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Hematopoiesis and stem cells: plasticity versus developmental heterogeneity

Nature Immunology volume 3, pages 323–328 (2002)Cite this article

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.

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Figure 1: Pathways of mesoderm to blood during development.

Bob Crimi

Figure 2

Bob Crimi

Figure 3: Alternate views of muscle and HSC contributions on transplantation.

Bob Crimi

Figure 4: Developmental heterogeneity of stem cell types in bone marrow as basis for apparent plasticity of tissue stem cells.

Bob Crimi

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References

  1. Orkin, S. H. Development of the hematopoietic system. Curr. Opin. Genet. Dev. 6, 597–602 (1996).

    Article  CAS  PubMed  Google Scholar 

  2. Orkin, S. H. Diversification of haematopoietic stem cells to specific lineages. Nature Rev. Genet. 1, 57–64 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. 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).

    Article  CAS  PubMed  Google Scholar 

  4. 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).

    CAS  PubMed  Google Scholar 

  5. Pardanaud, L., Yassine, F. & Dieterlen-Lievre, F. Relationship between vasculogenesis, angiogenesis, and haemopoiesis during avian ontogeny. Development 105, 473–485 (1989).

    CAS  PubMed  Google Scholar 

  6. Choi, K., Kennedy, M., Kazarov, A., Papadimitriou, J. C. & Keller, G. A common precursor for hematopoietic and endothelial cells. Development 125, 725–732 (1998).

    CAS  PubMed  Google Scholar 

  7. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kennedy, M. et al. A common precursor for primitive erythropoiesis and definitive hematopoiesis. Nature 386, 488–493 (1997).

    Article  CAS  PubMed  Google Scholar 

  9. 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).

    CAS  PubMed  Google Scholar 

  10. 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).

    CAS  PubMed  Google Scholar 

  11. 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).

    Article  CAS  PubMed  Google Scholar 

  12. Chen, X. D. & Turpen, J. B. Intraembryonic origin of hepatic hematopoiesis in Xenopus laevis. J. Immunol. 154, 2557–2567 (1995).

    CAS  PubMed  Google Scholar 

  13. 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).

    CAS  PubMed  Google Scholar 

  14. 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).

    Article  CAS  PubMed  Google Scholar 

  15. Jordan, H. E. Evidence for the hemogenic capacity of endothelium. Anat. Rec. 10, 417–420 (1916).

    Article  Google Scholar 

  16. Maximow, A. A. Tissue cultures of young mammalian embryos. The Carnegie Institute 80, 91 (1925).

    Google Scholar 

  17. Tavian, M. et al. Aorta-associated CD34+ hematopoietic cells in the early human embryo. Blood 87, 67–72 (1996).

    CAS  PubMed  Google Scholar 

  18. North, T. et al. Cbfa2 is required for the formation of intra-aortic hematopoietic clusters. Development 126, 2563–2575 (1999).

    CAS  PubMed  Google Scholar 

  19. 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).

    Article  CAS  PubMed  Google Scholar 

  20. 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).

    Google Scholar 

  21. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Medvinsky, A. & Dzierzak, E. Definitive hematopoiesis is autonomously initiated by the AGM region. Cell 86, 897–906 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Yoder, M. C. et al. Characterization of definitive lymphohematopoietic stem cells in the day 9 murine yolk sac. Immunity 7, 335–344 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 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).

    Article  CAS  PubMed  Google Scholar 

  26. 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).

    Article  CAS  PubMed  Google Scholar 

  27. 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).

    Article  CAS  PubMed  Google Scholar 

  28. Ciau-Uitz, A., Walmsley, M. & Patient, R. Distinct origins of adult and embryonic blood in Xenopus. Cell 102, 787–796 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. 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).

    Article  CAS  PubMed  Google Scholar 

  30. 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).

    CAS  PubMed  Google Scholar 

  31. 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).

    CAS  PubMed  Google Scholar 

  32. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Charbord, P. in Hematopoiesis: a developmental approach (ed. Zon, L. I.) 702–717 (Oxford University Press, New York, 2001).

    Google Scholar 

  34. Chambord, P. in Hematopoiesis: a developmental approach (ed. Zon, L. I.) 691–701 (Oxford University Press, New York, 2001).

    Google Scholar 

  35. Bhatia, M. et al. Bone morphogenetic proteins regulate the developmental program of human hematopoietic stem cells. J. Exp. Med. 189, 1139–1148 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bhardwaj, G. et al. Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nature Immunol. 2, 172–180 (2001).

    Article  CAS  Google Scholar 

  37. 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).

    Article  CAS  PubMed  Google Scholar 

  38. 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).

    CAS  PubMed  Google Scholar 

  39. 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).

    CAS  PubMed  Google Scholar 

  40. 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).

    Article  CAS  PubMed  Google Scholar 

  41. 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).

    Article  CAS  PubMed  Google Scholar 

  42. 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).

    Article  CAS  PubMed  Google Scholar 

  43. Shen, H. et al. CXCR-4 desensitization is associated with tissue localization of hemopoietic progenitor cells. J. Immunol. 166, 5027–5033 (2001).

    Article  CAS  PubMed  Google Scholar 

  44. Nishikawa, S.-I. et al. In vitro generation of lymphohematopoietic cells from endothelial cells purified from murine embryos. Immunity 8, 761–769 (1998).

    Article  CAS  PubMed  Google Scholar 

  45. Pardanaud, L. & Dieterlen-Lievre, F. Manipulation of the angiopoietic/hemangiopoietic commitment in the avian embryo. Development 126, 617–627 (1999).

    CAS  PubMed  Google Scholar 

  46. Jaffredo, T., Gautier, R., Eichmann, A. & Dieterlen-Lievre, F. Intraaortic hemopoietic cells are derived from endothelial cells during ontogeny. Development 125, 4575–4583 (1998).

    CAS  PubMed  Google Scholar 

  47. 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).

    Article  CAS  PubMed  Google Scholar 

  48. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 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).

    CAS  PubMed  Google Scholar 

  50. Zhong, T. P., Childs, S., Leu, J. P. & Fishman, M. C. Gridlock signalling pathway fashions the first embryonic artery. Nature 414, 216–220 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Weissman, I. L. Translating stem and progenitor cell biology to the clinic: barriers and opportunities. Science 287, 1442–1446 (2000).

    Article  CAS  PubMed  Google Scholar 

  52. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Gussoni, E. et al. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 401, 390–394 (1999).

    CAS  PubMed  Google Scholar 

  54. Lagasse, E. et al. Purified hematopoietic stem cells can differentiate to hepatocytes in vivo. Nature Med. 6, 1229–1234 (2000).

    Article  CAS  PubMed  Google Scholar 

  55. Orkin, S. H. Stem cell alchemy. Nature Med. 6, 1212–1214 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Krause, D. S. et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105, 369–377 (2001).

    CAS  PubMed  Google Scholar 

  57. Orlic, D. et al. Transplanted adult bone marrow cells repair myocardial infarcts in mice. Ann. NY Acad. Sci. 938, 221–230 (2001).

    Article  CAS  PubMed  Google Scholar 

  58. Orlic, D. et al. Bone marrow cells regenerate infarcted myocardium. Nature 410, 701–705 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Jackson, K. A. et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J. Clin. Invest. 107, 1395–1402 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 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).

    Article  CAS  PubMed  Google Scholar 

  62. Graf, T. Plasticity of hematopoietic cells. Blood (in the press, 2002).

  63. Kawada, H. & Ogawa, M. Bone marrow origin of hematopoietic progenitors and stem cells in murine muscle. Blood 98, 2008–2013 (2001).

    Article  CAS  PubMed  Google Scholar 

  64. McKinney-Freeman, S. L. et al. Muscle-derived hematopoietic stem cells are hematopoietic in origin. Proc. Natl Acad. Sci. USA 99, 1341–1346 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 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).

    Google Scholar 

  66. 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).

    Article  CAS  PubMed  Google Scholar 

  67. 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).

    Article  CAS  PubMed  Google Scholar 

  68. Sato, T., Laver, J. H. & Ogawa, M. Reversible expression of CD34 by murine hematopoietic stem cells. Blood 94, 2548–2554 (1999).

    CAS  PubMed  Google Scholar 

  69. Reyes, M. et al. Purification and ex vivo expansion of postnatal human marrow mesodermal progenitor cells. Blood 98, 2615–2625 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Fridenshtein, A. I. Stromal bone marrow cells and the hematopoietic microenvironment. Arkh Patol. 44, 3–11 (1982).

    PubMed  Google Scholar 

  71. Pittenger, M. F. et al. Multilineage potential of adult human mesenchymal stem cells. Science 284, 143–147 (1999).

    Article  CAS  PubMed  Google Scholar 

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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.

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  1. Division of Hematology and Oncology, Department of Pediatrics, Dana-Farber Cancer Institute and Children's Hospital, Harvard Medical School and the Howard Hughes Medical Institute, Boston, 02115, MA, USA

    Stuart H. Orkin & Leonard I. Zon

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Correspondence to Stuart H. Orkin.

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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

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