NOD Hematopoietic Stem Cells Exhibit Autonomous Behavior and a Competitive Advantage in Allogeneic Recipients That Maps to the Idd9 Locus.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2676-2676
Author(s):  
Paula M. Chilton ◽  
Francine Rezzoug ◽  
Janina Ratajczak ◽  
Mariusz Ratajczak ◽  
Yiming Huang ◽  
...  
Keyword(s):  
Bone Marrow Cells ◽  
Type I Diabetes ◽  
Nod Mice ◽  
Cell Phenotype ◽  
Type I ◽  
Hematopoietic Stem ◽  
Autonomous Behavior ◽  
Insulin Dependent

Abstract Multiple hematopoietic defects have been defined in NOD mice and in humans with type I diabetes, including defects in myeloid cells and antigen presenting cells that correlate with diabetes progression. Since the replacement of HSC in NOD mice can eliminate the progression of autoimmunity and control on-going autoimmune responses, we characterized the function of HSC from NOD mice. We found that purified HSC from NOD mice have an autonomous behavior when transplanted in allogeneic recipient strains as reflected by significantly enhanced engraftment in allogeneic recipients. NOD HSC were able to compete for engraftment with syngeneic HSC even when the NOD and syngeneic HSC were given at a 1:1 ratio. NOD BMC produced a higher number of splenic colonies compared to B10.BR BMC in the allogeneic day 12 CFU-S assay. We also demonstrated that NOD HSC had a high resistance to irradiation, as reflected by the cell survival 20 hours after irradiation and in the in vitro CFC assay. These data suggest that NOD HSC escape alloreactivity and compete with normal HSC. The enhanced engraftment ability in allogeneic recipients of NOD HSC was not due to an increase in frequency of primitive HSC, enumerated by day 35 cobblestone area forming cells (CAFC). This finding was further confirmed by the fact that there was no difference in the long-term repopulating cell phenotype (CD49e+/CD49ddim) between HSC obtained from NOD, B10.BR or C57BL/10 mice. Notably, NOD bone marrow cells exhibit significantly enhanced chemotaxis to SDF-1 in vitro and significantly increased HSC adhesion to primary stroma. This was associated with an increase in the expression of VCAM-1, ICAM-1 and ICAM-2 on NOD HSC. Using NOD mice congenic at selected Idd loci with C57BL/10, we determined that the enhanced engraftment potential of NOD HSC mapped to the Idd9 (insulin-dependent diabetes) locus and, as such, the TNF receptor family as well as ski/sno genes may be involved in the mechanism underlying the autonomy of NOD HSC. In conclusion, NOD HSC exhibit increased autonomy in vivo and in vitro compared to non-diabetic strains, and engraft better in allogeneic recipients, possibly due to enhanced migration and adherence to the microenvironment. This finding may be of interest for a better understanding of disease pathogenesis and in developing cell-based strategies to cure diabetes.

Hepatogenic Potential of Stem Cells and Lymphoid Precursors.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1696-1696
Author(s):  
Yasuhiro Yamada ◽  
Hirosada Miyake ◽  
Eishi Nishimoto ◽  
Hiroaki Mitsuya ◽  
Yuji Yonemura
Keyword(s):  
Stem Cells ◽  
Bone Marrow Cells ◽  
Fetal Liver ◽  
Green Fluorescence Protein ◽  
Type I ◽  
Tyrosinaemia Type ◽  
Hematopoietic Stem ◽  
Titration Assay

Abstract Several research groups have recently reported that certain bone marrow cells (BMCs) differentiate into hepatocytes in vitro as well as in vivo in rodents through both transdifferentiation and cell fusion. Hematopoietic myelomonocytic cells are thought to be the major source of hepatocyte fusion partners in the tyrosinaemia type I mouce transplantation model. Transdifferentiation of murine BMCs can be induced with various cytokines and extracellular matrix. We previously reported that when Sca-1+ BMCs were co-cultured with fetal liver cells (FLCs) on laminin-coated dishes, alpha-fetoprotein (AFP)-expressing BMCs became completely adherent by day 4 and expressed albumin as assessed with immunochemistry and RNA-PCR (Yamada et al., Exp Hematol. in press). In the present study, we attempted to further delineate the characteristics of BMCs that differentiate into hepatic-like cells. It was found that AFP-expressing cells were in CD5+ or B220+ lymphoid lineage, mostly Sca-1+CD5+ lineage and that CD5+CD4−CD8− and CD5+CD4+CD8+ thymocytes expressed AFP. When cKit+Sca-1+ lineage BMCs (KSLs) which did not express AFP, CD5+ BMCs, and CD5+ thymocytes, all from green fluorescence protein (GFP)-expressing transgenic mice, were co-cultured with FLCs from ROSA26 mice (X-gal+ FLCs), fractionated cells gave rise to adherent hepatic-like cells, which expressed albumin and cytokeratin 8 (CK 8) as assessed with immunochemistry and AFP, albumin, transthyretin and dipeptidylpeptidase IV as examined with RNA-PCR. The hepatic-like cells from KSLs, CD5+ BMCs and CD5+ thymocytes emerged at the frequency of 1 in 50, 1x103 and 3.5x105 by titration assay. These data suggest that AFP-expressing cells in BMCs were derived from hematopoietic stem cells and that lymphoid precursors differentiated into hepatic-like cells and their hepatogenic ability could diminish over lymphoid maturation.

New approach for in vivo detection of insulitis in type I diabetes: activated lymphocyte targeting with 123I-labelled interleukin 2

1994 ◽  
Vol 131 (4) ◽  
pp. 431-437 ◽  
Author(s):  
Alberto Signore ◽  
Marco Chianelli ◽  
Elisabetta Ferretti ◽  
Anna Toscano ◽  
Keith E Britton ◽  
...  
Keyword(s):  
Gamma Camera ◽  
Type I Diabetes ◽  
Interleukin 2 ◽  
Nod Mice ◽  
Insulin Dependent Diabetes ◽  
Type I ◽  
New Approach ◽  
In Vivo Detection ◽  
Insulin Dependent

Signore A, Chianelli M, Ferretti E, Toscano A, Britton KE, Andreani D, Gale EAM, Pozzilli P. New approach for in vivo detection of insulitis in type I diabetes: activated lymphocyte targeting with 123I-labelled interleukin 2. Eur J Endocrinol 1994;131:431–7. ISSN 0804–4643 Insulitis is considered the histopathological hallmark of type I (insulin-dependent) diabetes. In the nonobese diabetic (NOD) mouse, diabetes has never been observed in the absence of insulitis. The in vivo detection of insulitis could be of relevance for early prediction of diabetes. As approximately 15% of islet-infiltrating lymphocytes express interleukin 2 receptors, we have labelled recombinant interleukin 2 with 123I and used this radiopharmaceutical to detect insulitis by gamma camera imaging. We studied 71 prediabetic NOD and 27 normal Balb/c mice. Labelled α-lactalbumin was used as the control protein. In the first set of experiments we studied the tissue distribution of radiolabelled interleukin 2 in isolated organs from animals sacrificed at different time points. Higher radioactivity was detected in the pancreas of NOD mice injected with labelled interleukin 2, as compared to NOD mice receiving labelled α-lactalbumin (p < 0.003 at 20 min; p< 0.001 at 40 min; p< 0.0001 at 60 min) or Balb/c mice injected with labelled interleukin 2 (p< 0.05 at 40 min; p< 0.001 at 60 min). In another set of experiments, gamma camera images have been acquired after injection of 123I-labelled interleukin 2. Radioactivity in the pancreatic region of prediabetic NOD and Balb/c mice showed similar kinetics to those observed by single organ counting, with higher accumulation in the pancreatic region of NOD mice (p < 0.04 after 22–45 min in NOD mice vs Balb/c mice). Finally, a positive correlation was found between the radioactivity in the pancreas and the extent of lymphocytic infiltration (p < 0.01 for pancreas radioactivity counted in vitro and p< 0.004 for pancreas radioactivity counted in vivo by gamma camera). This study demonstrates that 123I-labelled interleukin 2 administered iv accumulates specifically in the inflamed pancreas of diabetes-prone NOD mice, suggesting its potential application in human insulin-dependent diabetes mellitus. A Signore, Servizio Speciale di Medicina Nucleare, II Clinica Medica, Policlinico Umberto I, 00161 Roma, Italy

Interleukin-3 supports expansion of long-term multilineage repopulating activity after multiple stem cell divisions in vitro

Blood ◽  
2000 ◽  
Vol 96 (5) ◽  
pp. 1748-1755 ◽  
Author(s):  
David Bryder ◽  
Sten E. W. Jacobsen
Keyword(s):  
Bone Marrow Cells ◽  
Ex Vivo ◽  
Calf Serum ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Cell Divisions ◽  
Stem Cell Divisions

Abstract Although long-term repopulating hematopoietic stem cells (HSC) can self-renew and expand extensively in vivo, most efforts at expanding HSC in vitro have proved unsuccessful and have frequently resulted in compromised rather than improved HSC grafts. This has triggered the search for the optimal combination of cytokines for HSC expansion. Through such studies, c-kit ligand (KL), flt3 ligand (FL), thrombopoietin, and IL-11 have emerged as likely positive regulators of HSC self-renewal. In contrast, numerous studies have implicated a unique and potent negative regulatory role of IL-3, suggesting perhaps distinct regulation of HSC fate by different cytokines. However, the interpretations of these findings are complicated by the fact that different cytokines might target distinct subpopulations within the HSC compartment and by the lack of evidence for HSC undergoing self-renewal. Here, in the presence of KL+FL+megakaryocyte growth and development factor (MGDF), which recruits virtually all Lin−Sca-1+kit+ bone marrow cells into proliferation and promotes their self-renewal under serum-free conditions, IL-3 and IL-11 revealed an indistinguishable ability to further enhance proliferation. Surprisingly, and similar to IL-11, IL-3 supported KL+FL+MGDF-induced expansion of multilineage, long-term reconstituting activity in primary and secondary recipients. Furthermore, high-resolution cell division tracking demonstrated that all HSC underwent a minimum of 5 cell divisions, suggesting that long-term repopulating HSC are not compromised by IL-3 stimulation after multiple cell divisions. In striking contrast, the ex vivo expansion of murine HSC in fetal calf serum-containing medium resulted in extensive loss of reconstituting activity, an effect further facilitated by the presence of IL-3.

Involvement of the Integrin Alpha 6 Receptor in the Homing and Engraftment of Hematopoietic Stem and Progenitor Cells to Bone Marrow.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1293-1293
Author(s):  
Hong Qian ◽  
Sten Eirik W. Jacobsen ◽  
Marja Ekblom
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Progenitor Cells ◽  
Progenitor Cell ◽  
Bone Marrow Cells ◽  
Hematopoietic Stem ◽  
Stem And Progenitor Cells ◽  
Functional Blocking

Abstract Within the bone marrow environment, adhesive interactions between stromal cells and extracellular matrix molecules are required for stem and progenitor cell survival, proliferation and differentiation as well as their transmigration between bone marrow (BM) and the circulation. This regulation is mediated by cell surface adhesion receptors. In experimental mouse stem cell transplantation models, several classes of cell adhesion receptors have been shown to be involved in the homing and engraftment of stem and progenitor cells in BM. We have previously found that integrin a6 mediates human hematopoietic stem and progenitor cell adhesion to and migration on its specific ligands, laminin-8 and laminin-10/11 in vitro (Gu et al, Blood, 2003; 101:877). Using FACS analysis, the integrin a6 chain was now found to be ubiquitously (>95%) expressed in mouse hematopoietic stem and progenitor cells (lin−Sca-1+c-Kit+, lin−Sca-1+c-Kit+CD34+) both in adult bone marrow and in fetal liver. In vitro, about 70% of mouse BM lin−Sca-1+c-Kit+ cells adhered to laminin-10/11 and 40% adhered to laminin-8. This adhesion was mediated by integrin a6b1 receptor, as shown by functional blocking monoclonal antibodies. We also used a functional blocking monoclonal antibody (GoH3) against integrin a6 to analyse the role of the integrin a6 receptor for the in vivo homing of hematopoietic stem and progenitor cells. We found that the integrin a6 antibody inhibited the homing of bone marrow progenitors (CFU-C) into BM of lethally irradiated recipients. The number of homed CFU-C was reduced by about 40% as compared to cells incubated with an isotype matched control antibody. To study homing of long-term repopulating stem cells (LTR), antibody treated bone marrow cells were first injected intravenously into lethally irradiated primary recipients. After three hours, bone marrow cells of the primary recipients were analysed by competitive repopulation assay in secondary recipients. Blood analysis 16 weeks after transplantation revealed an 80% reduction of stem cell activity of integrin a6 antibody treated cells as compared to cells treated with control antibody. These results suggest that integrin a6 plays an important role for hematopoietic stem and progenitor cell homing in vivo.

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

Blood ◽  
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.

Interleukin-3 supports expansion of long-term multilineage repopulating activity after multiple stem cell divisions in vitro

Blood ◽  
2000 ◽  
Vol 96 (5) ◽  
pp. 1748-1755 ◽  
Author(s):  
David Bryder ◽  
Sten E. W. Jacobsen
Keyword(s):  
Bone Marrow Cells ◽  
Ex Vivo ◽  
Calf Serum ◽  
Self Renewal ◽  
Hematopoietic Stem ◽  
Cell Divisions ◽  
Stem Cell Divisions

Although long-term repopulating hematopoietic stem cells (HSC) can self-renew and expand extensively in vivo, most efforts at expanding HSC in vitro have proved unsuccessful and have frequently resulted in compromised rather than improved HSC grafts. This has triggered the search for the optimal combination of cytokines for HSC expansion. Through such studies, c-kit ligand (KL), flt3 ligand (FL), thrombopoietin, and IL-11 have emerged as likely positive regulators of HSC self-renewal. In contrast, numerous studies have implicated a unique and potent negative regulatory role of IL-3, suggesting perhaps distinct regulation of HSC fate by different cytokines. However, the interpretations of these findings are complicated by the fact that different cytokines might target distinct subpopulations within the HSC compartment and by the lack of evidence for HSC undergoing self-renewal. Here, in the presence of KL+FL+megakaryocyte growth and development factor (MGDF), which recruits virtually all Lin−Sca-1+kit+ bone marrow cells into proliferation and promotes their self-renewal under serum-free conditions, IL-3 and IL-11 revealed an indistinguishable ability to further enhance proliferation. Surprisingly, and similar to IL-11, IL-3 supported KL+FL+MGDF-induced expansion of multilineage, long-term reconstituting activity in primary and secondary recipients. Furthermore, high-resolution cell division tracking demonstrated that all HSC underwent a minimum of 5 cell divisions, suggesting that long-term repopulating HSC are not compromised by IL-3 stimulation after multiple cell divisions. In striking contrast, the ex vivo expansion of murine HSC in fetal calf serum-containing medium resulted in extensive loss of reconstituting activity, an effect further facilitated by the presence of IL-3.

scholarly journals HIF-1α is a negative regulator of plasmacytoid DC development in vitro and in vivo

Blood ◽  
2012 ◽  
Vol 120 (15) ◽  
pp. 3001-3006 ◽  
Author(s):  
Andreas Weigert ◽  
Benjamin Weichand ◽  
Divya Sekar ◽  
Weixiao Sha ◽  
Christina Hahn ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Function ◽  
Bone Marrow Cells ◽  
Negative Regulator ◽  
Low Oxygen ◽  
Hematopoietic Stem ◽  
Lineage Differentiation ◽  
Marrow Cells

Abstract Hypoxia-inducible factors (HIFs) regulate hematopoiesis in the embryo and maintain hematopoietic stem cell function in the adult. How hypoxia and HIFs contribute to hematopoietic lineage differentiation in the adult is ill defined. Here we provide evidence that HIF-1 limits differentiation of precursors into plasmacytoid dendritic cells (pDCs). Low oxygen up-regulated inhibitor of DNA binding 2 (ID2) and suppressed Flt3-L–induced differentiation of bone marrow cells to pDCs in wild-type but not HIF-1αfl/fl LysM-Cre bone marrow cells. Moreover, pDC differentiated normally in hypoxic ID2−/− bone marrow cultures. Finally, we observed elevated pDC frequencies in bone marrow, blood, and spleen of HIF-1αfl/fl LysM-Cre and ID2−/−, but not HIF-2αfl/fl LysM-Cre mice. Our data indicate that the low oxygen content in the bone marrow might limit pDC development. This might be an environmental mechanism to restrict the numbers of these potentially autoreactive cells.

Type I interferons produced by dendritic cells promote their phenotypic and functional activation

Blood ◽  
2002 ◽  
Vol 99 (9) ◽  
pp. 3263-3271 ◽  
Author(s):  
Maria Montoya ◽  
Giovanna Schiavoni ◽  
Fabrizio Mattei ◽  
Ion Gresser ◽  
Filippo Belardelli ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dendritic Cells ◽  
T Cell ◽  
Bone Marrow Cells ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Type I Ifns

Abstract Resting dendritic cells (DCs) are resident in most tissues and can be activated by environmental stimuli to mature into potent antigen-presenting cells. One important stimulus for DC activation is infection; DCs can be triggered through receptors that recognize microbial components directly or by contact with infection-induced cytokines. We show here that murine DCs undergo phenotypic maturation upon exposure to type I interferons (type I IFNs) in vivo or in vitro. Moreover, DCs either derived from bone marrow cells in vitro or isolated from the spleens of normal animals express IFN-α and IFN-β, suggesting that type I IFNs can act in an autocrine manner to activate DCs. Consistent with this idea, the ability to respond to type I IFN was required for the generation of fully activated DCs from bone marrow precursors, as DCs derived from the bone marrow of mice lacking a functional receptor for type I IFN had reduced expression of costimulatory and adhesion molecules and a diminished ability to stimulate naive T-cell proliferation compared with DCs derived from control bone marrow. Furthermore, the addition of neutralizing anti–IFN-α/β antibody to purified splenic DCs in vitro partially blocked the “spontaneous” activation of these cells, inhibiting the up-regulation of costimulatory molecules, secretion of IFN-γ, and T-cell stimulatory activity. These results show that DCs both secrete and respond to type I IFN, identifying type I interferons as autocrine DC activators.

scholarly journals The Repertoire of Newly Developing Regulatory T Cells in the Type I Diabetes-Prone NOD Mouse is Very Diverse

2021 ◽  
Author(s):  
Ariel Galindo-Albarrán ◽  
Sarah Castan ◽  
Jérémy C. Santamaria ◽  
Olivier P. Joffre ◽  
Bart Haegeman ◽  
...  
Keyword(s):  
Type I Diabetes ◽  
Nod Mice ◽  
Vital Role ◽  
Nod Mouse ◽  
Type I ◽  
Antigen Specificity ◽  
Regulatory T Lymphocytes ◽  
Winged Helix Transcription Factor ◽  
Complementarity Determining Region

Regulatory T lymphocytes expressing the forkhead/winged helix transcription factor Foxp3 (Treg) play a vital role in the protection of the organism from autoimmune disease and other immunopathologies. The antigen-specificity of Treg plays an important role in their <i>in vivo</i> activity. We therefore assessed the diversity of the T cell receptors for antigen (TCR) expressed by Treg newly developed in the thymus of autoimmune type I diabetes-prone NOD mice and compared it to the control mouse strain C57BL/6. Our results demonstrate that usage of the TCRa and TCRb variable (V) and joining (J) segments, length of the complementarity determining region (CDR) 3, and the diversity of the TCRa and TCRb chains are comparable between NOD and C57BL/6 mice. Genetic defects affecting the diversity of the TCR expressed by newly developed Treg therefore do not appear to be involved in the etiology of type I diabetes in the NOD mouse.

scholarly journals Human fetal bone marrow early progenitors for T, B, and myeloid cells are found exclusively in the population expressing high levels of CD34

Blood ◽  
1994 ◽  
Vol 84 (2) ◽  
pp. 421-432 ◽  
Author(s):  
D DiGiusto ◽  
S Chen ◽  
J Combs ◽  
S Webb ◽  
R Namikawa ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Bone Marrow Cells ◽  
Cell Activity ◽  
Hematopoietic Stem ◽  
Fetal Bone ◽  
Cd34 Antigen

Experimentation on human stem cells is hampered by the relative paucity of this population and by the lack of assays identifying multilineage differentiation, particularly along the lymphoid lineages. In our current study, phenotypic analysis of low-density fetal bone marrow cells showed two distinct populations of CD34+ cells: those expressing a high density of CD34 antigen on their surface (CD34hi) and those expressing an intermediate level of CD34 antigen (CD34lo). Multiple tissues were used to characterize the in vitro and in vivo potential of these subsets and showed that only CD34hi cells support long-term B lymphopoiesis and myelopoiesis in vitro and mediate T, B, and myeloid repopulation of human tissues implanted into SCID mice. CD34lo cells repeatedly failed to provide long-term hematopoietic activity in vivo or in vitro. These results indicate that a simple fractionation based on well-defined CD34 antigen levels can be used to reproducibly isolate cells highly enriched for in vivo long-term repopulating activity and for multipotent progenitors, including T- and B-cell precursors. Additionally, given the limited variability in the results and the high correlation between in vitro and in vivo hematopoietic potential, we propose that the CD34hi population contains virtually all of the stem cell activity in fetal bone marrow and therefore is the population of choice for future studies in hematopoietic stem cell development and gene therapy.

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