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Hematopoietic Cytokines, Transcription Factors and Lineage Commitment

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Hematopoietic Cytokines, Transcription Factors and Lineage Commitment Oncogene (2002) 21, 3295 ± 3313 ã 2002 Nature Publishing Group All rights reserved 0950 ± 9232/02 $25.00 www.nature.com/onc Hematopoietic cytokines, transcription factors and lineage commitment Jiang Zhu1,2 and Stephen G Emerson*,1,2 1Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, PA 19104, USA; 2Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, PA 19104, USA The past two decades have witnessed signi®cant advances achieved by using many fewer stem cell-enriched cells, in our understanding of the cellular physiology and isolated by any one of a variety of methods, either from molecular regulation of hematopoiesis. At the heart of bone marrow, peripheral blood or fetal liver. Most stem cell self-renewal and lineage commitment decisions recently, careful studies suggest that within the subset lies the relative expression levels of lineage-speci®c of cells previously viewed as uniquely hematopoietic transcription factors. The expression of these transcrip- stem cells may lie a subset with truly multi-lineage tion factors in early stem cells may be promiscuous and hematopoietic potential, capable of giving rise to many ¯uctuate, but ultimately comes under the in¯uence of non-hematopoietic lineages as well, including myocytes, extracellular regulatory signals in the form of hemato- epithelial cells, hepatocytes, and neurons. poietic cytokines. In this review, we ®rst summarize our The phenotypic speci®cation has become progres- current understanding of the phenotypic characterization sively more sophisticated over the past two decades. of hematopoietic stem cells. Next, we describe key Although the precise relationship between cell surface known transcription factors which govern stem cell self- phenotype and cellular plasticity within the stem cell renewal and lineage commitment decisions. Finally, we compartment is still not clear, the murine Sca-1+ C- review data concerning the role of speci®c cytokines in kit+ Lin7 (SKL) population clearly contain most, if in¯uencing these decisions. From this review, a picture not all of the cells with HSC potential, and the same is emerges in which stem cell fate decisions are governed by likely true of the equivalent population in humans. the integrated eects of intrinsic transcription factors This SKL population is further characterized by the and external signaling pathways initiated by regulatory dierential expression of CD34 and CD38, with SKL cytokines. cells being functionally divided between CD34+ and Oncogene (2002) 21, 3295 ± 3313. DOI: 10.1038/sj/ CD347/lo sub-populations. The CD34+ cells provided onc/1205318 immediate radioprotection for lethally irradiated recipient mice while CD347/lo cells were responsible Keywords: transcription factor; cytokines; hematopoi- for long-term reconstitution of both myeloid and esis lymphoid lineages (Osawa et al., 1996). The authors postulated that CD34+ sub-population basically con- sists of multilineage progenitor cells with low self- renewal capacity, while the real stem cells are The cell biology of primitive stem cells contained in CD347/lo fraction. Similarly, it was recently reported that only the descendants from Diverse results from many experimental systems CD38+CD347 SKL cells, but not from CD34+ SKL indicate that the proliferative and self-renewal capacity cells could be easily detected in the re-constituted BM of a given hematopoietic cell, as well as the diversity of cells in lethally irradiated secondary, and tertiary lineages to which it can dierentiate, decrease progres- recipients over a long term (Zhao et al., 2000). sively with dierentiation (Figure 1). In the now Developmentally, there are two waves of hematopoi- classical view, the earliest cell in this hierarchy is the esis, so probably with two corresponding origins for pluripotent hematopoietic stem cell (HSC), whose HSCs (Ciau-Uitz et al., 2000). Primitive hematopoiesis, existence was demonstrated by serial bone marrow distinguished from de®nitive hematopoiesis by large transplantation (BMT) experiments. In these studies, all and nucleated erythrocytes and speci®cally expressed lineages of derived hematopoiesis could be successfully fetal hemoglobin isoforms, occurs as a transient wave reconstituted in lethally irradiated tertiary recipient preceding the advent of de®nitive hematopoiesis. mice by bone marrow cells from secondary recipients. Primitive hematopoiesis in the mouse begins within Furthermore, successful reconstitution could also be the blood islands in yolk sac around 7.5 days post coitum (d.p.c.). Independently, the stem cells for de®nitive hematopoiesis originate within embryonic SP/AGM (splanchnopleur, aorta, gonads, and mesone- *Correspondence: SG Emerson, Division of Hematology/Oncology, phros) during 9.5 to 11.5 d.p.c. in mouse and 30 to 37 Departments of Medicine and Pediatrics, Maloney 510, 3600 Spruce Street, University of Pennsylvania School of Medicine, Philadelphia, days of gestation in the human, where the hemato- PA 19104, USA; E-mail: [email protected] poietic cells are found adhering to the ventral wall of Transcriptional regulation of hematopoiesis J Zhu and SG Emerson 3296 Figure 1 Transcriptional regulation of early hematopoietic stem cell development. HSCs, as one progeny of hemangioblasts or hemogenic endothelium, are faced with the cell fate choice either to self-renew or to dierentiate into committed common lymphoid or common myeloid hematopoietic precursors. The transcription factors involved in each development direction are depicted dorsal aorta (Medvinsky and Dzierzak, 1996). Only tion factors and surface markers, including SCL, these de®nitive hematopoietic stem/progenitor cells GATA-2, C-kit, AA-4.1, CD34, Flit-3 ligand, Sca-1, originating from AGM, but not primitive HSCs' are VEGFR-1 and -2, only with the exception of CD45. able to repopulate the entire hematopoietic system in Actually endothelial speci®c receptor VEGFR-2 was the lethally irradiated adult recipient mice (Cumano recently found a key marker for isolating hematopoie- and Godin, 2001). De®nitive HSCs expand in number tic reconstituting cell in NOD/SCID mice from human in the AGM, and then migrate to and colonize fetal circulating CD34+ cells (Ziegler et al., 1999). This close liver and spleen where they continue to dierentiate relationship between HSC and endothelial development into recognizable hematopoietic precursors. After birth, can be further visualized in embryonic stem cell de®nitive hematopoiesis is primarily con®ned to bone cultures. During the in vitro embryo body development marrow, and in some pathological conditions also to of mouse, the blast colony-forming cells (BL-CFC) extramedullary sites such as spleen, liver, and occa- develop within 4 days in the presence of vascular sionally lung and brain. endothelial growth factor (VEGF) and are lost quickly. Because both endothelial and hematopoietic cells These BL-CFCs within embryonic bodies can produce seemed to simultaneously derive from clusters of adherent endothelial cells, and primitive or de®nitive phenotypically similar cells within the yolk sac, it has erythroid cells, as well as macrophages and neutrophils been suggested that hematopoietic and endothelial cells recognized by morphology examination. These BL- share an immediate embryonic parental cell, either a CFCs may thus indeed be the in vitro counterpart to hemangioblast that serves as the common precursor for the long-hypothesized hemangioblasts (Choi et al., hematopoietic and endothelial lineages, or a hemogenic 1998). It is also possible that hemangioblasts may endothelium that gives rise to hematopoietic stem cells persist after birth. Shi et al. (1998) showed evidence (see Figure 1). Although de®nitive hematopoietic stem/ indicating that the endothelial cells lining the Dacron progenitor cells do not resemble endothelial cells graft implanted in the aorta were actually derived from morphologically, they do share a number of transcrip- the pre-transplanted BM cells 8 weeks before. They Oncogene Transcriptional regulation of hematopoiesis J Zhu and SG Emerson 3297 also showed that some of CD34+ BM cells could be hematopoietic lineages were expressed normally in induced to endothelial cells in vitro culture system with SCL-null embryonic stem cell lines. However, hemato- cytokines like VEGF. poietic-restricted genes, including transcription factors One of the most exciting ®ndings in the past 2 ± 3 GATA-1, EKLF (erythroid kruppel-like factor), and years has been that cells with the phenotype of PU.1 as well as globin genes and MPO (myeloperox- hematopoietic stem cells, but derived from non- idase), were only expressed in wild type and SCL- hematopoietic tissues such as brain and muscle, can heterozygous ES cells. SCL protein shares homology eciently repopulate hematopoiesis in lethally-irra- within a restricted region of 56 amino acids with a diated mice (Bjornson et al., 1999; Jackson et al., number of bHLH transcription factors, and it is 1999). Conversely, numerous laboratories have found capable of binding to E-box motif of DNA that transplanted BM cells could contribute to the (CANNTG) in vitro, and forms heterodimers with regeneration of multiple tissue cell types, including other HLH factors, such as E47 and E12. Strikingly, brain, muscle, hepatocytes, lung, GI epithelium, and SCL mutants unable to bind to E-box were found to skin (Brazelton et al., 2000; Gussoni et al., 1999; be able to nearly fully rescue the hematopoietic
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