control embryos collected at E14.5 showed decreased short-term reconstitution (5weeks) and severely impaired long-term reconstitution (10 and 16 weeks) compared to control fetal liver cells. In contrast, fetal liver cells from CXCR4−/− embryos still showed partial reconstitution after 16 weeks. These data are consistent with defective homing of hematopoietic stem cells (HSCs) from fetal liver to bone marrow, but also with decreased proliferation, survival, and/or differentiation of HSCs once they reach their marrow niche. When fetal liver cells were grown in vitro, cells from Vav-PTX embryos showed decreased survival and proliferation when stimulated with cytokine promoting either B-cell, erythroid or granulocyte/macrophage lineages. This suggested a role for Gi signaling in proliferation in all hematopoietic lineages. In addition, early data suggest that the population of Lin−, c-kit+, Sca1+ cells in fetal liver from Vav-PTX embryos is decreased compared to their littermate controls. Our results suggest a key role for Gi and hence Gi-coupled GPCRs in several mechanisms required for normal hematopoiesis.

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The role of the PZP domain of AF10 in acute leukemia driven by AF10 translocations

Nature Communications ◽

10.1038/s41467-021-24418-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Brianna J. Klein ◽

Anagha Deshpande ◽

Khan L. Cox ◽

Fan Xuan ◽

Mohamad Zandian ◽

...

Keyword(s):

Critical Role ◽

Cellular Transformation ◽

Acute Leukemias ◽

Hematopoietic Stem ◽

Nucleosome Core ◽

Stem And Progenitor Cells ◽

Transforming Activity

AbstractChromosomal translocations of the AF10 (or MLLT10) gene are frequently found in acute leukemias. Here, we show that the PZP domain of AF10 (AF10PZP), which is consistently impaired or deleted in leukemogenic AF10 translocations, plays a critical role in blocking malignant transformation. Incorporation of functional AF10PZP into the leukemogenic CALM-AF10 fusion prevents the transforming activity of the fusion in bone marrow-derived hematopoietic stem and progenitor cells in vitro and in vivo and abrogates CALM-AF10-mediated leukemogenesis in vivo. Crystallographic, biochemical and mutagenesis studies reveal that AF10PZP binds to the nucleosome core particle through multivalent contacts with the histone H3 tail and DNA and associates with chromatin in cells, colocalizing with active methylation marks and discriminating against the repressive H3K27me3 mark. AF10PZP promotes nuclear localization of CALM-AF10 and is required for association with chromatin. Our data indicate that the disruption of AF10PZP function in the CALM-AF10 fusion directly leads to transformation, whereas the inclusion of AF10PZP downregulates Hoxa genes and reverses cellular transformation. Our findings highlight the molecular mechanism by which AF10 targets chromatin and suggest a model for the AF10PZP-dependent CALM-AF10-mediated leukemogenesis.

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Elevated Mcl-1 perturbs lymphopoiesis, promotes transformation of hematopoietic stem/progenitor cells, and enhances drug resistance

Blood ◽

10.1182/blood-2010-04-281071 ◽

2010 ◽

Vol 116 (17) ◽

pp. 3197-3207 ◽

Cited By ~ 80

Author(s):

Kirsteen J. Campbell ◽

Mary L. Bath ◽

Marian L. Turner ◽

Cassandra J. Vandenberg ◽

Philippe Bouillet ◽

...

Keyword(s):

Progenitor Cells ◽

Progenitor Cell ◽

Fetal Liver ◽

Cytotoxic Agents ◽

Hematopoietic Stem ◽

Stem And Progenitor Cells ◽

Fetal Liver Cells ◽

Follicular Lymphomas ◽

The Impact

Abstract Diverse human cancers with poor prognosis, including many lymphoid and myeloid malignancies, exhibit high levels of Mcl-1. To explore the impact of Mcl-1 overexpression on the hematopoietic compartment, we have generated vavP-Mcl-1 transgenic mice. Their lymphoid and myeloid cells displayed increased resistance to a variety of cytotoxic agents. Myelopoiesis was relatively normal, but lymphopoiesis was clearly perturbed, with excess mature B and T cells accumulating. Rather than the follicular lymphomas typical of vavP-BCL-2 mice, aging vavP-Mcl-1 mice were primarily susceptible to lymphomas having the phenotype of a stem/progenitor cell (11 of 30 tumors) or pre-B cell (12 of 30 tumors). Mcl-1 overexpression dramatically accelerated Myc-driven lymphomagenesis. Most vavP-Mcl-1/ Eμ-Myc mice died around birth, and transplantation of blood from bitransgenic E18 embryos into unirradiated mice resulted in stem/progenitor cell tumors. Furthermore, lethally irradiated mice transplanted with E13 fetal liver cells from Mcl-1/Myc bitransgenic mice uniformly died of stem/progenitor cell tumors. When treated in vivo with cyclophosphamide, tumors coexpressing Mcl-1 and Myc transgenes were significantly more resistant than conventional Eμ-Myc lymphomas. Collectively, these results demonstrate that Mcl-1 overexpression renders hematopoietic cells refractory to many cytotoxic insults, perturbs lymphopoiesis and promotes malignant transformation of hematopoietic stem and progenitor cells.

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A critical role of VLA-4 in erythropoiesis in vivo

Blood ◽

10.1182/blood.v87.6.2513.bloodjournal8762513 ◽

1996 ◽

Vol 87 (6) ◽

pp. 2513-2517 ◽

Cited By ~ 54

Author(s):

K Hamamura ◽

H Matsuda ◽

Y Takeuchi ◽

S Habu ◽

H Yagita ◽

...

Keyword(s):

Monoclonal Antibody ◽

Fetal Liver ◽

Critical Role ◽

In Utero ◽

In Vitro Studies ◽

Specific Interactions ◽

Erythroid Progenitors

Hematopoiesis requires specific interactions with the microenvironments, and VLA-4 has been implicated in these interactions based on in vitro studies. To study the role of VLA-4 in hematopoiesis in vivo, we performed in utero treatment of mice with an anti-VLA-4 monoclonal antibody. Although all hematopoietic cells in fetal liver expressed VLA-4, the treatment specifically induced anemia. It had no effect on the development of nonerythroid lineage cells, including lymphoids and myeloids. In the treated liver almost no erythroblast was detected, whereas the erythroid progenitors, which give rise to erythroid colonies in vitro, were present. These results indicate that VLA-4 plays a critical role in erythropoiesis, while it is not critical in lymphopoiesis in vivo.

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Expansion of mouse hematopoietic stem/progenitor cells in three-dimensional cocultures on growth-suppressed stromal cell layer

The International Journal of Artificial Organs ◽

10.1177/0391398819827596 ◽

2019 ◽

Vol 42 (7) ◽

pp. 374-379 ◽

Cited By ~ 1

Author(s):

Hirotoshi Miyoshi ◽

Chiaki Sato ◽

Yuichiro Shimizu ◽

Misa Morita

Keyword(s):

Progenitor Cells ◽

Mitomycin C ◽

Stromal Cells ◽

Fetal Liver ◽

Three Dimensional ◽

Hematopoietic Cells ◽

Liver Cells ◽

Hematopoietic Progenitor ◽

Hematopoietic Stem ◽

Fetal Liver Cells

With the aim of establishing an effective method to expand hematopoietic stem/progenitor cells for application in hematopoietic stem cell transplantation, we performed ex vivo expansion of hematopoietic stem/progenitor cells derived from mouse fetal liver cells in three-dimensional cocultures with stromal cells. In these cocultures, stromal cells were first cultured within three-dimensional scaffolds to form stromal layers and then fetal liver cells containing hematopoietic cells were seeded on these scaffolds to expand the hematopoietic cells over the 2 weeks of coculture in a serum-containing medium without the addition of cytokines. Prior to coculture, stromal cell growth was suppressed by treatment with the DNA synthesis inhibitor mitomycin C, and its effect on hematopoietic stem/progenitor cell expansion was compared with that in control cocultures in which fetal liver cells were cocultured with three-dimensional freeze-thawed stromal cells. After coculture with mitomycin C-treated stromal cells, we achieved a several-fold expansion of the primitive hematopoietic cells (c-kit+hematopoietic progenitor cells >7.8-fold, and CD34+hematopoietic stem/progenitor cells >3.5-fold). Compared with control cocultures, expansion of hematopoietic stem/progenitor cells tended to be lower, although that of hematopoietic progenitor cells was comparable. Thus, our results suggest that three-dimensional freeze-thawed stromal cells have higher potential to expand hematopoietic stem/progenitor cells compared with mitomycin C-treated stromal cells.

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Expansion of hematopoietic stem cells in the developing liver of a mouse embryo

Blood ◽

10.1182/blood.v95.7.2284 ◽

2000 ◽

Vol 95 (7) ◽

pp. 2284-2288 ◽

Cited By ~ 210

Author(s):

Hideo Ema ◽

Hiromitsu Nakauchi

Keyword(s):

Stem Cells ◽

Hematopoietic Stem Cells ◽

Mouse Embryo ◽

Bone Marrow Cells ◽

Fetal Liver ◽

Cell Number ◽

Liver Cells ◽

Single Wave ◽

Hematopoietic Stem ◽

Fetal Liver Cells

Abstract The activity of hematopoietic stem cells in the developing liver of a C57BL/6 mouse embryo was quantified by a competitive repopulation assay. Different doses of fetal liver cells at days 11 to 18 of gestation were transplanted into irradiated mice together with 2 × 105 adult bone marrow cells. A long-term repopulation in myeloid-, B-cell, and T-cell lineage by fetal liver cells was evaluated at 20 weeks after transplantation. At day 12 of gestation multilineage repopulating activity was first detected in the liver as 50 repopulating units (RU) per liver. The number of RU per liver increased 10-fold and 33-fold by day 14 and day 16 of gestation, and decreased thereafter, suggesting a single wave of stem cell development in the fetal liver. A limiting dilution analysis revealed that the frequency of competitive repopulating units (CRU) in fetal liver cells at day 12 of gestation was similar to that at day 16 of gestation. Because of an increase of total fetal liver cell number, the absolute number of CRU per liver from days 12 to 16 of gestation increased 38-fold. Hence, the mean activity of stem cells (MAS) that is given by RU per CRU remained constant from days 12 to 16 of gestation. From these data we conclude that hematopoietic stem cells expand in the fetal liver maintaining their level of repopulating potential.

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Constitutive TGF-β1 Deficiency Induces a Defect in Hematopoietic Stem/Progenitor Cell Compartment in Fetus and Neonate.

Blood ◽

10.1182/blood.v112.11.1397.1397 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1397-1397

Author(s):

Claude Capron ◽

Catherine Lacout ◽

Yann Lecluse ◽

Valérie Jalbert ◽

Elisabeth Cramer Bordé ◽

...

Keyword(s):

Fetal Liver ◽

Hematopoietic Cells ◽

Type I ◽

Activated T Cells ◽

Hematopoietic Stem ◽

Tgf Β1

Abstract TGF-β1 is a cytokine with pleiotropic effects. It has been considered that TGF-β1plays a major role on hematopoietic stem cells (HSC) based on in vitro experiment. Achieving in vivo experiments proved to be difficult because constitutive TGF-β1 knock-out (KO) in mice leads to lethality during the first 4 weeks of life from a wasting syndrome related to tissue infiltration by activated T cells and macrophages. For this reason, hematopoiesis of TGF-β1−/− mice has not been studied in details. In contrast the role of TGF-β1 has been recently extensively studied in conditional TGF-β type I receptor (TβRI) KO mice. No clear effect was observed on HSC functions, suggesting that TGF-β1 was not a key physiological regulator of hematopoiesis in the adult. However, these experiments have some limitations. They do not exclude a putative role for TGF-β1 during fetal hematopoiesis and they do not specifically address the role of TGF-β1 on hematopoiesis because KO of TGF-β receptor leads to signaling arrest for all TGF-βs. In addition, other receptors may be involved in TGF-β1 signaling. For these reasons, we have investigated the hematopoiesis of constitutive TGF-β1 KO mice with a mixed Sv129 × CF-1 genetic background allowing the birth of a high proportion of homozygotes. In 2 week-old neonate mice, we have shown a decrease of bone marrow (BM) and spleen progenitors and a decrease of immature progenitors colony forming unit of the spleen (CFU-s). Moreover this was associated with a loss in reconstitutive activity of TGF-β1−/− HSC from BM. However, although asymptomatic, these mice had an excess of activated lymphocytes and an augmentation of Sca-1 antigen on hematopoietic cells suggesting an excess of γ-interferon release. Thus we studied hematopoiesis of 7 to 10 days-old neonate mice, before phenotypic modification and inflammatory cytokine release. Similar results were observed with a decrease in the number of progenitors and in the proliferation of TGF-β1−/− BM cells along with an increased differentiation but without an augmentation in apoptosis. Moreoever, a loss of long term reconstitutive capacity of BM Lineage negative (Lin−) TGF-β1−/− cells along with a diminution of homing of TGF-β1−/− progenitors was found. These results demonstrate that TGF-β1 may play a major role on the HSC/Progenitor compartment in vivo and that this defect does not seem to be linked to the immune disease. To completely overpass the risk of the inflammatory syndrome, we analyzed hematopoiesis of fetal liver (FL) of TGF-β1−/− mice and still found a decrease in progenitors, a profound defect in the proliferative capacities, in long term reconstitutive activity and homing potential of primitive FL hematopoietic cells. Our results demonstrate that TGF-β1 plays an important role during hematopoietic embryonic development. Altogether these findings suggest that TGF-β1 is a potent positive regulator for the in vivo homeostasis of the HSC compartment.

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