Abstract
Hematopoietic stem cells (HSCs) provide for blood formation throughout the life of the individual. Studies of HSCs form a conceptual framework for the analysis of stem cells of other organ systems. We review here the origin of HSCs during embryological development, the relationship between hematopoiesis and vascular development and the potential plasticity of HSCs and other tissue stem cells. Recent experiments in the mouse have been widely interpreted as evidence for unprecedented transdifferentiation of tissue stem cells. The use of enriched, but impure, cell populations allows for alternative interpretation. In considering these findings, we draw a distinction here between the plasticity of adult stem cells and the heterogeneity of stem cell types that pre-exist within tissues.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Orkin, S. H. Development of the hematopoietic system. Curr. Opin. Genet. Dev. 6, 597–602 (1996).
Orkin, S. H. Diversification of haematopoietic stem cells to specific lineages. Nature Rev. Genet. 1, 57–64 (2000).
Winnier, G., Blesing, M., Labosky, P. A. & Hogan, B. L. M. Bone morphogenetic protein-4 (BMP-4) is required for mesoderm formation and patterning in the mouse. Genes Dev. 9, 2105–2116 (1995).
Kishimoto, Y., Lee, K. H., Zon, L., Hammerschmidt, M. & Schulte-Merker, S. The molecular nature of zebrafish swirl: BMP2 function is essential during early dorsoventral patterning. Development 124, 4457–4466 (1997).
Pardanaud, L., Yassine, F. & Dieterlen-Lievre, F. Relationship between vasculogenesis, angiogenesis, and haemopoiesis during avian ontogeny. Development 105, 473–485 (1989).
Choi, K., Kennedy, M., Kazarov, A., Papadimitriou, J. C. & Keller, G. A common precursor for hematopoietic and endothelial cells. Development 125, 725–732 (1998).
Gering, M., Rodaway, A. R. F., Gottgens, B., Patient, R. K. & Green, A. R. The SCL gene specifies haemangioblast development from early mesoderm. EMBO J. 17, 4029–4045 (1998).
Kennedy, M. et al. A common precursor for primitive erythropoiesis and definitive hematopoiesis. Nature 386, 488–493 (1997).
Perlingeiro, R. C., Kyba, M. & Daley, G. Q. Clonal analysis of differentiating embryonic stem cells reveals a hematopoietic progenitor with primitive erythroid and adult lymphoid- myeloid potential. Development 128, 4597–604 (2001).
Lassila, O., Martin, C., Toivanen, P. & Dieterlen-Lievre, F. Erythropoiesis and lymphopoiesis in the chick yolk-sac-embryo chimeras: contribution of yolk sac and intraembryonic stem cells. Blood 59, 377–381 (1982).
Turpen, J. B., Kelley, C. M., Mead, P. E. & Zon, L. I. Bipotential primitive-definitive hematopoietic progenitors in the vertebrate embryo. Immunity 7, 325–334 (1997).
Chen, X. D. & Turpen, J. B. Intraembryonic origin of hepatic hematopoiesis in Xenopus laevis. J. Immunol. 154, 2557–2567 (1995).
Kau, C.-L. & Turpen, J. B. Dual contribution of embryonic ventral blood island and dorsal lateral plate mesoderm during ontogeny of hemopoietic cells in Xenopus laevis. J. Immunol. 131, 2262–2266 (1983).
Medvinsky, A. L., Samoylina, N. L., Muller, A. M. & Dzierzak, E. A. An early pre-liver intraembryonic source of CFU-S in the developing mouse. Nature 364, 64–66 (1993).
Jordan, H. E. Evidence for the hemogenic capacity of endothelium. Anat. Rec. 10, 417–420 (1916).
Maximow, A. A. Tissue cultures of young mammalian embryos. The Carnegie Institute 80, 91 (1925).
Tavian, M. et al. Aorta-associated CD34+ hematopoietic cells in the early human embryo. Blood 87, 67–72 (1996).
North, T. et al. Cbfa2 is required for the formation of intra-aortic hematopoietic clusters. Development 126, 2563–2575 (1999).
Moore, M. S. A. & Metcalf, D. Ontogeny of the haemopoietic system: yolk sac origin of in vivo and in vitro colony forming cells in the developing mouse embryo. Brit. J. Haemat. 18, 279–296 (1970).
Weissman, I. L., Papioannou, V. & Gardner, R. in Differentiation of Normal and Neoplastic Hematopoietic Cells (eds Clarkson, B., Mark, P. & Till, J.) 33–47 (Cold Spring Harbor Laboratory Press, New York, 1978).
Toles, J. F., Chui, D. H., Belbeck, L. W., Starr, E. & Barker, J. E. Hemopoietic stem cells in murine embryonic yolk sac and peripheral blood. Proc. Natl Acad. Sci. USA 86, 7456–7459 (1989).
Medvinsky, A. & Dzierzak, E. Definitive hematopoiesis is autonomously initiated by the AGM region. Cell 86, 897–906 (1996).
Yoder, M. C. et al. Characterization of definitive lymphohematopoietic stem cells in the day 9 murine yolk sac. Immunity 7, 335–344 (1997).
Yoder, M. C., Hiatt, K. & Mukherjee, P. In vivo repopulating hematopoietic stem cells are present in the murine yolk sac at day 9.0 postcoitus. Proc. Natl Acad. Sci. USA 94, 6776–6780 (1997).
Yoder, M. C. & Hiatt, K. Murine yolk sac and bone marrow hematopoietic cells with high proliferative potential display different capacities for producing colony-forming cells ex vivo. J. Hematother. Stem Cell Res. 8, 421–430 (1999).
Matsuoka, S. et al. Generation of definitive hematopoietic stem cells from murine early yolk sac and paraaortic splanchnopleures by aorta-gonad-mesonephros region-derived stromal cells. Blood 98, 6–12 (2001).
Cai, Z. et al. Haploinsufficiency of AML1 affects the temporal and spatial generation of hematopoietic stem cells in the mouse embryo. Immunity 13, 423–431 (2000).
Ciau-Uitz, A., Walmsley, M. & Patient, R. Distinct origins of adult and embryonic blood in Xenopus. Cell 102, 787–796 (2000).
Lassila, O., Eskola, J., Toivanen, P., Martin, C. & Dieterlen-Lievre, F. The origin of lymphoid stem cells studied in chick yolk sac-embryo chimaeras. Nature 272, 353–354 (1978).
Wineman, J., Moore, K., Lemischka, I. & Muller-Sieburg, C. Functional heterogeneity of the hematopoietic microenvironment: rare stromal elements maintain long-term repopulating stem cells. Blood 87, 4082–4090 (1996).
Thiemann, F. T., Moore, K. A., Smogorzewska, E. M., Lemischka, I. R. & Crooks, G. M. The murine stromal cell line AFT024 acts specifically on human CD34+CD38− progenitors to maintain primitive function and immunophenotype in vitro. Exp. Hematol. 26, 612–619 (1998).
Moore, K. A., Pytowski, B., Witte, L., Hicklin, D. & Lemischka, I. R. Hematopoietic activity of a stromal cell transmembrane protein containing epidermal growth factor-like repeat motifs. Proc. Natl Acad. Sci. USA 94, 4011–4016 (1997).
Charbord, P. in Hematopoiesis: a developmental approach (ed. Zon, L. I.) 702–717 (Oxford University Press, New York, 2001).
Chambord, P. in Hematopoiesis: a developmental approach (ed. Zon, L. I.) 691–701 (Oxford University Press, New York, 2001).
Bhatia, M. et al. Bone morphogenetic proteins regulate the developmental program of human hematopoietic stem cells. J. Exp. Med. 189, 1139–1148 (1999).
Bhardwaj, G. et al. Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nature Immunol. 2, 172–180 (2001).
Farrington, S. M., Belaoussoff, M. & Baron, M. H. Winged-helix, Hedgehog and Bmp genes are differentially expressed in distinct cell layers of the murine yolk sac. Mech. Dev. 62, 197–211 (1997).
Van Den Berg, D. J., Sharma, A. K., Bruno, E. & Hoffman, R. Role of members of the Wnt gene family in human hematopoiesis. Blood 92, 3189–3202 (1998).
Kapur, R. et al. Signaling through the interaction of membrane-restricted stem cell factor and c-kit receptor tyrosine kinase: genetic evidence for a differential role in erythropoiesis. Blood 91, 879–889 (1998).
Kusadasi, N., Koevoet, J. L., van Soest, P. L. & Ploemacher, R. E. Stromal support augments extended long-term ex vivo expansion of hemopoietic progenitor cells. Leukemia 15, 1347–1358 (2001).
Papayannopoulou, T., Priestley, G. V., Nakamoto, B., Zafiropoulos, V. & Scott, L. M. Molecular pathways in bone marrow homing: dominant role of α4β1 over β2-integrins and selectins. Blood 98, 2403–2411 (2001).
Kollet, O. et al. Rapid and efficient homing of human CD34+CD38−/lowCXCR4+ stem and progenitor cells to the bone marrow and spleen of NOD/SCID and NOD/SCID/B2mnull mice. Blood 97, 3283–91 (2001).
Shen, H. et al. CXCR-4 desensitization is associated with tissue localization of hemopoietic progenitor cells. J. Immunol. 166, 5027–5033 (2001).
Nishikawa, S.-I. et al. In vitro generation of lymphohematopoietic cells from endothelial cells purified from murine embryos. Immunity 8, 761–769 (1998).
Pardanaud, L. & Dieterlen-Lievre, F. Manipulation of the angiopoietic/hemangiopoietic commitment in the avian embryo. Development 126, 617–627 (1999).
Jaffredo, T., Gautier, R., Eichmann, A. & Dieterlen-Lievre, F. Intraaortic hemopoietic cells are derived from endothelial cells during ontogeny. Development 125, 4575–4583 (1998).
Cumano, A., Dieterlen-Lievre, F. & Godin, I. The splanchnopleura/AGM region is the prime site for the generation of multipotent hemopoietic precursors, in the mouse embryo. Vaccine 18, 1621–1623 (2000).
Caprioli, A., Jaffredo, T., Gautier, R., Dubourg, C. & Dieterlen-Lievre, F. Blood-borne seeding by hematopoietic and endothelial precursors from the allantois. Proc. Natl Acad. Sci. USA 95, 1641–1646 (1998).
Wood, H. B., May, G., Healy, L., Enver, T. & Morriss-Kay, G. M. CD34 expression patterns during early mouse development are related to modes of blood vessel formation and reveal additional sites of hematopoiesis. Blood 90, 2300–2311 (1997).
Zhong, T. P., Childs, S., Leu, J. P. & Fishman, M. C. Gridlock signalling pathway fashions the first embryonic artery. Nature 414, 216–220 (2001).
Weissman, I. L. Translating stem and progenitor cell biology to the clinic: barriers and opportunities. Science 287, 1442–1446 (2000).
Jackson, K. A., Mi, T. & Goodell, M. A. Hematopoietic potential of stem cells isolated from murine skeletal muscle. Proc. Natl Acad. Sci. USA 96, 14482–14486 (1999).
Gussoni, E. et al. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 401, 390–394 (1999).
Lagasse, E. et al. Purified hematopoietic stem cells can differentiate to hepatocytes in vivo. Nature Med. 6, 1229–1234 (2000).
Orkin, S. H. Stem cell alchemy. Nature Med. 6, 1212–1214 (2000).
Krause, D. S. et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105, 369–377 (2001).
Orlic, D. et al. Transplanted adult bone marrow cells repair myocardial infarcts in mice. Ann. NY Acad. Sci. 938, 221–230 (2001).
Orlic, D. et al. Bone marrow cells regenerate infarcted myocardium. Nature 410, 701–705 (2001).
Jackson, K. A. et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J. Clin. Invest. 107, 1395–1402 (2001).
Orlic, D. et al. Mobilized bone marrow cells repair the infarcted heart, improving function and survival. Proc. Natl Acad. Sci. USA 98, 10344–10349 (2001).
Klinken, S. P., Alexander, W. S. & Adams, J. M. Hemopoietic lineage switch: v-raf oncogene converts Eμ–myc transgenic B cells into macrophages. Cell 53, 857–867 (1988).
Graf, T. Plasticity of hematopoietic cells. Blood (in the press, 2002).
Kawada, H. & Ogawa, M. Bone marrow origin of hematopoietic progenitors and stem cells in murine muscle. Blood 98, 2008–2013 (2001).
McKinney-Freeman, S. L. et al. Muscle-derived hematopoietic stem cells are hematopoietic in origin. Proc. Natl Acad. Sci. USA 99, 1341–1346 (2002).
Lyden, D. et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nature Med. 11, 194–201 (2001).
Wright, D. E., Wagers, A. J., Gulati, A. P., Johnson, F. L. & Weissman, I. L. Physiological migration of hematopoietic stem and progenitor cells. Science 294, 1933–1936 (2001).
Goodell, M. A., Brose, K., Paradis, G., Conner, A. S. & Mulligan, R. C. Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J. Exp. Med. 183, 1797–1806 (1996).
Sato, T., Laver, J. H. & Ogawa, M. Reversible expression of CD34 by murine hematopoietic stem cells. Blood 94, 2548–2554 (1999).
Reyes, M. et al. Purification and ex vivo expansion of postnatal human marrow mesodermal progenitor cells. Blood 98, 2615–2625 (2001).
Fridenshtein, A. I. Stromal bone marrow cells and the hematopoietic microenvironment. Arkh Patol. 44, 3–11 (1982).
Pittenger, M. F. et al. Multilineage potential of adult human mesenchymal stem cells. Science 284, 143–147 (1999).
Acknowledgements
Supported by the Howard Hughes Medical Institute. Due to space constraints we are unable to include all relevant publications. We apologize to colleagues whose primary work may not be directly cited.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Orkin, S., Zon, L. Hematopoiesis and stem cells: plasticity versus developmental heterogeneity. Nat Immunol 3, 323–328 (2002). https://doi.org/10.1038/ni0402-323
Issue Date:
DOI: https://doi.org/10.1038/ni0402-323
This article is cited by
-
Ocimum flavone Orientin as a countermeasure for thrombocytopenia
Scientific Reports (2018)
-
Conversion of adult endothelium to immunocompetent haematopoietic stem cells
Nature (2017)
-
Epigenetic silencing of the oncogenic miR-17-92 cluster during PU.1-directed macrophage differentiation
The EMBO Journal (2011)
-
A Comparison of Stem Cells for Therapeutic Use
Stem Cell Reviews and Reports (2011)
-
β-Catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukemia
Leukemia (2009)