Skip to main content

Very Small Embryonic Like Stem Cells (VSELs) and Their Hematopoietic Specification

  • Chapter
  • First Online:
Working with Stem Cells

Abstract

Evidence has accumulated that adult tissues, including bone marrow, contain developmentally early stem cells that remain in a dormant state as well as stem cells that are more proliferative, supplying tissue-specific progenitor cells, which, therefore, display an active role in the turnover of adult tissues. To support this idea, we have identified in adult tissues a population of dormant pluripotent very small embryonic/epiblast like stem cells (VSELs) that, as we hypothesize, are deposited at the begining of gastrulation in developing tissues and play an important role as backup population of tissue committed stem cells. We envision that during steady state conditions VSELs may be involved in tissue rejuvenation and in processes of regeneration/repair after organ injuries. These small cells, similarly to epiblast-derived migrating primordial germ cells, change the epigenetic signature of some of the parentally imprinted genes and remain quiescent in adult tissues, not growing into teratoma. In this chapter, we will present FACS based strategies on how to correctly detect, enumerate and sort these cells in murine bone marrow. We will also provide a protocol for hematopoietic specification of VSELs in a co-culture system using adherent OP-9 supportive cell line.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Anjos-Afonso F, Bonnet D (2007) Nonhematopoietic/endothelial SSEA-1+ cells define the most primitive progenitors in the adult murine bone marrow mesenchymal compartment. Blood 109:1298–1306

    Article  CAS  PubMed  Google Scholar 

  • Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM (1997) Isolation of putative progenitor endothelial cells for angiogenesis. Science 275:964–967

    Article  CAS  PubMed  Google Scholar 

  • Beltrami AP, Cesselli D, Bergamin N, Marcon P, Rigo S, Puppato E, D'Aurizio F, Verardo R, Piazza S, Pignatelli A, Poz A, Baccarani U, Damiani D, Fanin R, Mariuzzi L, Finato N, Masolini P, Burelli S, Belluzzi O, Schneider C, Beltrami CA (2007) Multipotent cells can be generated in vitro from several adult human organs (heart, liver, and bone marrow). Blood 110:3438–3446

    Article  CAS  PubMed  Google Scholar 

  • Chaganti RS, Ladanyi M, Samaniego F, Offit K, Reuter VE, Jhanwar SC, Bosl GJ (1989) Leukemic differentiation of a mediastinal germ cell tumor. Gene Chomosome Canc 1:83–87

    Article  CAS  Google Scholar 

  • D'Ippolito G, Diabira S, Howard GA, Menei P, Roos BA, Schiller PC (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

    Article  PubMed  Google Scholar 

  • Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM (2002) Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418:41–49

    Article  CAS  PubMed  Google Scholar 

  • Kogler G, Sensken S, Airey JA, Trapp T, Muschen M, Feldhahn N, Liedtke S, Sorg RV, Fischer J, Rosenbaum C, Greschat S, Knipper A, Bender J, Degistirici O, Gao J, Caplan AI, Colletti EJ, Almeida-Porada G, Muller HW, Zanjani E, Wernet P (2004) A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential. J Exp Med 200:123–135

    Article  PubMed  PubMed Central  Google Scholar 

  • Kucia M, Reca R, Campbell FR, Zuba-Surma E, Majka M, Ratajczak J, Ratajczak MZ (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

    Article  CAS  PubMed  Google Scholar 

  • Kucia M, Halasa M, Wysoczynski M, Baskiewicz-Masiuk M, Moldenhawer S, Zuba-Surma E, Czajka R, Wojakowski W, Machalinski B, Ratajczak MZ (2007a) 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 21:297–303

    Article  CAS  PubMed  Google Scholar 

  • Kucia M, Wu W, Ratajczak MZ (2007b) Bone marrow-derived very small embryonic-like stem cells: their developmental origin and biological significance. Dev Dyn 236:3309–3320

    Article  CAS  PubMed  Google Scholar 

  • Kucia M, Wysoczynski M, Ratajczak J, Ratajczak MZ (2008) Identification of very small embryonic like (VSEL) stem cells in bone marrow. Cell Tissue Res 331:125–134

    Article  CAS  PubMed  Google Scholar 

  • Li L, Clevers H (2010) Coexistence of quiescent and active adult stem cells in mammals. Science 327:542–545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ling TY, Kuo MD, Li CL, Yu AL, Huang YH, Wu TJ, Lin YC, Chen SH, Yu J (2006) Identification of pulmonary Oct-4+ stem/progenitor cells and demonstration of their susceptibility to SARS coronavirus (SARS-CoV) infection in vitro. Proc Natl Acad Sci U S A 103:9530–9535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mierzejewska K, Borkowska S, Suszynska E, Suszynska M, Poniewierska-Baran A, Maj M, Pedziwiatr D, Adamiak M, Abdel-Latif A, Kakar SS, Ratajczak J, Kucia M, Ratajczak MZ (2015) Hematopoietic stem/progenitor cells express several functional sex hormone receptors-novel evidence for a potential developmental link between hematopoiesis and primordial germ cells. Stem Cells Dev 24:927–937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nichols CR, Hoffman R, Einhorn LH, Williams SD, Wheeler LA, Garnick MB (1985) Hematologic malignancies associated with primary mediastinal germ-cell tumors. Ann Intern Med 102:603–609

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Petersen BE, Bowen WC, Patrene KD, Mars WM, Sullivan AK, Murase N, Boggs SS, Greenberger JS, Goff JP (1999) Bone marrow as a potential source of hepatic oval cells. Science 284:1168–1170

    Article  CAS  PubMed  Google Scholar 

  • Prockop DJ (1997) Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 276:71–74

    Article  CAS  PubMed  Google Scholar 

  • Ratajczak J, Wysoczynski M, Zuba-Surma E, Wan W, Kucia M, Yoder MC, Ratajczak MZ (2011a) Adult murine bone marrow-derived very small embryonic-like stem cells differentiate into the hematopoietic lineage after coculture over OP9 stromal cells. Exp Hematol 39:225–237

    Article  CAS  PubMed  Google Scholar 

  • Ratajczak J, Zuba-Surma E, Klich I, Liu R, Wysoczynski M, Greco N, Kucia M, Laughlin MJ, Ratajczak MZ (2011b) Hematopoietic differentiation of umbilical cord blood-derived very small embryonic/epiblast-like stem cells. Leukemia 25:1278–1285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  • Serafini M, Dylla SJ, Oki M, Heremans Y, Tolar J, Jiang Y, Buckley SM, Pelacho B, Burns TC, Frommer S, Rossi DJ, Bryder D, Panoskaltsis-Mortari A, O’Shaughnessy MJ, Nelson-Holte M, Fine GC, Weissman IL, Blazar BR, Verfaillie CM (2007) Hematopoietic reconstitution by multipotent adult progenitor cells: precursors to long-term hematopoietic stem cells. J Exp Med 204:129–139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shin DM, Liu R, Klich I, Ratajczak J, Kucia M, Ratajczak MZ (2010a) Molecular characterization of isolated from murine adult tissues very small embryonic/epiblast like stem cells (VSELs). Mol Cells 29:533–538

    Article  CAS  PubMed  Google Scholar 

  • Shin DM, Liu R, Klich I, Wu W, Ratajczak J, Kucia M, Ratajczak MZ (2010b) Molecular signature of adult bone marrow-purified very small embryonic-like stem cells supports their developmental epiblast/germ line origin. Leukemia 24:1450–1461

    Article  CAS  PubMed  Google Scholar 

  • Shin DM, Liu R, Wu W, Waigel SJ, Zacharias W, Ratajczak MZ, Kucia M (2012) Global gene expression analysis of very small embryonic-like stem cells reveals that the Ezh2-dependent bivalent domain mechanism contributes to their pluripotent state. Stem Cells Dev 21:1639–1652

    Article  CAS  PubMed  Google Scholar 

  • Sovalat H, Scrofani M, Eidenschenk A, Pasquet S, Rimelen V, Henon P (2011) Identification and isolation from either adult human bone marrow or G-CSF-mobilized peripheral blood of CD34(+)/CD133(+)/CXCR4(+)/ Lin(-)CD45(-) cells, featuring morphological, molecular, and phenotypic characteristics of very small embryonic-like (VSEL) stem cells. Exp Hematol 39:495–505

    CAS  PubMed  Google Scholar 

  • Suszynska M, Poniewierska-Baran A, Gunjal P, Ratajczak J, Marycz K, Kakar SS, Kucia M, Ratajczak MZ (2014) Expression of the erythopoietin receptor by germline-derived cells - further support for a potential developmental link between the germline and hematopoiesis. J Ovarian Res 7:66

    Article  PubMed  PubMed Central  Google Scholar 

  • Wakao S, Kitada M, Kuroda Y, Shigemoto T, Matsuse D, Akashi H, Tanimura Y, Tsuchiyama K, Kikuchi T, Goda M, Nakahata T, Fujiyoshi Y, Dezawa M (2011) Multilineage-differentiating stress-enduring (Muse) cells are a primary source of induced pluripotent stem cells in human fibroblasts. Proc Natl Acad Sci U S A 108:9875–9880

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Yoshimoto M, Heike T, Chang H, Kanatsu-Shinohara M, Baba S, Varnau JT, Shinohara T, Yoder MC, Nakahata T (2009) Bone marrow engraftment but limited expansion of hematopoietic cells from multipotent germline stem cells derived from neonatal mouse testis. Exp Hematol 37:1400–1410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu H, Fang D, Kumar SM, Li L, Nguyen TK, Acs G, Herlyn M, Xu X (2006) Isolation of a novel population of multipotent adult stem cells from human hair follicles. Am J Pathol 168:1879–1888

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zuba-Surma EK, Kucia M, Wu W, Klich I, Lillard JW Jr, Ratajczak J, Ratajczak MZ (2008) Very small embryonic-like stem cells are present in adult murine organs: ImageStream-based morphological analysis and distribution studies. Cytometry A 73A:1116–1127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zuba-Surma EK, Klich I, Greco N, Laughlin MJ, Ratajczak J, Ratajczak MZ (2010) Optimization of isolation and further characterization of umbilical-cord-blood-derived very small embryonic/epiblast-like stem cells (VSELs). Eur J Haematol 84:34–46

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by NIH grants 2R01 DK074720 and R01HL112788, NCN Harmonia Grant UMO-2014/14/M/NZ3/00475 and the Stella and Henry Endowment to MZR.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Mariusz Z. Ratajczak .

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Suszynska, M., Ratajczak, M.Z., Ratajczak, J. (2016). Very Small Embryonic Like Stem Cells (VSELs) and Their Hematopoietic Specification. In: Working with Stem Cells. Springer, Cham. https://doi.org/10.1007/978-3-319-30582-0_6

Download citation

Publish with us

Policies and ethics