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Stem Cells

Molecular signature of adult bone marrow-purified very small embryonic-like stem cells supports their developmental epiblast/germ line origin

Leukemia volume 24, pages 1450–1461 (2010)Cite this article

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Abstract

We postulated that Oct4+SSEA-1+Sca-1+Lin−CD45− very small embryonic-like stem cells (VSELs) isolated from adult bone marrow (BM) could be a reserve population for tissue-committed stem cells. The aim of this study was to elucidate the developmental origin of these cells. We report that during embryogenesis, VSELs are enriched in embryonic day (E)12.5 murine fetal livers (FLs) and subsequently follow the developmental route of hematopoietic stem cells (H)SCs to colonize BM. Molecular analysis of purified VSELs revealed that both FL-derived VSELs and their adult BM-derived counterparts express: (i) several epiblast/primordial germ cell (PGC) markers; (ii) migrating PGC-like epigenetic reprogramming profiles of Oct4, Nanog and Stella loci; as well as (iii) a unique pattern of genomic imprinting. Thus, these data suggest that VSELs may originate from epiblast/migrating PGC-like cells and, in spite of the expression of pluripotent stem cell markers, changes in the epigenetic signature of imprinted genes keep these cells quiescent in adult tissues and prevent them from teratoma formation.

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References

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

    Article  CAS  PubMed  Google Scholar 

  2. Evans MJ, Kaufman MH . Establishment in culture of pluripotential cells from mouse embryos. Nature 1981; 292: 154–156.

    Article  CAS  PubMed  Google Scholar 

  3. Takahashi K, Yamanaka S . Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006; 126: 663–676.

    Article  CAS  PubMed  Google Scholar 

  4. Kucia M, Reca R, Campbell FR, Zuba-Surma E, Majka M, Ratajczak J et al. A population of very small embryonic-like (VSEL) CXCR4+SSEA-1+Oct-4+ stem cells identified in adult bone marrow. Leukemia 2006; 20: 857–869.

    Article  CAS  PubMed  Google Scholar 

  5. Zuba-Surma EK, Kucia M, Rui L, Shin D-M, Wojakowski W, Ratajczak J et al. Fetal liver very small embryonic/epiblast like stem cells follow developmental migratory pathway of hematopoietic stem cells. Ann NY Acad Sci 2009; 1176: 205–218.

    Article  PubMed  Google Scholar 

  6. Shin DM, Zuba-Surma EK, Wu W, Ratajczak J, Wysoczynski M, Ratajczak MZ et al. Novel epigenetic mechanisms that control pluripotency and quiescence of adult bone marrow-derived Oct4+ very small embryonic-like stem cells. Leukemia 2009; 23: 2042–2051.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Reik W, Walter J . Genomic imprinting: parental influence on the genome. Nat Rev Genet 2001; 2: 21–32.

    Article  CAS  PubMed  Google Scholar 

  8. Surani MA, Hayashi K, Hajkova P . Genetic and epigenetic regulators of pluripotency. Cell 2007; 128: 747–762.

    Article  CAS  PubMed  Google Scholar 

  9. Ginsburg M, Snow MH, McLaren A . Primordial germ cells in the mouse embryo during gastrulation. Development 1990; 110: 521–528.

    CAS  PubMed  Google Scholar 

  10. Rich IN . Primordial germ cells are capable of producing cells of the hematopoietic system in vitro. Blood 1995; 86: 463–472.

    CAS  PubMed  Google Scholar 

  11. Mikkola HKA, Orkin SH . The journey of developing hematopoietic stem cells. Development 2006; 133: 3733–3744.

    Article  CAS  PubMed  Google Scholar 

  12. De Miguel MP, Arnalich Montiel F, Lopez Iglesias P, Blazquez Martinez A, Nistal M . Epiblast-derived stem cells in embryonic and adult tissues. Int J Dev Biol 2009; 53: 1529–1540.

    Article  PubMed  Google Scholar 

  13. Hayashi K, Lopes SMCdS, Tang F, Surani MA . Dynamic equilibrium and heterogeneity of mouse pluripotent stem cells with distinct functional and epigenetic states. Cell Stem Cell 2008; 3: 391–401.

    Article  CAS  PubMed  Google Scholar 

  14. Brons IGM, Smithers LE, Trotter MWB, Rugg-Gunn P, Sun B, Chuva de Sousa Lopes SM et al. Derivation of pluripotent epiblast stem cells from mammalian embryos. Nature 2007; 448: 191–195.

    Article  CAS  PubMed  Google Scholar 

  15. Hayashi K, de Sousa Lopes SMC, Surani MA . Germ cell specification in mice. Science 2007; 316: 394–396.

    Article  CAS  PubMed  Google Scholar 

  16. Kurimoto K, Yabuta Y, Ohinata Y, Shigeta M, Yamanaka K, Saitou M . Complex genome-wide transcription dynamics orchestrated by Blimp1 for the specification of the germ cell lineage in mice. Genes Dev 2008; 22: 1617–1635.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hayashi K, Surani MA . Self-renewing epiblast stem cells exhibit continual delineation of germ cells with epigenetic reprogramming in vitro. Development 2009; 136: 3549–3556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Maatouk DM, Kellam LD, Mann MRW, Lei H, Li E, Bartolomei MS et al. DNA methylation is a primary mechanism for silencing postmigratory primordial germ cell genes in both germ cell and somatic cell lineages. Development 2006; 133: 3411–3418.

    Article  CAS  PubMed  Google Scholar 

  19. Hajkova P, Ancelin K, Waldmann T, Lacoste N, Lange UC, Cesari F et al. Chromatin dynamics during epigenetic reprogramming in the mouse germ line. Nature 2008; 452: 877–881.

    Article  CAS  PubMed  Google Scholar 

  20. Maldonado-Saldivia J, van den Bergen J, Krouskos M, Gilchrist M, Lee C, Li R et al. Dppa2 and Dppa4 are closely linked sap motif genes restricted to pluripotent cells and the germ line. Stem Cells 2007; 25: 19–28.

    Article  CAS  PubMed  Google Scholar 

  21. Lane N, Dean W, Erhardt S, Hajkova P, Surani A, Walter J et al. Resistance of IAPs to methylation reprogramming may provide a mechanism for epigenetic inheritance in the mouse. Genesis 2003; 35: 88–93.

    Article  CAS  PubMed  Google Scholar 

  22. Hajkova P, Erhardt S, Lane N, Haaf T, El-Maarri O, Reik W et al. Epigenetic reprogramming in mouse primordial germ cells. Mech Dev 2002; 117: 15–23.

    Article  CAS  PubMed  Google Scholar 

  23. Molyneaux KA, Stallock J, Schaible K, Wylie C . Time-lapse analysis of living mouse germ cell migration. Dev Biol 2001; 240: 488–498.

    Article  CAS  PubMed  Google Scholar 

  24. Vodyanik MA, Bork JA, Thomson JA, Slukvin II . Human embryonic stem cell-derived CD34+ cells: efficient production in the coculture with OP9 stromal cells and analysis of lymphohematopoietic potential. Blood 2005; 105: 617–626.

    Article  CAS  PubMed  Google Scholar 

  25. Ohtaka T, Matsui Y, Obinata M . Hematopoietic development of primordial germ cell-derived mouse embryonic germ cells in culture. Biochem Biophys Res Commun 1999; 260: 475–482.

    Article  CAS  PubMed  Google Scholar 

  26. Woodruff K, Wang N, May W, Adrone E, Denny C, Feig SA . The clonal nature of mediastinal germ cell tumors and acute myelogenous leukemia: A case report and review of the literature. Cancer Genet Cytogenet 1995; 79: 25–31.

    Article  CAS  PubMed  Google Scholar 

  27. Saito A, Watanabe K, Kusakabe T, Abe M, Suzuki T . 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 1998; 48: 749–753.

    Article  CAS  PubMed  Google Scholar 

  28. Kritzenberger M, Wrobel K-H . 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 2004; 121: 273–289.

    Article  CAS  PubMed  Google Scholar 

  29. Zuba-Surma EK, Klich I, Wysoczynski M, Greco NJ, Laughlin MJ, Ratajczak MZ et al. 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. Blood 2009; 114: 35.

    Google Scholar 

  30. Lux CT, Yoshimoto M, McGrath K, Conway SJ, Palis J, Yoder MC . All primitive and definitive hematopoietic progenitor cells emerging before E10 in the mouse embryo are products of the yolk sac. Blood 2008; 111: 3435–3438.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Shovlin TC, Durcova-Hills G, Surani A, McLaren A . Heterogeneity in imprinted methylation patterns of pluripotent embryonic germ cells derived from pre-migratory mouse germ cells. Dev Biol 2008; 313: 674–681.

    Article  CAS  PubMed  Google Scholar 

  32. Yabuta Y, Kurimoto K, Ohinata Y, Seki Y, Saitou M . Gene expression dynamics during germline specification in mice identified by quantitative single-cell gene expression profiling. Biol Reprod 2006; 75: 705–716.

    Article  CAS  PubMed  Google Scholar 

  33. Szabó PE, Mann JR . Biallelic expression of imprinted genes in the mouse germ line: implications for erasure, establishment, and mechanisms of genomic imprinting. Genes Dev 1995; 9: 1857–1868.

    Article  PubMed  Google Scholar 

  34. Lee J, Inoue K, Ono R, Ogonuki N, Kohda T, Kaneko-Ishino T et al. Erasing genomic imprinting memory in mouse clone embryos produced from day 11.5 primordial germ cells. Development 2002; 129: 1807–1817.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by NIH P20RR018733 from the National Center for Research Resources to MK and NIH R01 CA106281-01, NIH R01 DK074720, European Union structural funds, Innovative Economy Operational Program POIG.01.01.01-00-109/09-01 and the Henry M and Stella M Hoenig Endowment to MZR.

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

    D-M Shin, R Liu, I Klich, W Wu, J Ratajczak, M Kucia & M Z Ratajczak

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  1. D-M Shin
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  2. R Liu
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  3. I Klich
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  4. W Wu
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Correspondence to M Kucia or M Z Ratajczak.

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Shin, DM., Liu, R., Klich, I. et al. Molecular signature of adult bone marrow-purified very small embryonic-like stem cells supports their developmental epiblast/germ line origin. Leukemia 24, 1450–1461 (2010). https://doi.org/10.1038/leu.2010.121

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