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Stem Cells

A population of very small embryonic-like (VSEL) CXCR4+SSEA-1+Oct-4+ stem cells identified in adult bone marrow

Leukemia volume 20, pages 857–869 (2006)Cite this article

Abstract

By employing multiparameter sorting, we identified in murine bone marrow (BM) a homogenous population of rare (∼0.02% of BMMNC) Sca-1+lin−CD45− cells that express by RQ-PCR and immunohistochemistry markers of pluripotent stem cells (PSC) such as SSEA-1, Oct-4, Nanog and Rex-1. The direct electronmicroscopical analysis revealed that these cells are small (∼2–4 μm), posses large nuclei surrounded by a narrow rim of cytoplasm, and contain open-type chromatin (euchromatin) that is typical for embryonic stem cells. In vitro cultures these cells are able to differentiate into all three germ-layer lineages. The number of these cells is highest in BM from young (∼1-month-old) mice and decreases with age. It is also significantly diminished in short living DBA/2J mice as compared to long living B6 animals. These cells in vitro respond strongly to SDF-1, HGF/SF and LIF and express CXCR4, c-met and LIF-R, respectively, and since they adhere to fibroblasts they may be coisolated with BM adherent cells. We hypothesize that this population of Sca-1+lin−CD45− very small embryonic-like (VSEL) stem cells is deposited early during development in BM and could be a source of pluripotent stem cells for tissue/organ regeneration.

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References

  1. Orlic D, Kajstura J, Chimenti S, Bodine DM, Leri A, Anversa P . Bone marrow stem cells regenerate infarcted myocardium. Pediatr Transplant 2003; 7 (Suppl 3): 86–88.

    Article  Google Scholar 

  2. Shackel N, Rockey D . In pursuit of the ‘Holy Grail’ – stem cells, hepatic injury, fibrogenesis and repair. Hepatology 2005; 41: 16–18.

    Google Scholar 

  3. Corti S, Locatelli F, Papadimitriou D, Strazzer S, Comi GP . Somatic stem cell research for neural repair: current evidence and emerging perspectives. J Cell Mol Med 2004; 8: 329–337.

    Google Scholar 

  4. Mezey E, Chandross KJ, Harta G, Maki RA, McKercher SR . Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science 2000; 290: 1779–1782.

    Article  CAS  Google Scholar 

  5. Wagers AJ, Weissman IL . Plasticity of adult stem cells. Cell 2004; 116: 639–648.

    Article  CAS  Google Scholar 

  6. Castro RF, Jackson KA, Goodell MA, Robertson CS, Liu H, Shine HD . Failure of bone marrow cells to transdifferentiate into neural cells in vivo. Science 2002; 297: 1299.

    CAS  Google Scholar 

  7. Nygren JM, Jovinge S, Breitbach M, Sawen P, Roll W, Hescheler J et al. Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nat Med 2004; 10: 494–501.

    CAS  Google Scholar 

  8. Murry CE, Soonpaa MH, Reinecke H, Nakajima H, Nakajima HO, Rubart M et al. Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature 2004; 428: 664–668.

    CAS  Google Scholar 

  9. Balsam LB, Wagers AJ, Christensen JL, Kofidis T, Weissman IL, Robbins RC . Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature 2004; 428: 668–673.

    CAS  Google Scholar 

  10. Kashofer K, Bonnet D . Gene therapy progress and prospects: stem cell plasticity. Gene Therapy 2005; 12: 1229–1234.

    Article  CAS  Google Scholar 

  11. Orkin SH, Zon LI . Hematopoiesis and stem cells: plasticity versus developmental heterogeneity. Nat Immunol 2002; 3: 323–328.

    Article  CAS  Google Scholar 

  12. Lemischka I . A few thoughts about the plasticity of stem cells. Exp Hematol 2002; 30: 848–852.

    Article  Google Scholar 

  13. Spyridonidis A, Tomann T, Zeiser R, Follo M, Metaxas Y, Finke J . Stem cell plasticity: The debate begins to clarify. Stem Cell Rev 2005; 1: 37–43.

    Article  CAS  Google Scholar 

  14. Terada N, Hamazaki T, Oka M, Hoki M, Mastalerz DM, Nakano Y et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 2002; 416: 542–545.

    Article  CAS  Google Scholar 

  15. Ying QL, Nichols J, Evans EP, Smith AG . Changing potency by spontaneous fusion. Nature 2002; 416: 545–548.

    Article  CAS  Google Scholar 

  16. Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, Fike JR, Lee HO, Pfeffer K et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 2003; 425: 968–973.

    Article  CAS  Google Scholar 

  17. Morshead CM, Benveniste P, Iscove NN, van der Kooy D . Hematopoietic competence is a rare property of neural stem cells that may depend on genetic and epigenetic alterations. Nat Med 2002; 8: 268–273.

    Article  CAS  Google Scholar 

  18. Jang YY, Sharkis SJ . Metamorphosis from bone marrow derived primitive stem cells to functional liver cells. Cell Cycle 2004; 3: 980–982.

    Article  CAS  Google Scholar 

  19. Harris RG, Herzog EL, Bruscia EM, Grove JE, Van Arnam JS, Krause DS . Lack of a fusion requirement for development of bone marrow-derived epithelia. Science 2004; 305: 90–93.

    Article  CAS  Google Scholar 

  20. Almeida-Porada G, Porada CD, Chamberlain J, Torabi A, Zanjani ED . Formation of human hepatocytes by human hematopoietic stem cells in sheep. Blood 2004; 104: 2582–2590.

    Article  CAS  Google Scholar 

  21. Shefer G, Wleklinski-Lee M, Yablonka-Reuveni Z . Skeletal muscle satellite cells can spontaneously enter an alternative mesenchymal pathway. J Cell Sci 2004; 117: 5393–5404.

    Article  CAS  Google Scholar 

  22. Wurmser AE, Nakashima K, Summers RG, Toni N, D’Amour KA, Lie DC et al. Cell fusion-independent differentiation of neural stem cells to the endothelial lineage. Nature 2004; 430: 350–356.

    Article  CAS  Google Scholar 

  23. Quesenberry PJ, Dooner G, Dooner M, Abedi M . Developmental biology: Ignoratio elenchi: red herrings in stem cell research. Science 2005; 308: 1121–1122.

    Article  CAS  Google Scholar 

  24. Bonde J, Hess DA, Nolta JA . Recent advances in hematopoietic stem cell biology. Curr Opin Hematol 2004; 11: 392–398.

    Article  Google Scholar 

  25. Loutit JF, Marshall MJ, Nisbet NW, Vaughan JM . Versatile stem cells in bone marrow. Lancet 1982; 2: 1090–1093.

    Article  CAS  Google Scholar 

  26. Ratajczak MZ, Kucia M, Reca R, Majka M, Janowska-Wieczorek A, Ratajczak J . Stem cell plasticity revisited: CXCR4-positive cells expressing mRNA for early muscle, liver and neural cells ‘hide out’ in the bone marrow. Leukemia 2004; 18: 29–40.

    Article  CAS  Google Scholar 

  27. Kucia M, Reca R, Jala VR, Dawn B, Ratajczak J, Ratajczak MZ . Bone marrow as a home of heterogenous populations of nonhematopoietic stem cells. Leukemia 2005; 19: 1118–1127.

    Article  CAS  Google Scholar 

  28. Johnson J, Bagley J, Skaznik-Wikiel M, Lee HJ, Adams GB, Niikura Y et al. Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell 2005; 122: 303–315.

    Article  CAS  Google Scholar 

  29. Howell JC, Lee WH, Morrison P, Zhong J, Yoder MC, Srour EF . Pluripotent stem cells identified in multiple murine tissues. Ann NY Acad Sci 2003; 996: 158–173.

    Article  CAS  Google Scholar 

  30. Edelberg JM, Tang L, Hattori K, Lyden D, Rafii S . Young adult bone marrow-derived endothelial precursor cells restore aging-impaired cardiac angiogenic function. Circ Res 2002; 90: E89–E93.

    Article  CAS  Google Scholar 

  31. Murayama T, Asahara T . Bone marrow-derived endothelial progenitor cells for vascular regeneration. Curr Opin Mol Ther 2002; 4: 395–402.

    PubMed  Google Scholar 

  32. Friedenstein AJ, Chailakhyan RK, Gerasimov UV . Bone marrow osteogenic stem cells: in vitro cultivation and transplantation in diffusion chambers. Cell Tissue Kinet 1987; 20: 263–272.

    CAS  PubMed  Google Scholar 

  33. Kassem M, Mosekilde L, Rungby J, Melsen F, Eriksen EF . Formation of osteoclasts and osteoblast-like cells in long-term human bone marrow cultures. Apmis 1991; 99: 262–268.

    Article  CAS  Google Scholar 

  34. Eghbali-Fatourechi GZ, Lamsam J, Fraser D, Nagel D, Riggs BL, Khosla S . Circulating osteoblast-lineage cells in humans. N Engl J Med 2005; 352: 1959–1966.

    Article  CAS  Google Scholar 

  35. LaBarge MA, Blau HM . Biological progression from adult bone marrow to mononucleate muscle stem cell to multinucleate muscle fiber in response to injury. Cell 2002; 111: 589–601.

    Article  CAS  Google Scholar 

  36. Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B et al. Bone marrow cells regenerate infarcted myocardium. Nature 2001; 410: 701–705.

    Article  CAS  Google Scholar 

  37. Wojakowski W, Tendera M, Michalowska A, Majka M, Kucia M, Maslankiewicz K et al. Mobilization of CD34/CXCR4+, CD34/CD117+, c-met+ stem cells, and mononuclear cells expressing early cardiac, muscle, and endothelial markers into peripheral blood in patients with acute myocardial infarction. Circulation 2004; 110: 3213–3220.

    Article  CAS  Google Scholar 

  38. Petersen BE, Bowen WC, Patrene KD, Mars WM, Sullivan AK, Murase N et al. Bone marrow as a potential source of hepatic oval cells. Science 1999; 284: 1168–1170.

    Article  CAS  Google Scholar 

  39. Korbling M, Katz RL, Khanna A, Ruifrok AC, Rondon G, Albitar M et al. Hepatocytes and epithelial cells of donor origin in recipients of peripheral-blood stem cells. N Engl J Med 2002; 346: 738–746.

    Article  Google Scholar 

  40. Kollet O, Shivtiel S, Chen YQ, Suriawinata J, Thung SN, Dabeva MD et al. HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34+ stem cell recruitment to the liver. J Clin Invest 2003; 112: 160–169.

    Article  CAS  Google Scholar 

  41. Brazelton TR, Rossi FM, Keshet GI, Blau HM . From marrow to brain: expression of neuronal phenotypes in adult mice. Science 2000; 290: 1775–1779.

    Article  CAS  Google Scholar 

  42. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002; 418: 41–49.

    Article  CAS  Google Scholar 

  43. Jiang Y, Vaessen B, Lenvik T, Blackstad M, Reyes M, Verfaillie CM . Multipotent progenitor cells can be isolated from postnatal murine bone marrow, muscle, and brain. Exp Hematol 2002; 30: 896–904.

    Article  CAS  Google Scholar 

  44. Kucia M, Ratajczak J, Ratajczak MZ . Bone marrow as a source of circulating CXCR4+ tissue-committed stem cells. Biol Cell 2005; 97: 133–146.

    Article  CAS  Google Scholar 

  45. Kucia M, Ratajczak J, Ratajczak MZ . Are bone marrow stem cells plastic or heterogenous—that is the question. Exp Hematol 2005; 33: 613–623.

    Article  Google Scholar 

  46. Kucia M, Dawn B, Hunt G, Guo Y, Wysoczynski M, Majka M et al. Cells expressing early cardiac markers reside in the bone marrow and are mobilized into the peripheral blood after myocardial infarction. Circ Res 2004; 95: 1191–1199.

    Article  CAS  Google Scholar 

  47. Kucia M, Zhang PY, Reca R, Wysoczynski M, Machalinski B, Ildstad ST et al. Cells enriched in markers of neural tissue-committed stem cells (TCSC) reside in the bone marrow and are mobilized into the peripheral blood following stroke. Leukemia 2006; 20: 18–28.

    Article  CAS  Google Scholar 

  48. Goodell MA, McKinney-Freeman S, Camargo FD . Isolation and characterization of side population cells. Methods Mol Biol 2005; 290: 343–352.

    Google Scholar 

  49. Goodell MA, Brose K, Paradis G, Conner AS, Mulligan RC . Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. J Exp Med 1996; 183: 1797–1806.

    Article  CAS  Google Scholar 

  50. Jackson KA, Majka SM, Wang H, Pocius J, Hartley CJ, Majesky MW et al. Regeneration of ischemic cardiac muscle and vascular endothelium by adult stem cells. J Clin Invest 2001; 107: 1395–1402.

    Article  CAS  Google Scholar 

  51. Macpherson H, Keir P, Webb S, Samuel K, Boyle S, Bickmore W et al. Bone marrow-derived SP cells can contribute to the respiratory tract of mice in vivo. J Cell Sci 2005; 118: 2441–2450.

    Article  CAS  Google Scholar 

  52. Ponomaryov T, Peled A, Petit I, Taichman RS, Habler L, Sandbank J et al. Induction of the chemokine stromal-derived factor-1 following DNA damage improves human stem cell function. J Clin Invest 2000; 106: 1331–1339.

    Article  CAS  Google Scholar 

  53. Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 2004; 10: 858–864.

    Article  CAS  Google Scholar 

  54. Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM . Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene. Cancer Cell 2003; 3: 347–361.

    Article  Google Scholar 

  55. Kucia M, Reca R, Miekus K, Wanzeck J, Wojakowski W, Janowska-Wieczorek A et al. Trafficking of normal stem cells and metastasis of cancer stem cells involve similar mechanisms: pivotal role of the SDF-1-CXCR4 axis. Stem Cells 2005; 23: 879–894.

    Article  CAS  Google Scholar 

  56. Kucia M, Reca R, Baran J, Machalinski B, Ratajczak J, Ratajczak MZ . The migration of bone marrow-derived non-hematopoietic tissue committed stem cells (TCSC) is regulated in SDF-1, HGF and LIF-dependent manner. Arch Immun et Ther Exp 2006 (in press).

  57. Guo Y, Hangoc G, Bian H, Pelus LM, Broxmeyer HE . SDF-1/CXCL12 enhances survival and chemotaxis of murine embryonic stem cells and production of primitive and definitive hematopoietic progenitor cells. Stem Cells 2005; 23: 1324–1332.

    Article  CAS  Google Scholar 

  58. Schwartz RE, Reyes M, Koodie L, Jiang Y, Blackstad M, Lund T et al. Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. J Clin Invest 2002; 109: 1291–1302.

    Article  CAS  Google Scholar 

  59. Kogler G, Sensken S, Airey JA, Trapp T, Muschen M, Feldhahn N et al. A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential. J Exp Med 2004; 200: 123–135.

    Article  Google Scholar 

  60. D’Ippolito G, Diabira S, Howard GA, Menei P, Roos BA, Schiller PC . Marrow-isolated adult multilineage inducible (MIAMI) cells, a unique population of postnatal young and old human cells with extensive expansion and differentiation potential. J Cell Sci 2004; 117: 2971–2981.

    Article  Google Scholar 

  61. Vacanti MP, Roy A, Cortiella J, Bonassar L, Vacanti CA . Identification and initial characterization of spore-like cells in adult mammals. J Cell Biochem 2001; 80: 455–460.

    Article  CAS  Google Scholar 

  62. Houghton J, Stoicov C, Nomura S, Rogers AB, Carlson J, Li H et al. Gastric cancer originating from bone marrow-derived cells. Science 2004; 306: 1568–1571.

    Article  CAS  Google Scholar 

  63. Sell S . Stem cell origin of cancer and differentiation therapy. Crit Rev Oncol Hematol 2004; 51: 1–28.

    Article  Google Scholar 

  64. Gazitt Y . Homing and mobilization of hematopoietic stem cells and hematopoietic cancer cells are mirror image processes, utilizing similar signaling pathways and occurring concurrently: circulating cancer cells constitute an ideal target for concurrent treatment with chemotherapy and antilineage-specific antibodies. Leukemia 2004; 18: 1–10.

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by an NIH Grant R01 CA106281-01 and KLCRP Grant to MZR. The authors thank Chris Worth from JGB Cancer Center and Sue Rice from cytometry facility at Indiana University for help with sorting cells. The technical help of Cathie Caple for preparing TEM analysis is also appreciated.

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  1. Stem Cell Biology Program at James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA

    M Kucia, R Reca, F R Campbell, E Zuba-Surma, M Majka, J Ratajczak & M Z Ratajczak

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  1. M Kucia
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Correspondence to M Z Ratajczak.

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Kucia, M., Reca, R., Campbell, F. et al. A population of very small embryonic-like (VSEL) CXCR4+SSEA-1+Oct-4+ stem cells identified in adult bone marrow. Leukemia 20, 857–869 (2006). https://doi.org/10.1038/sj.leu.2404171

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