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Very Small Embryonic-Like (VSEL) Stem Cells: Purification from Adult Organs, Characterization, and Biological Significance

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Abstract

In this review, we discuss current views of the bone marrow (BM) stem cell (SC) compartment and present data showing that BM contains heterogeneous populations of hematopoietic (H)SCs and non-HSCs. These cells are variously described in the literature as: endothelial progenitor cells (EPCs); mesenchymal (M)SCs; multipotent adult progenitor cells (MAPCs); marrow-isolated adult multilineage inducible (MIAMI) cells; and multipotent adult (MA)SCs. In some cases, it is likely that similar or overlapping populations of primitive SCs in the BM detected using various experimental strategies were assigned different names. Recently, we purified rare CXC chemokine receptor 4 expressing (CXCR4+) small SCs from the murine BM that express markers characteristic for embryonic (E)SCs, epiblast (EP)SCs, and primordial germ cells (PGCs). We named these primitive cells very small embryonic-like (VSEL) SCs. Our data indicate that VSELs may differentiate into cells from all three germ layers.

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References

  1. Asahara, T., Murohara, T., Sullivan, A., et al. (1997). Isolation of putative progenitor endothelial cells for angiogenesis. Science, 275(5302), 964–967.

    Article  PubMed  CAS  Google Scholar 

  2. Shi, Q., Rafii, S., Wu, M. H., et al. (1998). Evidence for circulating bone marrow-derived endothelial cells. Blood, 92(2), 362–367.

    PubMed  CAS  Google Scholar 

  3. Peister, A., Mellad, J. A., Larson, B. L., Hall, B. M., Gibson, L. F., & Prockop, D. J. (2004). Adult stem cells from bone marrow (MSCs) isolated from different strains of inbred mice vary in surface epitopes, rates of proliferation, and differentiation potential. Blood, 103(5), 1662–1668.

    Article  PubMed  CAS  Google Scholar 

  4. Prockop, D. J. (1997). Marrow stromal cells as stem cells for nonhematopoietic tissues. Science, 276(5309), 71–74.

    Article  PubMed  CAS  Google Scholar 

  5. Jiang, Y., Vaessen, B., Lenvik, T., Blackstad, M., Reyes, M., & Verfaillie, C. M. (2002). Multipotent progenitor cells can be isolated from postnatal murine bone marrow, muscle, and brain. Experimental Hematology, 30(8), 896–904.

    Article  PubMed  CAS  Google Scholar 

  6. D’Ippolito, G., Diabira, S., Howard, G. A., Menei, P., Roos, B. A., & Schiller, P. C. (2004). Marrow-isolated adult multilineage inducible (MIAMI) cells, a unique population of postnatal young and old human cells with extensive expansion and differentiation potential. Journal of Cell Science, 117(14), 2971–2981.

    Article  PubMed  CAS  Google Scholar 

  7. Beltrami, A. P., Cesselli, D., Bergamin, N., et al. (2007). Multipotent cells can be generated in vitro from several adult human organs (heart, liver and bone marrow). Blood, 110(9), 3438–3446.

    Article  PubMed  CAS  Google Scholar 

  8. Johnson, J., Bagley, J., Skaznik-Wikiel, M., et al. (2005). Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood. Cell, 122(2), 303–315.

    Article  PubMed  CAS  Google Scholar 

  9. Nayernia, K., Lee, J. H., Drusenheimer, N., et al. (2006). Derivation of male germ cells from bone marrow stem cells. Laboratory Investigation, 86(7), 654–663.

    Article  PubMed  CAS  Google Scholar 

  10. Nagasawa, T. (2000). A chemokine, SDF-1/PBSF, and its receptor, CXC chemokine receptor 4, as mediators of hematopoiesis. International Journal of Hematology, 72(4), 408–411.

    PubMed  CAS  Google Scholar 

  11. Kollet, O., Shivtiel, S., Chen, Y. Q., et al. (2003). HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34+ stem cell recruitment to the liver. Journal of Clinical Investigation, 112(2), 160–169.

    PubMed  CAS  Google Scholar 

  12. Kucia, M., Dawn, B., Hunt, G., et al. (2004). Cells expressing early cardiac markers reside in the bone marrow and are mobilized into the peripheral blood after myocardial infarction. Circulation Research, 95(12), 1191–1199.

    Article  PubMed  CAS  Google Scholar 

  13. Kucia, M., Reca, R., Campbell, F. R., et al. (2006). A population of very small embryonic-like (VSEL) CXCR4(+)SSEA-1(+)Oct-4+ stem cells identified in adult bone marrow. Leukemia, 20(5), 857–869.

    Article  PubMed  CAS  Google Scholar 

  14. Kucia, M., Wojakowski, W., Reca, R., et al. (2006). The migration of bone marrow-derived non-hematopoietic tissue-committed stem cells is regulated in an SDF-1-, HGF-, and LIF-dependent manner. Archivum Immunologiae Et Therapiae Experimentalis (Warsz), 54(2), 121–135.

    Article  CAS  Google Scholar 

  15. Kucia, M., Zhang, Y. P., Reca, R., et al. (2006). Cells enriched in markers of neural tissue-committed stem cells reside in the bone marrow and are mobilized into the peripheral blood following stroke. Leukemia, 20(1), 18–28.

    Article  PubMed  CAS  Google Scholar 

  16. Di Campli, C., Piscaglia, A. C., Pierelli, L., et al. (2004). A human umbilical cord stem cell rescue therapy in a murine model of toxic liver injury. Digestive and Liver Disease, 36(9), 603–613.

    Article  PubMed  Google Scholar 

  17. Orlic, D., Kajstura, J., Chimenti, S., et al. (2001). Bone marrow cells regenerate infarcted myocardium. Nature, 410(6829), 701–715.

    Article  PubMed  CAS  Google Scholar 

  18. Lagasse, E., Connors, H., Al-Dhalimy, M., et al. (2000). Purified hematopoietic stem cells can differentiate into hepatocytes in vivo. Natural Medicines, 6(11), 1229–1234.

    Article  CAS  Google Scholar 

  19. Mezey, E., Chandross, K. J., Harta, G., Maki, R. A., & McKercher, S. R. (2000). Turning blood into brain: Cells bearing neuronal antigens generated in vivo from bone marrow. Science, 290(5497), 1779–1782.

    Article  PubMed  CAS  Google Scholar 

  20. Herzog, E. L., Chai, L., & Krause, D. S. (2003). Plasticity of marrow-derived stem cells. Blood, 102(10), 3483–3493.

    Article  PubMed  CAS  Google Scholar 

  21. Hess, D. C., Abe, T., Hill, W. D., et al. (2004). Hematopoietic origin of microglial and perivascular cells in brain. Experimental Neurology, 186(2), 134–144.

    Article  PubMed  CAS  Google Scholar 

  22. Corti, S., Locatelli, F., Donadoni, C., et al. (2002). Neuroectodermal and microglial differentiation of bone marrow cells in the mouse spinal cord and sensory ganglia. Journal of Neuroscience Research, 70(6), 721–733.

    Article  PubMed  CAS  Google Scholar 

  23. Petersen, B. E., Bowen, W. C., Patrene, K. D., et al. (1999). Bone marrow as a potential source of hepatic oval cells. Science, 284(5417), 1168–1170.

    Article  PubMed  CAS  Google Scholar 

  24. Orkin, S. H., & Zon, L. I. (2002). Hematopoiesis and stem cells: Plasticity versus developmental heterogeneity. Nature Immunology, 3(4), 323–328.

    Article  PubMed  CAS  Google Scholar 

  25. Wagers, A. J., Sherwood, R. I., Christensen, J. L., & Weissman, I. L. (2002). Little evidence for developmental plasticity of adult hematopoietic stem cells. Science, 297(5590), 2256–2259.

    Article  PubMed  CAS  Google Scholar 

  26. Murry, C. E., Soonpaa, M. H., Reinecke, H., et al. (2004). Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature, 428(6983), 664–668.

    Article  PubMed  CAS  Google Scholar 

  27. Castro, R. F., Jackson, K. A., Goodell, M. A., Robertson, C. S., Liu, H., & Shine, H. D. (2002). Failure of bone marrow cells to transdifferentiate into neural cells in vivo. Science, 297(5585), 1299.

    Article  PubMed  CAS  Google Scholar 

  28. Morshead, C. M., Benveniste, P., Iscove, N. N., & van der Kooy, D. ( 2002). Hematopoietic competence is a rare property of neural stem cells that may depend on genetic and epigenetic alterations. Natural Medicines, 8(3), 268–273.

    Article  CAS  Google Scholar 

  29. Quesenberry, P. J., Colvin, G., Dooner, G., Dooner, M., Aliotta, J. M., & Johnson, K. (2007). The stem cell continuum: Cell cycle, injury, and phenotype lability. Annals of the New York Academy of Sciences, 1106, 20–29.

    Article  PubMed  Google Scholar 

  30. Terada, N., Hamazaki, T., Oka, M., et al. (2002). Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature, 416(6880), 542–545.

    Article  PubMed  CAS  Google Scholar 

  31. Harris, R. G., Herzog, E. L., Bruscia, E. M., Grove, J. E., Van Arnam, J. S., & Krause, D. S. (2004). Lack of a fusion requirement for development of bone marrow-derived epithelia. Science, 305(5680), 90–93.

    Article  PubMed  CAS  Google Scholar 

  32. Rafii, S., & Lyden, D. L. (2003). Therapeutic stem and progenitor cell transplantation for organ vascularization and regeneration. Natural Medicines, 9(6), 702–712.

    Article  CAS  Google Scholar 

  33. Ratajczak, J., Wysoczynski, M., Hayek, F., Janowska-Wieczorek, A., & Ratajczak, M. Z. (2006). Membrane-derived microvesicles: Important and underappreciated mediators of cell-to-cell communication. Leukemia, 20(9), 1487–1495.

    Article  PubMed  CAS  Google Scholar 

  34. Morel, O., Toti, F., Hugel, B., & Freyssinet, J. M. (2004). Cellular microparticles: A disseminated storage pool of bioactive vascular effectors. Current Opinion in Hematology, 11(3), 156–164.

    Article  PubMed  CAS  Google Scholar 

  35. Ratajczak, J., Miekus, K., Kucia, M., et al. (2006). Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: Evidence for horizontal transfer of mRNA and protein delivery. Leukemia, 20(5), 847–856.

    Article  PubMed  CAS  Google Scholar 

  36. Aliotta, J. M., Sanchez-Guijo, F. M., Dooner, G. J., et al. (2007). Alteration of marrow cell gene expression, protein production, and engraftment into lung by lung-derived microvesicles: A novel mechanism for phenotype modulation. Stem Cells, 25(9), 2245–2256.

    Article  PubMed  Google Scholar 

  37. Deregibus, M. C., Cantaluppi, V., Calogero, R., et al. (2007). Endothelial progenitor cell derived microvesicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA. Blood, 110(7), 2440–2448.

    Article  PubMed  CAS  Google Scholar 

  38. Ratajczak, M. Z., Kucia, M., Reca, R., Majka, M., Janowska-Wieczorek, A., & Ratajczak, J. (2004). Stem cell plasticity revisited: CXCR4-positive cells expressing mRNA for early muscle, liver and neural cells ‘‘hide out’’ in the bone marrow. Leukemia, 18(1), 29–40.

    Article  PubMed  CAS  Google Scholar 

  39. Kucia, M., Reca, R., Jala, V. R., Dawn, B., Ratajczak, J., & Ratajczak, M. Z. (2005). Bone marrow as a home of heterogenous populations of nonhematopoietic stem cells. Leukemia, 19(7), 1118–1127.

    Article  PubMed  CAS  Google Scholar 

  40. Lengner, C. J., Camargo, F. D., Hochedlinger, K., et al. (2007). Oct4 expression is not required for mouse somatic stem cell self-renewal. Cell Stem Cell, 1(4), 403–415.

    Article  PubMed  CAS  Google Scholar 

  41. Asahara, T., Masuda, H., Takahashi, T., et al. (1999). Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circulation Research, 85(3), 221–228.

    PubMed  CAS  Google Scholar 

  42. Bailey, A. S., Willenbring, H., Jiang, S., et al. (2006). Myeloid lineage progenitors give rise to vascular endothelium. Proceedings of the National Academy of Sciences of the United States of America, 103(35), 13156–13161.

    Article  PubMed  CAS  Google Scholar 

  43. Ingram, D. A., Caplice, N. M., & Yoder, M. C. (2005). Unresolved questions, changing definitions, and novel paradigms for defining endothelial progenitor cells. Blood, 106(5), 1525–1531.

    Article  PubMed  CAS  Google Scholar 

  44. Friedenstein, A. J., Piatetzky-Shapiro, I. I., & Petrakova, K. V. (1966). Osteogenesis in transplants of bone marrow cells. Journal of Embryology and Experimental Morphology, 16(3), 381–390.

    PubMed  CAS  Google Scholar 

  45. Friedenstein, A. J., Petrakova, K. V., Kurolesova, A. I., & Frolova, G. P. (1968). Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation, 6(2), 230–247.

    Article  PubMed  CAS  Google Scholar 

  46. Friedenstein, A. J., Deriglasova, U. F., Kulagina, N. N., et al. (1974). Precursors for fibroblasts in different populations of hematopoietic cells as detected by the in vitro colony assay method. Experimental Hematology, 2(2), 83–92.

    PubMed  CAS  Google Scholar 

  47. Pittenger, M. F., Mackay, A. M., Beck, S. C., et al. (1999). Multilineage potential of adult human mesenchymal stem cells. Science, 284(5411), 143–147.

    Article  PubMed  CAS  Google Scholar 

  48. Son, B. R., Marquez-Curtis, L. A., Kucia, M., et al. (2006). Migration of bone marrow and cord blood mesenchymal stem cells in vitro is regulated by stromal-derived factor-1-CXCR4 and hepatocyte growth factor-c-met axes and involves matrix metalloproteinases. Stem Cells, 24(5), 1254–1264.

    Article  PubMed  CAS  Google Scholar 

  49. Colter, D. C., Sekiya, I., & Prockop, D. J. (2001). Identification of a subpopulation of rapidly self-renewing and multipotential adult stem cells in colonies of human marrow stromal cells. Proceedings of the National Academy of Sciences of the United States of America, 98(14), 7841–7845.

    Article  PubMed  CAS  Google Scholar 

  50. Pochampally, R. R., Smith, J. R., Ylostalo, J., & Prockop, D. J. (2004). Serum deprivation of human marrow stromal cells (hMSCs) selects for a subpopulation of early progenitor cells with enhanced expression of OCT-4 and other embryonic genes. Blood, 103(5), 1647–1652.

    Article  PubMed  CAS  Google Scholar 

  51. Lamoury, F. M., Croitoru-Lamoury, J., & Brew, B. J. (2006). Undifferentiated mouse mesenchymal stem cells spontaneously express neural and stem cell markers Oct-4 and Rex-1. Cytotherapy, 8(3), 228–242.

    Article  PubMed  CAS  Google Scholar 

  52. Eggan, K., Jurga, S., Gosden, R., Min, I. M., & Wagers, A. J. (2006). Ovulated oocytes in adult mice derive from non-circulating germ cells. Nature, 441(7097), 1109–1114.

    Article  PubMed  CAS  Google Scholar 

  53. Zuba-Surma, E. K., Kucia, M., Abdel-Latif, A., et al. (2008). Morphological characterization of very small embryonic-like stem cells (VSELs) by ImageStream system analysis. Journal of Cellular and Molecular Medicine, 12, 292–303 (Nov 20).

    Article  PubMed  Google Scholar 

  54. Basiji, D. A., Ortyn, W. E., Liang, L., Venkatachalam, V., & Morrissey, P. (2007). Cellular image analysis and imaging by flow cytometry. Clinical Laboratory Management Review, 27(3), 653–670.

    Article  Google Scholar 

  55. Zuba-Surma, E. K., Kucia, M., Abdel-Latif, A., Lillard, J. J., & Ratajczak, M. Z. (2007). The ImageStream System: A key step to a new era in imaging. Folia Histochemica et Cytobiologica, 45(5), 279–290.

    PubMed  Google Scholar 

  56. Zuba-Surma, E. K., Kucia, M., & Ratajczak, M. Z. (2008). “Decoding of Dot”: The ImageStream System (ISS) as a supportive tool for flow cytometric analysis. Central European Journal of Biology, 3(1), 1–10.

    Article  Google Scholar 

  57. Ortyn, W. E., Hall, B. E., George, T. C., et al. (2006). Sensitivity measurement and compensation in spectral imaging. Cytometry A, 69A, 852–862.

    Article  Google Scholar 

  58. Kucia, M., Halasa, M., Wysoczynski, M., et al. (2007). Morphological and molecular characterization of novel population of CXCR4(+) SSEA-4(+) Oct-4(+) very small embryonic-like cells purified from human cord blood—Preliminary report. Leukemia, 21(2), 297–303.

    Article  PubMed  CAS  Google Scholar 

  59. Krause, D. S., Theise, N. D., Collector, M. I., et al. (2001). Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell, 105(3), 369–377.

    Article  PubMed  CAS  Google Scholar 

  60. Ratajczak, M. Z., Machalinski, B., Wojakowski, W., Ratajczak, J., & Kucia, M. A. (2007). hypothesis for an embryonic origin of pluripotent Oct-4+ stem cells in adult bone marrow and other tissues. Leukemia, 21, 860–867.

    PubMed  CAS  Google Scholar 

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Acknowledgments

Supported by NIH grant R01 CA106281-01 to MZR. The authors wish to thank for critical evaluation and discussion. We also thank Andrew Marsh at the JGBCC for editorial help.

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Authors and Affiliations

  1. Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, 500 South Floyd Street, Louisville, KY, 40202, USA

    Mariusz Z. Ratajczak, Ewa K. Zuba-Surma, Bogdan Machalinski, Janina Ratajczak & Magda Kucia

  2. Department of Physiopathology, Pomeranian Medical University, Szczecin, Poland

    Mariusz Z. Ratajczak, Ewa K. Zuba-Surma, Bogdan Machalinski, Janina Ratajczak & Magda Kucia

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  1. Mariusz Z. Ratajczak
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  2. Ewa K. Zuba-Surma
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Correspondence to Mariusz Z. Ratajczak.

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Ratajczak, M.Z., Zuba-Surma, E.K., Machalinski, B. et al. Very Small Embryonic-Like (VSEL) Stem Cells: Purification from Adult Organs, Characterization, and Biological Significance. Stem Cell Rev 4, 89–99 (2008). https://doi.org/10.1007/s12015-008-9018-0

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