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HEMATOPOIESIS
From the Departments of Pathology and Developmental Biology,
Stanford University School of Medicine, CA; and the Department of
Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA.
Hematopoietic fate maps in the developing mouse embryo remain
imprecise. Definitive, adult-type hematopoiesis first appears in the
fetal liver, then progresses to the spleen and bone marrow. Clonogenic
common lymphoid progenitors and clonogenic common myeloid progenitors
(CMPs) in adult mouse bone marrow that give rise to all lymphoid and
myeloid lineages, respectively, have recently been identified. Here it
is shown that myelopoiesis in the fetal liver similarly proceeds
through a CMP equivalent. Fetal liver CMPs give rise to
megakaryocyte-erythrocyte-restricted progenitors (MEPs) and
granulocyte-monocyte-restricted progenitors (GMPs) that can also be
prospectively isolated by cell surface phenotype. MEPs and GMPs
generate mutually exclusive cell types in clonogenic colony assays and
in transplantation experiments, suggesting that the lineage restriction
observed within each progenitor subset is absolute under normal
conditions. Purified progenitor populations were used to analyze
expression profiles of various hematopoiesis-related genes. Expression
patterns closely matched those of the adult counterpart populations.
These results suggest that adult hematopoietic hierarchies are
determined early in the development of the definitive immune system and
suggest that the molecular mechanisms underlying cell fate decisions
within the myeloerythroid lineages are conserved from embryo to adult.
(Blood. 2001;98:627-635) The genesis of the mammalian immune system has best
been studied in the mouse, where hematopoiesis occurs through a
stepwise process that begins in the yolk sac (YS) on embryonic day 7 (E7).1 Only primitive erythropoiesis is evident in this
organ, which is characterized by the production of erythrocytes with
unextruded nuclei and expression of embryonic globin
genes.2 Hematopoiesis then appears in the
aorta-gonad-mesonephros (AGM) region of the para-aortic splanchnopleura
in the developing mouse embryo from E8 to E10, after which the fetal
liver (FL) becomes the major site of embryonic blood production from
approximately E12 to birth.2 Although culture and
transplantation experiments have shown that both the YS1,3
and AGM4,5 regions contain multipotent hematopoietic stem
cells (HSCs), definitive, multi-lineage hematopoiesis does not occur
until the FL becomes the predominant hematopoietic organ.2
This suggests that environmental cues may restrict and specify the cell
fate determinations of HSCs. Cellular transplants of identical
hematopoietic progenitors clearly show that differing environments can
lead to different cell fates,1,3,6 suggesting that local
niches specify lineage determination. Alternatively, hematopoietic
precursors may be genetically distinct among the shifting sites of
hematopoiesis in the developing immune system.
HSCs capable of long-term, multilineage reconstitution are
prospectively isolatable from murine FL using cell surface marker profiles roughly equivalent to those of adult HSCs.7
FL-HSCs, however, show several phenotypic and functional differences
when compared to their adult counterparts. Phenotypically, FL-HSCs express AA4.18 and Mac-17 cell surface
proteins, whereas adult HSCs do not. Functionally, FL-HSCs show much
higher rates of proliferation and more rapid and robust reconstitution
ability than adult HSCs.9-12 FL-HSCs also have differing
cell fate potentials than adult HSCs. For example, early FL-HSCs give
rise to V Adult hematopoiesis takes place in bone marrow (BM) and occurs through
a hierarchy of defined, lineage-restricted progenitors that are
isolatable by cell surface phenotype. Common lymphoid progenitors
(CLPs) are clonogenic precursors of T lymphocytes, B lymphocytes, and
natural killer cells,15 whereas common myeloid progenitors
(CMPs) give rise to all myeloerythroid lineages.16 CMPs
are clonogenic precursors of megakaryocyte-erythrocyte-restricted progenitors (MEPs) and granulocyte-monocyte-restricted progenitors (GMPs) that respectively generate either platelets and red blood cells
or granulocytes and monocytes.16 Taken together, these populations appear to represent the major pathways of blood cell development in adult BM.
In this study, we sought to determine whether the hematopoietic
hierarchies of adult hematopoiesis are present in the first site of
definitive hematopoiesis. We therefore searched for counterparts of
adult CMPs, MEPs, and GMPs in the developing FL. We show, through the
use of multiparameter flow cytometry and clonal assessment of
progenitor potentials, that the lineage relationships of the adult
hematopoietic system are determined early in development. Prospectively
isolated CMP, MEP, and GMP counterparts from FL show transcriptional
profiles nearly identical to their adult homologues, suggesting that
the molecular foundations of adult lineal hierarchies are established
after the development of the definitive immune system. We also report
that, despite the general similarities between FL and BM fate maps,
significant differences in proliferative capacity, colony-forming
activity, and differentiation fidelity exist between progenitors in
these 2 locations. These findings highlight the importance of
prospective identification of progenitor populations for a more
precise understanding of their biology.
Mouse strains
Cell staining and sorting
Fetal liver HSCs were stained as sorted as described.7 All cell populations were sorted or analyzed using a highly modified triple laser (488-nm argon laser, 599-nm dye laser, and UV laser) FACS Vantage (Becton Dickinson Immunocytometry Systems, Mountain View, CA). Progenitors were purified by sorting and re-sorting to obtain precise numbers of cells that were essentially pure for the indicated surface marker phenotype. In limiting-dilution assays and single-cell clonogenic assays, the re-sort was performed by using a carefully calibrated automatic cell deposition unit system (Becton Dickinson). This system deposited a specific number of purified cells onto either methylcellulose medium or OP9 stromal cell cultures in 96-well or 24-well plates, respectively, as previously described.16 In vivo and in vitro assays to determine differentiation potential of progenitors For reconstitution assays, purified progenitors were injected into the retro-orbital venous sinus of either lethally irradiated (9.5 Gy delivered in a split dose) or sublethally irradiated (4.75 Gy single dose) congenic mice (differing only at the CD45 allele). Host-type whole BM cells (2-5 × 105) were co-injected into lethally irradiated recipients for radioprotection. Intrathymic injections were performed by directly injecting cells into thymi of mice that had been irradiated (6 Gy) as described previously.15,17 CFU-S assays were performed with 100 to 500 double-sorted progenitors per mouse as previously described.18To support the formation of myeloid colonies, progenitors were cultured in Methocult M3434 or H4100 methylcellulose media (Stemcell Technologies, Vancouver, BC, Canada) supplemented with 20% fetal bovine serum (FBS), 1% bovine serum albumin, 2 mM L-glutamine, 50 µM 2-mercaptoethanol, and 10% FL-conditioned medium. Cytokines such as mouse SLF (20 ng/mL; R&D Systems), mouse IL-3 (30 ng/mL; Genzyme, Cambridge, MA), mouse IL-11 (10 ng/mL; R&D Systems), mouse GM-CSF (10 ng/mL; R&D Systems), mouse TPO (10 ng/mL; R&D Systems), mouse Flt-3 ligand (10 ng/mL; R&D Systems), and human erythropoietin (1 U/mL; R&D Systems) were added at the start of the culture. Colonies were enumerated under an inverted microscope consecutively from day 5 to day 12. CFU-mix such as CFU-GEMMeg, CFU-GEM, and CFU-GEMeg was determined by Giemsa staining of cells plucked as individual colonies using fine-drawn Pasteur pipettes. To evaluate the B-cell differentiation potential of FL CMPs in vitro by limiting-dilution analysis, specific numbers of cells were sorted onto irradiated (30 Gy) OP9 stromal cell layers19 in 24-well plates with Iscove modified Dulbecco medium (IMDM) containing 10% FBS (Gemini Bioproducts, Woodland, CA), mouse SLF (10 ng/mL), and mouse IL-7 (10 ng/mL; R&D Systems). Similarly, to test the lineage relationships of each myeloid progenitor subset, 1000 cells from each population were sorted in triplicate onto irradiated OP9 stromal layers in 6-well plates containing IMDM supplemented with 10% FBS, mouse SLF (10 ng/mL), mouse IL-11 (10 ng/mL), and mouse TPO (10 ng/mL). Nonadherent cells were recovered 48 hours later, stained as described above, and sorted into methylcellulose cultures as described above. All cultures were incubated at 37°C in a humidified chamber under 7% CO2. Evaluation of transcription factor expression Total RNA was purified from 1000 double-sorted cells from each population and was amplified by reverse transcription-polymerase chain reaction (RT-PCR) as previously reported.16 Primer sequences, conditions for amplification, and the expected lengths of products are shown in Table 1. Quantitation of expression of each gene was performed by a relative determination, comparing the level of any subject sequence in target samples to that in control cDNA prepared from 2 × 105 whole fetal liver cells or thymocytes, using the Integrated Image analysis system (Bio-Rad Laboratories, Hercules, CA).
Prospective isolation of fetal liver myeloerythroid progenitors We have previously reported that the IL-7R +
fraction of adult mouse BM does not contain myeloid
progenitors,15 and we have recently determined that the
IL-7R+ fraction of E14 FL largely lacks myeloid
potential.74 In initial studies, we could detect no
colony-forming activity within 1000 cells plated from the lineage
(Lin)+ fraction of whole FL (not shown). Figure
1A shows the Sca-1/c-Kit expression
profile of the Lin IL-7R fraction of
E14.5 FL. Similar to the Lin+ fraction, we could detect no
colony-forming activity from cultures containing up to 10 000
LinIL-7Rc-Kit cells (not
shown). When the
LinIL-7Rc-Kit+ fraction
of whole FL was assayed, however, robust myeloerythroid colony-forming
activity was observed. We estimate that approximately 99% of
myeloerythroid colony-forming cells can be found within the
LinIL-7Rc-Kit+ fraction when
cultured in methylcellulose containing steel factor (SLF), flt-3 ligand
(FL), interleukin (IL)-3, IL-11, granulocyte-macrophage colony-stimulating factor (GM-CSF), thrombopoietin (TPO), and erythropoietin (EPO). We therefore focused our search for primitive myeloid progenitors within the
LinIL-7Rc-Kit+ fraction. The
LinIL-7Rc-Kit+ fraction can
be divided into Sca-1+ and Sca-1 subsets,
each comprising roughly 0.2% to 0.4% and 4% to 6% of E14.5 FL
cells, respectively. The
Linc-Kit+Sca-1+
(Thy-1.1lo) population has been shown to be highly enriched
for HSCs in both BM20-22 and FL.7,8
AA4.1 is another important marker of FL HSCs8 and can
similarly be used to further enrich the Linc-Kit+Sca-1+ fraction for HSC
activity. Cells within the
LinIL-7R c-Kit+Sca-1
fraction did not express Thy1.1 or AA4.1 at levels above background staining (not shown). To prevent HSCs from confounding our search for
lineage-committed progenitors, we added Thy1.1 and AA4.1 to the lineage
cocktail to visualize and remove antigen-positive cells by flow
cytometry. The
LinIL-7Rc-Kit+Sca-1AA4.1
fraction was subsequently divided into 3 subpopulations according to
the expression profiles of the Fc receptor II/III (FcR), an
important marker of myelomonocytic cells and a progenitor marker in
fetal liver hematopoiesis,23 and CD34, previously shown to mark hematopoietic progenitors.24-26 The FACS profiles of
these FcRloCD34+,
FcRloCD34, and
FcRhiCD34+ subpopulations is shown in Figure
1A. Each of these populations was distinct and could be sorted to
purity (Figure 1B-C). FL HSCs (LinIL-7Rc-Kit+Sca-1+AA4.1+)
were FcRlo and were approximately 90% CD34+
(not shown).
In vitro characterization of FL progenitors We evaluated the myeloid colony-forming activity for each of the above populations in methylcellulose. Results are shown in Figures 2 and 3. In the presence of SLF, FL, IL-3, IL-6, IL-11, EPO, and TPO, more than 90% of sorted single FcRloCD34+ cells gave
rise to various types of myeloid colonies including CFU-Mix, CFU-MegE,
BFU-E, CFU-Meg, CFU-GM, CFU-G, and CFU-M (Figures 2, 3). The
distribution of colony types arising from single
FcRloCD34+ cells is shown in Figure 3, where
colonies of all myeloerythroid lineages were found. In contrast,
approximately 90% of single FcRhiCD34+
cells formed colonies composed only of macrophages or granulocytes, such as CFU-M, CFU-G, or CFU-GM, in response to any of the growth factor combinations. Megakaryocyte-erythroid (MegE) cells were not
found in day 7 or day 10 colonies formed from 200 sorted
FcRhiCD34+ cells (data not shown). As with
adult MEPs,16 FL FcRloCD34
cells gave rise exclusively to CFU-Meg, CFU-E, or CFU-MegE colonies that contained only megakaryocytes or erythrocytes in response to the
above growth factors, but they did not form colonies in the absence of
TPO and EPO (not shown). GM cells were similarly not found in day 7 or
day 10 colonies formed from 200 sorted
FcRloCD34cells (not shown). Thus, the
FcRhiCD34+ and
FcRloCD34 progenitors are entirely
restricted to GM and MegE lineages and are termed FL GMPs and FL MEPs,
respectively.
Fc RloCD34+ cells gave rise to
FcRloCD34 cells and
FcRhiCD34+ cells (Figure 3 B-D). When
FcRloCD34 cells and
FcRhiCD34+ cells derived from cultured
FcRloCD34+ cells were resorted into
methylcellulose, they formed colonies consisting only of MegE or GM,
respectively (not shown). In contrast, neither
FcRloCD34 MEPs nor
FcRhiCD34+ GMPs gave rise to the other 2 progenitor subtypes; progeny from these populations appeared to rapidly
lose c-Kit expression and differentiated into mature cell types (not
shown). Thus, FcRloCD34+ cells generate both
FcRloCD34 MEP and
FcRhiCD34+ GMP daughter cells that are
respectively committed to either the MegE or GM lineages.
Based on these data, we term FcRloCD34+
cells FL CMPs.
In vivo differentiation potential of FL progenitor populations We next tested the in vivo differentiation potential of these 3 progenitor populations. All 3 progenitor populations rapidly differentiated into mature cells in vivo, and their outcomes corresponded with those of vitro colony assays. Six days after the injection of 10 000 FL CMPs into lethally irradiated recipient mice, both Gr-1+/Mac-1+ myelomonocytic cells and TER119+ erythroid cells were detectable in spleen and BM (not shown). In contrast, 10 000 FcRloCD34 MEPs transiently reconstituted
only TER119+ cells (not shown). Conversely,
FcRhiCD34+ GMP cells transiently gave rise
only to Mac-1+ cells (not shown). In vivo demonstration of
lineage restrictions identical to those observed in vitro suggested
that the culture conditions described above were fully permissive for
the generation of all myeloerythroid cell fates. Interestingly, though
FL CMPs showed robust colony formation in vitro and generated large
numbers of myeloerythroid progeny in vivo, FL MEPs and FL GMPs showed very small burst sizes (Figure 2A-C) when compared to their adult BM
equivalents.16 This may partially explain our finding that none of the FL myeloid progenitor populations had significant day 8 spleen colony-forming unit (CFU-S) activity (Table
2). Although most day 8 CFU-S potential
within adult BM was found in MEPs, FL MEPs displayed no detectable
activity. Similarly, adult CMPs had some day 8 CFU-S activity, whereas
FL CMPs showed no detectable colony formation. It is important to note
that FL HSCs were the only population tested that had day 8 CFU-S
activity and formed colonies with high efficiency (Table 2). BM HSCs, however, did not show significant day 8 activity, as previously reported.22 Potential reasons for these differences
between FL and BM are discussed below.
To evaluate self-renewal potential and proliferative capacity, we co-injected 200 HSCs (C57Bl6-CD45.2) with 10 000 cells of each FL myeloid progenitor population (C57Bl6-CD45.1) into lethally irradiated C57Bl6-CD45.2 hosts. In this competitive reconstitution assay, the progeny from either FL MEPs or FL GMPs cells were undetectable after 2 weeks (not shown). Myeloid progeny from FL CMPs were detectable at 2 weeks after injection but disappeared after 3 weeks (not shown). This indicates that in the context of transplantation, these populations have limited or no self-renewal capacity. Myeloid progenitor populations largely lack lymphoid differentiation potential We did not detect B-cell or T-cell progeny from either 20 000 FL MEPs or FL GMPs in the competitive reconstitution assays described above nor after intrathymic injections into sublethally irradiated congenic mice (not shown). Differentiation potentials of both FL GMPs and FL MEPs are thus entirely restricted to the myeloid lineages. FL CMPs did not generate T cells in either assay. B-cell progeny, however, were found in recipient spleens beginning at 14 days after transplantation (Figure 4A). To gauge the B-cell differentiation potential of FL CMPs, we performed limiting-dilution analysis on OP9 stromal layers supplemented with IL-7 as described.15 In this assay, 1 in 160 cells gave rise to B cells (Figure 4B). We have previously reported that the limiting-dilution frequency of B cells from adult CMPs was 1 in 2780.16 Thus, the FL CMP has significant B- but not T-lymphocyte differentiation potential, highlighting the close link between B cells and the myeloid lineage that has previously been described.27-29 Although FL CMPs can form significant numbers of B cells, the FL equivalent of the adult CLP has a limiting-dilution B-cell readout of 1 in 7 cells.74 Thus, the vast majority of the FL CMP population has myeloid-restricted differentiation potential.
Transcriptional profiles of fetal hematopoietic progenitors Because FL progenitor populations showed nearly identical lineage outcomes compared to their adult counterparts, we evaluated the expression of lineage-associated transcription factors in FL HSCs, the 3 subsets of myeloid progenitors, and the recently isolated FL counterpart of the CLP. Results are shown in Figure 5. Among the panel of genes tested, GATA-230 and c-mpl31 were expressed in FL HSCs, FL CMPs, and FL MEPs, but not in FL GMP or FL CLP counterparts. Other MegE-related genes, such as NF-E2,32 GATA-1,33-35 and the EPO receptor,36 were expressed in FL CMPs and FL MEPs but not in FL GMPs, and their expression levels were highest in FL MEPs. In contrast, the expression of C/EBP, previously suggested to
be a master regulatory gene in myelomonocytic cell development,37,38 was found in FL HSCs, FL CMPs, and FL
GMPs but not in FL MEPs, and its expression level was highest in FL GMPs. All these genes were expressed in FL CMPs but not in FL CLP
counterparts, suggesting potential roles for each in myeloid-specific cell fate decisions (Figure
6).
It has been reported that c-myb and PU.1 play important roles in the differentiation of myeloid/T cell39-41 and myeloid/B cell42-44 lineages, respectively. Both c-myb and PU.1 were expressed in HSCs, CLP counterparts, and all myeloid progenitors (not shown). The lymphoid-related transcription factor Aiolos45 was expressed at high levels in CLP counterparts but not in any other progenitor tested. GATA-3 has been reported to be expressed mainly in T cells.46 The expression of GATA-3 gradually increased from HSC to CLP counterparts but was not seen in any of the myeloid progenitor populations. These data indicate that transcription factor expression is differentially regulated in these purified progenitor populations, and they are in agreement with the lineages affected in knock-out studies.47
Definitive hematopoiesis in the FL has been suggested to differ significantly from adult hematopoiesis from the level of HSCs to committed progenitors.1,2,7,8,12,48 Here we sought to determine whether the lineage relationships we identified recently in adult murine BM15,16 are established early after the shift from primitive to definitive hematopoiesis during the development of the immune system. Our data suggest that the basic programs underlying the development of CMP, MEP, and GMP homologues are in fact established in the developing FL, similar to our recent description of an FL CLP counterpart.74 Expression patterns of transcription factors and growth factor receptors previously described as master regulators of lineage determination38,47 are similar between FL and BM counterpart populations. Interestingly, our expression results uniformly show that multipotent HSCs, CMPs, and CLPs appear to express most of these genes at low levels. This may reflect priming stages in which lineage commitment remains flexible49,50 because once these progenitors give rise to daughters with progressively limited differentiation capacity, the expression of many of these factors is quenched. Low-level expression of multiple master regulators in multipotent progenitors may suggest that chromatin remains relatively accessible to poise differentiation to any particular lineage. The isolation of progenitors downstream of HSCs that are restricted to either the lymphoid or the myeloid lineage and of MEPs and GMPs downstream of CMPs that are restricted to mutually exclusive progeny suggests that fate commitments are normally irreversible once made by upstream progenitors. Priming stages may thus exist as a hierarchy of diminishing flexibility that eventually restricts a stem cell to a particular effector cell fate. This program is likely dependent on instructive signals from the environment,51 and recent findings strongly suggest that lineage determination is controlled by the down-regulation of inappropriate growth factor receptors.52 Although the major pathways of definitive hematopoiesis appear to be
established in embryogenesis, there exist several important differences
between fetal and adult stem and progenitor cells. We have previously
shown that FL HSCs can give rise to V Pbx1-deficient mice have recently been created by targeted deletion and
show a number of defects, the most important of which is embryonic
death by day 16 that is likely the result of profound anemia (DiMartino
et al,73 accompanying article, page 618). Phenotypic analyses of stem and progenitor cells in E14 FL showed approximate 2-fold decreases in total numbers of HSCs, MEPs, and GMPs.
Strikingly, the FL CMP population showed 5- to 10-fold decreases. Analysis of clonal colony distributions showed that FL CMPs
preferentially differentiated to GM lineages and showed approximately a
3-fold decrease in erythroid-containing colonies (DiMartino et
al73). Taken together, our results in both wild-type and
Pbx-1 Although the basic relationships among blood cell lineages are
conserved from embryo to adult, the fidelity of progenitors normally
restricted to either the lymphoid or myeloid lineages in BM is
incomplete in the fetus. We have recently shown that FL progenitors,
isolated based on the adult
Lin The FL counterpart of the adult CLP can generate
CD4+CD3 FL CLP counterparts also generate both CD8 In summary, the present report, along with the previous descriptions of embryonic and adult hematopoietic progenitor populations, provides a means to isolate cells at several stages of hematopoietic differentiation. The ability to isolate each population prospectively should allow the identification of candidate genes for lineage commitment and the transduction of these genes into isolated progenitors to resolve their roles. Comparison of the genetic profiles of fetal versus adult progenitors may identify pathways that restrict differentiation potentials that may lead to a better understanding of the development of mixed-lineage leukemias. Finally, the identification of counterpart populations in humans may allow the elucidation of target cells for oncogenic events underlying early hematologic malignancies.
We thank S.-I. Nishikawa for anti-IL-7R antibody, Amy Kiger and Len Zon for critical evaluation of the manuscript, Libuse Jerabek for excellent laboratory management and assistance with animal procedures, Veronica Braunstein for antibody preparation, the Stanford FACS facility for flow cytometer maintenance, and Lucino Hidalgo, Bert Lavarro, and Diosdado Escoto for animal care.
Submitted December 18, 2000; accepted April 4, 2001.
Supported by National Institute of Allergy and Infectious Diseases Training Grant 5T32 AI-07290 (D.T.), by United States Public Health Service grant CA42551 (I.L.W.), and by 1997 Jose Carreras International Leukemia Foundation Claudia Adams-Barr grants (K.A.).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: David Traver, Children's Hospital, Enders 650, 320 Longwood Ave, Boston, MA 02115; e-mail: dtraver{at}genetics.med.harvard.edu.
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H.-G. Kim, C. G. de Guzman, C. S. Swindle, C. V. Cotta, L. Gartland, E. W. Scott, and C. A. Klug The ETS family transcription factor PU.1 is necessary for the maintenance of fetal liver hematopoietic stem cells Blood, December 15, 2004; 104(13): 3894 - 3900. [Abstract] [Full Text] [PDF]
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P. Kumaravelu, L. Hook, A. M. Morrison, J. Ure, S. Zhao, S. Zuyev, J. Ansell, and A. Medvinsky Quantitative developmental anatomy of definitive haematopoietic stem cells/long-term repopulating units (HSC/RUs): role of the aorta-gonad-mesonephros (AGM) region and the yolk sac in colonisation of the mouse embryonic liver Development, January 11, 2002; 129(21): 4891 - 4899. [Abstract] [Full Text] [PDF]
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J. F. DiMartino, L. Selleri, D. Traver, M. T. Firpo, J. Rhee, R. Warnke, S. O'Gorman, I. L. Weissman, and M. L. Cleary The Hox cofactor and proto-oncogene Pbx1 is required for maintenance of definitive hematopoiesis in the fetal liver Blood, August 1, 2001; 98(3): 618 - 626. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
3+ and
V
T-cell
receptors.
CLPs, early thymocyte precursors, pro-T cells, and pre-T
cells
cells, as well as macrophages.
J Immunol.
2001;166:6593-6601