Molecules and Cells

, Volume 29, Issue 6, pp 533–538

Molecular characterization of isolated from murine adult tissues very small embryonic/epiblast like stem cells (VSELs)

  • Dong-Myung Shin
  • Rui Liu
  • Izabela Klich
  • Janina Ratajczak
  • Magda Kucia
  • Mariusz Z. Ratajczak
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Abstract

Pluripotent very small embryonic/epiblast derived stem cells (VSELs) as we hypothesize are deposited at begin of gastrulation in developing tissues and play an important role as backup population of pluripotent stem cells (PSCs) for tissue committed stem cells (TCSCs). We envision that during steady state conditions these cells may be involved in tissue rejuvenation and in processes of regeneration/repair after organ injuries. Molecular analysis of adult bone marrow (BM)-derived purified VSELs revealed that they i) express pluripotent stem cells markers e.g., Oct4, Nanog, Klf-4, SSEA-1 ii) share several markers characteristic for epiblast as well as migratory primordial germ cells (PGCs), and iii) possess a unique pattern of genomic imprinting (e.g., erasure of differently methylated regions at Igf2-H19 and Rasgrf1 loci and hypermethylation at KCNQ1 and Igf2R loci). This supports that VSELs are related to epiblast-derived migrating PGC-like cells and, despite their pluripotent stem cell character, changes in the epigenetic signature of imprinted genes keep these cells quiescent in adult tissues and prevent them from teratoma formation. In contrast epigenetic changes/mutations that lead to activation of imprinted genes could potentially lead to tumor formation by these cells. Mounting evidence accumulates that perturbation of expression of imprinted genes is a common phenomenon observed in developing tumors.

Keywords

epiblast genomic imprinting Oct4 PGC VSEL 

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References

  1. Beltrami, A.P., Cesselli, D., Bergamin, N., Marcon, P., Rigo, S., Puppato, E., D’Aurizio, F., Verardo, R., Piazza, S., Pignatelli, A., et al. (2007). Multipotent cells can be generated in vitro from several adult human organs (heart, liver, and bone marrow). Blood 110, 3438–3446.CrossRefPubMedGoogle Scholar
  2. D’Ippolito, G., Diabira, S., Howard, G.A., Menei, P., Roos, B.A., and 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. J. Cell Sci. 117, 2971–2981.CrossRefPubMedGoogle Scholar
  3. De Miguel, M.P., Arnalich Montiel, F., Lopez Iglesias, P., Blazquez Martinez, A., and Nistal, M. (2009). Epiblast-derived stem cells in embryonic and adult tissues. Int. J. Dev. Biol. 53, 1529–1540.CrossRefPubMedGoogle Scholar
  4. Hayashi, K., de Sousa Lopes, S.M., and Surani, M.A. (2007). Germ cell Specification in mice. Science 316, 394–396.CrossRefPubMedGoogle Scholar
  5. Hayashi, K., Lopes, S.M., Tang, F., and Surani, M.A. (2008). Dynamic equilibrium and heterogeneity of mouse pluripotent stem cells with distinct functional and epigenetic states. Cell Stem Cell 3, 391–401.CrossRefPubMedGoogle Scholar
  6. Jiang, Y., Jahagirdar, B.N., Reinhardt, R.L., Schwartz, R.E., Keene, C.D., Ortiz-Gonzalez, X.R., Reyes, M., Lenvik, T., Lund, T., Blackstad, M., et al. (2002). Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418, 41–49.CrossRefPubMedGoogle Scholar
  7. Kritzenberger, M., and Wrobel, K.-H. (2004). Histochemical in situ identification of bovine embryonic blood cells reveals differences to the adult haematopoietic system and suggests a close relationship between haematopoietic stem cells and primordial germ cells. Histochem. Cell Biol. 121, 273–289.CrossRefPubMedGoogle Scholar
  8. Kucia, M., Zhang, Y.P., Reca, R., Wysoczynski, M., Machalinski, B., Majka, M., Ildstad, S.T., Ratajczak, J., Shields, C.B., and Ratajczak, M.Z. (2005). 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, 18–28.CrossRefGoogle Scholar
  9. Kucia, M., Reca, R., Campbell, F.R., Zuba-Surma, E., Majka, M., Ratajczak, J., and Ratajczak, M.Z. (2006). A population of very small embryonic-like (VSEL) CXCR4+SSEA-1+Oct-4+ stem cells identified in adult bone marrow. Leukemia 20, 857–869.CrossRefPubMedGoogle Scholar
  10. Kucia, M., Wu, W., and Ratajczak, M.Z. (2007). Bone marrow-derived very small embryonic-like stem cells: Their developmental origin and biological significance. Dev. Dyn. 236, 3309–3320.CrossRefPubMedGoogle Scholar
  11. Lengner, C.J., Camargo, F.D., Hochedlinger, K., Welstead, G.G., Zaidi, S., Gokhale, S., Scholer, H.R., Tomilin, A., and Jaenisch, R. (2007). Oct4 Expression Is Not Required for Mouse Somatic Stem Cell Self-Renewal. Cell Stem Cell 1, 403–415.CrossRefPubMedGoogle Scholar
  12. Liedtke, S., Enczmann, J., Waclawczyk, S., Wernet, P., and Kögler, G. (2007). Oct4 and its pseudogenes confuse stem cell research. Cell Stem Cell 1, 364–366.CrossRefPubMedGoogle Scholar
  13. Lux, C.T., Yoshimoto, M., McGrath, K., Conway, S.J., Palis, J., and Yoder, M.C. (2008). All primitive and definitive hematopoietic progenitor cells emerging before E10 in the mouse embryo are products of the yolk sac. Blood 111, 3435–3438.CrossRefPubMedGoogle Scholar
  14. Mikkola, H.K.A., and Orkin, S.H. (2006). The journey of developing hematopoietic stem cells. Development 133, 3733–3744.CrossRefPubMedGoogle Scholar
  15. Ohtaka, T., Matsui, Y., and Obinata, M. (1999). Hematopoietic development of primordial germ cell-derived mouse embryonic germ cells in culture. Biochem. Biophys. Res. Commun. 260, 475–482.CrossRefPubMedGoogle Scholar
  16. Paczkowska, E., Kucia, M., Koziarska, D., Halasa, M., Safranow, K., Masiuk, M., Karbicka, A., Nowik, M., Nowacki, P., Ratajczak, M.Z. et al. (2009). Clinical evidence that very small embryoniclike stem cells are mobilized into peripheral blood in patients after stroke. Stroke 40, 1237–1244.CrossRefPubMedGoogle Scholar
  17. Pochampally, R.R., Smith, J.R., Ylostalo, J., and 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, 1647–1652.CrossRefPubMedGoogle Scholar
  18. Ratajczak, M. Z., Machalinski, B., Wojakowski, W., Ratajczak, J. and Kucia, M. (2007) A hypothesis for an embryonic origin of pluripotent Oct-4+ stem cells in adult bone marrow and other tissues. Leukemia 21, 860–867.PubMedGoogle Scholar
  19. Ratajczak, M. Z., Zuba-Surma, E. K., Shin, D.-M., Ratajczak, J. and Kucia, M. (2008) Very small embryonic-like (VSEL) stem cells in adult organs and their potential role in rejuvenation of tissues and longevity. Exp Gerontol 43, 1009–1017.CrossRefPubMedGoogle Scholar
  20. Ratajczak, M.Z., Lee, H., Wysoczynski, M., Wan, W., Marlicz, W., Laughlin, M.J., Kucia, M., Janowska-Wieczorek, A., and Ratajczak, J. (2010). Novel insight into stem cell mobilization-Plasma sphingosine-1-phosphate is a major chemoattractant that directs the egress of hematopoietic stem progenitor cells from the bone marrow and its level in peripheral blood increases during mobilization due to activation of complement cascade/membrane attack complex. Leukemia 24, 976–985.CrossRefPubMedGoogle Scholar
  21. Reik, W., and Walter, J. (2001). Genomic imprinting: parental influence on the genome. Nat. Rev. Genet 2, 21–32.CrossRefPubMedGoogle Scholar
  22. Rich, I.N. (1995). Primordial germ cells are capable of producing cells of the hematopoietic system in vitro. Blood 86, 463–472.PubMedGoogle Scholar
  23. Saito, A., Watanabe, K., Kusakabe, T., Abe, M., and Suzuki, T. (1998). Mediastinal mature teratoma with coexistence of angiosarcoma, granulocytic sarcoma and a hematopoietic region in the tumor: a rare case of association between hematological malignancy and mediastinal germ cell tumor. Pathol. Int. 48, 749–753.CrossRefPubMedGoogle Scholar
  24. Shin, D.M., Zuba-Surma, E.K., Wu, W., Ratajczak, J., Wysoczynski, M., Ratajczak, M.Z., and Kucia, M. (2009). Novel epigenetic mechanisms that control pluripotency and quiescence of adult bone marrow-derived Oct4+ very small embryonic-like stem cells. Leukemia 23, 2042–2051.CrossRefPubMedGoogle Scholar
  25. Shin, D.M., Rui, L., Klich I., Wu, W., Ratajczak, J., Kucia M., and Ratajczak, M.Z. (2010). Molecular signature of adult bone marrow-purified very small embryonic-like stem cells supports their developmental epiblast/germ line origin. Leukemia (In press, doi: 10.1038/leu.2010.121).Google Scholar
  26. Tam, P.P.L., and Loebel, D.A.F. (2007). Gene function in mouse embryogenesis: get set for gastrulation. Nat. Rev. Genet. 8, 368–381.CrossRefPubMedGoogle Scholar
  27. Wojakowski, W., Tendera, M., Kucia, M., Zuba-Surma, E., Paczkowska, E., Ciosek, J., Hałasa, M., Król, M., Kazmierski, M., Buszman, P., et al. (2009). Mobilization of bone marrow-derived Oct-4+ SSEA-4+ very small embryonic-like stem cells in patients with acute myocardial infarction. J. Am. Coll. Cardio. 53, 1–9.CrossRefGoogle Scholar
  28. Zuba-Surma, E.K., Kucia, M., Wu, W., Klich, I., Jr., J.W.L., Ratajczak, J., and Ratajczak, M.Z. (2008). Very small embryonic-like stem cells are present in adult murine organs: Image Stream-based morphological analysis and distribution studies. Cytometry Part A 73A, 1116–1127.CrossRefGoogle Scholar
  29. Zuba-Surma, E.K., Klich, I., Wysoczynski, M., Greco, N.J., Laughlin, M.J., Ratajczak, M.Z., and Ratajczak, J. (2009a). In vitro and in vivo evidence that umbilical cord blood (UCB)-derived CD45-/SSEA-4+/OCT-4+/CD133+/CXCR4+/Lin- very small embryonic/epiblast like stem cells (VSELs) do not contain clonogenic hematopoietic progenitors but are highly enriched in more primitive stem cells - novel view on hierarchy of UCB stem cell compartment. ASH Annual Meeting Abstracts 114, 35.Google Scholar
  30. Zuba-Surma, E.K., Kucia, M., Ratajczak, J., and Ratajczak, M.Z. (2009b). “Small stem cells” in adult tissues: Very small embryonic-like stem cells stand up! Cytometry Part A 75A, 4–13.CrossRefGoogle Scholar
  31. Zuba-Surma, E.K., Kucia, M., Rui, L., Shin, D.-M., Wojakowski, W., Ratajczak, J., and Ratajczak, M.Z. (2009c). Fetal liver very small embryonic/epiblast like stem cells follow developmental migratory pathway of hematopoietic stem cells. Ann. N Y Acad. Sci. 1176, 205–218.CrossRefPubMedGoogle Scholar

Copyright information

© The Korean Society for Molecular and Cellular Biology and Springer Netherlands 2010

Authors and Affiliations

  • Dong-Myung Shin
    • 1
  • Rui Liu
    • 1
  • Izabela Klich
    • 1
  • Janina Ratajczak
    • 1
    • 2
  • Magda Kucia
    • 1
    • 2
  • Mariusz Z. Ratajczak
    • 1
    • 2
  1. 1.Stem Cell Institute at the James Graham Brown Cancer CenterUniversity of LouisvilleLouisvilleUSA
  2. 2.Department of PhysiologyPomeranian Medcial UniversitySzczecinPoland

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