Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Manuscript
  • Published:

Stem Cells Plasticity: A Challenge

Stem cell plasticity revisited: CXCR4-positive cells expressing mRNA for early muscle, liver and neural cells ‘hide out’ in the bone marrow

Leukemia volume 18, pages 29–40 (2004)Cite this article

Abstract

It has been suggested that bone marrow (BM)-derived hematopoietic stem cells transdifferentiate into tissue-specific stem cells (the so-called phenomenon of stem cell plasticity), but the possibility of committed tissue-specific stem cells pre-existing in BM has not been given sufficient consideration. We hypothesized that (i) tissue-committed stem cells circulate at a low level in the peripheral blood (PB) under normal steady-state conditions, maintaining a pool of stem cells in peripheral tissues, and their levels increase in PB during stress/tissue injury, and (ii) they could be chemoattracted to the BM where they find a supportive environment and that the SDF-1–CXCR4 axis plays a prominent role in the homing/retention of these cells to BM niches. We performed all experiments using freshly isolated cells to exclude the potential for ‘transdifferentiation’ of hematopoietic stem or mesenchymal cells associated with in vitro culture systems. We detected mRNA for various early markers for muscle (Myf-5, Myo-D), neural (GFAP, nestin) and liver (CK19, fetoprotein) cells in circulating (adherent cell-depleted) PB mononuclear cells (MNC) and increased levels of expression of these markers in PB after mobilization by G-CSF (as measured using real-time RT-PCR). Furthermore, SDF-1 chemotaxis combined with real-time RT-PCR analysis revealed that (i) these early tissue-specific cells reside in normal murine BM, (ii) express CXCR4 on their surface and (iii) can be enriched (up to 60 ×) after chemotaxis to an SDF-1 gradient. These cells were also highly enriched within purified populations of murine Sca-1+ BM MNC as well as of human CD34+-, AC133+- and CXCR4-positive cells. We also found that the expression of mRNA for SDF-1 is upregulated in damaged heart, kidney and liver. Hence our data provide a new perspective on BM not only as a home for hematopoietic stem cells but also a ‘hideout’ for already differentiated CXCR4-positive tissue-committed stem/progenitor cells that follow an SDF-1 gradient, could be mobilized into PB, and subsequently take part in organ/tissue regeneration.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

References

  1. Caplice NM, Bunch TJ, Stalboerger PG, Wang SW, Simpler D, Miller DV et al. Smooth muscle cells in human coronary atherosclerosis can originate from cells administered at marrow transplantation. Proc Natl Acad Sci USA 2003; 100: 4754–4759.

    Article  CAS  Google Scholar 

  2. Qi H, Aguiar DJ, Williams SM, La Pean A, Pan W, Verfaillie CM . Identification of genes responsible for osteoblast differentiation from human mesodermal progenitor cells. Proc Natl Acad Sci USA 2003; 100: 3305–3310.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  5. Makino S, Fukuda K, Miyoshi S, Konishi F, Kodama H, Pan J et al. Cardiomyocytes can be generated from marrow stromal cells in vitro. J Clin Invest 1999; 103: 697–705.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Corti S, Strazzer S, Del Bo R, Salani S, Bossolasco P, Fortunato F et al. A subpopulation of murine bone marrow cells fully differentiates along the myogenic pathway and participates in muscle repair in the mdx dystrophic mouse. Exp Cell Res 2002; 277: 74–85.

    Article  CAS  Google Scholar 

  8. Sanchez-Ramos JR . Neural cells derived from adult bone marrow and umbilical cord blood. J Neurosci Res 2002; 69: 880–893.

    Article  CAS  Google Scholar 

  9. 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 

  10. Ianus A, Holz GG, Theise ND, Hussain MA . In vivo derivation of glucose-competent pancreatic endocrine cells from bone marrow without evidence of cell fusion. J Clin Invest 2003; 111: 843–850.

    Article  CAS  Google Scholar 

  11. Lee VM, Stoffel M . Bone marrow: an extra-pancreatic hideout for the elusive pancreatic stem cells? J Clin Invest 2003; 111: 799–801.

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  13. Hao HN, Zhao J, Thomas RL, Parker GC, Lyman WD . Fetal human hematopoietic cells can differentiate sequentially into neural stem cells and then astrocytes in vitro. J Hematother Stem Cell Res 2003; 12: 23–32.

    Article  CAS  Google Scholar 

  14. Stamm C, Westphal B, Kleine HD, Petzsch M, Kitter C, Klinge H et al. Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet 2003; 361: 45–46.

    Article  Google Scholar 

  15. Lemischka IA . Few thoughts about the plasticity of stem cells. Exp Hematol 2002; 30: 848–852.

    Article  Google Scholar 

  16. Holden C, Vogel G . Stem cells. Plasticity: time for a reappraisal? Science 2002; 296: 2126–2129.

    Article  CAS  Google Scholar 

  17. 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.

    Article  CAS  Google Scholar 

  18. McKinney-Freeman SL, Jackson KA, Camargo FD, Ferrari G, Mavilio F, Goodell MA . Muscle-derived hematopoietic stem cells are hematopoietic in origin. Proc Natl Acad Sci USA 2002; 99: 1341–1346.

    Article  CAS  Google Scholar 

  19. Geiger H, True JM, Grimes B, Carroll EJ, Fleischman RA, Van Zant G . Analysis of the hematopoietic potential of muscle-derived cells in mice. Blood 2002; 100: 721–723.

    Article  CAS  Google Scholar 

  20. Kawada H, Ogawa M . Bone marrow origin of hematopoietic progenitors and stem cells in murine muscle. Blood 2001; 98: 2008–2013.

    Article  CAS  Google Scholar 

  21. Wagers AJ, Sherwood RI, Christensen JL, Weissman IL . Little evidence for developmental plasticity of adult hematopoietic stem cells. Science 2002; 297: 2256–2259.

    Article  CAS  Google Scholar 

  22. Jackson KA, Mi T, Goodell MA . Hematopoietic potential of stem cells isolated from murine skeletal muscle. Proc Natl Acad Sci USA 1999; 96: 14482–14486.

    Article  CAS  Google Scholar 

  23. Terada N, Hamazaki T, Oka OM, Hoki M, Mastalerz DM, Nakano Y et al. Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature 2002; 416: 542–454.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  25. Wang X, Willenbring H, Akkari Y, Toriaru Y, Foster M, Al-Dhalimy M et al. Cell fusion is the principal source of bone-marrow-derived hepatocytes. Nature 2003; 422: 897–901.

    Article  CAS  Google Scholar 

  26. Morshead CM, Benvenite 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 

  27. Ogura A, Inoue K, Ogonuku N, Lee J, Kohda T, Ishino F . Phenotypic effects of somatic cell cloning in the mouse. Cloning Stem Cells 2002; 4: 397–405.

    Article  CAS  Google Scholar 

  28. Jaenisch R, Eggan K, Humpherys D, Rideout W, Hochedlinger K . Nuclear cloning, stem cells, and genomic reprogramming. Cloning Stem Cells 2002; 4: 389–396.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  30. Zou Y, Kottmann AH, Kuroda M, Taniuchi I, Littman DR . Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 1998; 393: 595–599.

    Article  CAS  Google Scholar 

  31. Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001; 410: 50–56.

    Article  CAS  Google Scholar 

  32. Cooper CR, Chay CH, Gendernalik JD, Lee HL, Bhatia J, Taichman RS et al. Stromal factors involved in prostate carcinoma metastasis to bone. Cancer 2003; 97: 739–747.

    Article  Google Scholar 

  33. Ellis WJ, Pfitzenmaier J, Colli J, Arfman E, Lange PH, Vessella RL . Detection and isolation of prostate cancer cells from peripheral blood and bone marrow. Urology 2003; 61: 277–281.

    Article  Google Scholar 

  34. Libura J, Drukala J, Majka M, Tomeascu O, Navenot JM, Kucia M et al. CXCR4–SDF-1 signaling is active in rhabdomyosarcoma cells and regulates locomotion, chemotaxis and adhesion. Blood 2002; 100: 2597–2606.

    Article  CAS  Google Scholar 

  35. Geminder H, Sagi-Assif O, Goldberg L, Meshel T, Rechavi G, Witz IP et al. A possible role for CXCR4 and its ligand the CXC chemokine stromal cell-derived factor-1 in the development of bone marrow metastasis in neuroblastoma. J Immunol 2001; 167: 4747–4757.

    Article  CAS  Google Scholar 

  36. Lazarini F, Tham TN, Casanova P, Arenzana-Seisdedos F, Dubois-Dalcq M . Role of the alpha-chemokine stromal cell-derived factor (SDF-1) in the developing and mature central nervous system. Glia 2003; 42: 139–148.

    Article  Google Scholar 

  37. Lu M, Grove EA, Miller RJ . Abnormal development of the hippocampal dentate gyrus in mice lacking the CXCR4 chemokine receptor. Proc Natl Acad Sci USA 2002; 99: 7090–7095.

    Article  CAS  Google Scholar 

  38. Pillarisetti K, Gupta SK . Cloning and relative expression analysis of rat stromal cell derived factor-1 (SDF-1): SDF-1 alpha mRNA is selectively induced in rat model of myocardial infarction. Inflammation 2001; 25: 293–300.

    Article  CAS  Google Scholar 

  39. Ara T, Nakamura Y, Egawa T, Sugiyama T, Abe K, Kishimoto T et al. Impaired colonization of the gonads by primordial germ cells in mice lacking a chemokine stromal cell-derived factor-1 (SDF-1). Proc Natl Acad Sci USA 2003; 100: 5319–5323.

    Article  CAS  Google Scholar 

  40. Doitsidou M, Reichman-Fried M, Stebler J, Köprunner M, Dörries J, Meyer D et al. Guidance of primordial germ cell migration by the chemokine SDF-1. Cell 2002; 111: 647–659.

    Article  CAS  Google Scholar 

  41. Reiss K, Mentlein R, Sievers J, Hartmann D . Stromal cell-derived factor 1 is secreted by meningeal cells and acts as chemotactic factor on neuronal stem cells of the cerebellar external granular layer. Neuroscience 2002; 115: 295–305.

    Article  CAS  Google Scholar 

  42. Crane IJ, Wallace CA, McKillop-Smith S, Forrester JV . CXCR4 receptor expression on human retinal pigment epithelial cells from blood–retina barrier leads to chemokine secretion and migration in response to stromal cell-derived factor 1α. J Immunol 2000; 165: 4372–4378.

    Article  CAS  Google Scholar 

  43. Ratajczak MZ, Majka M, Kucia M, Drukala J, Pietrzkowski Z, Peiper S et al. Expression of functional CXCR4 by muscle satellite cells and secretion of SDF-1 by muscle-derived fibroblasts is associated with the presence of both muscle progenitors in bone marrow and hematopoietic stem/progenitor cells in muscles. Stem Cells 2003; 21: 363–371.

    Article  CAS  Google Scholar 

  44. Pituch-Noworolska A, Majka M, Janowska-Wieczorek A, Baj-Krzyworzeka A, Urbanowicz B, Malec E et al. Circulating CXCR4-positive stem/progenitor cells compete for SDF-1-positive niches in bone marrow, muscle and neural tissues: an alternative hypothesis to stem cells plasticity. Folia Histochem Cytobiol 2003; 41: 13–21.

    PubMed  Google Scholar 

  45. Hatch H, Zheng D, Jorgensen ML, Petersen BE . SDF-1α/CXCR4: a mechanism for hepatic oval cell activation and bone marrow stem cell recruitment to the injured liver of rats. Cloning Stem Cells 2002; 4: 339–351.

    Article  CAS  Google Scholar 

  46. Bajetto A, Bonavia R, Barbero S, Piccioli P, Costa A, Florio T et al. Glial and neuronal cells express functional chemokine receptor CXCR4 and its natural ligand stromal cell-derived factor 1. J Neurochem 1999; 73: 2348–2357.

    Article  CAS  Google Scholar 

  47. Majka M, Janowska-Wieczorek A, Ratajczak J, Kowalska MA, Vilaire G, Pan ZK et al. Stromal derived factor-1 and thrombopoietin regulate distinct aspects of human megakaryopoiesis. Blood 2000; 96: 4142–4151.

    CAS  Google Scholar 

  48. Majka M, Janowska-Wieczorek A, Ratajczak J, Ehrenman K, Pietrzkowski Z, Kowalska MA et al. Numerous growth factors, cytokines, and chemokines are secreted by human CD34(+) cells, myeloblasts, erythroblasts, and megakaryoblasts and regulate normal hematopoiesis in an autocrine/paracrine manner. Blood 2001; 97: 3075–3085.

    Article  CAS  Google Scholar 

  49. Zhang W, Navenot JM, Haribabu B, Tamamura H, Hiramatu K, Omagari A et al. A point mutation that confers constitutive activity to CXCR4 reveals that T140 is an inverse agonist and that AMD3100 and ALX40-4C are weak partial agonists. J Biol Chem 2002; 277: 24515–24521.

    Article  CAS  Google Scholar 

  50. Kijowski J, Baj M, Majka M, Reca R, Marquez LA, Christofidou-Solomidou M et al. The SDF-1–CXCR4 axis stimulates VEGF secretion and activates integrins but does not affect proliferation and survival in lymphohematopoietic cells. Stem Cells 2001; 19: 453–466.

    Article  CAS  Google Scholar 

  51. 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 

  52. Vogel W, Grunebach F, Messam CA, Kanz L, Brugger W, Buhring HJ . Heterogeneity among human bone marrow-derived mesenchymal stem cells and neural progenitor cells. Haematologica 2003; 88: 126–133.

    PubMed  Google Scholar 

  53. Jankowski RJ, Deasy BM, Cao B, Gates C, Huard J . The role of CD34 expression and cellular fusion in the regeneration capacity of myogenic progenitor cells. J Cell Sci 2002; 115: 4361–4374.

    Article  CAS  Google Scholar 

  54. Gallacher L, Murdoch B, Wu DM, Karanu FN, Keeney M, Bhatia M . Isolation and characterization of human CD34−Lin− and CD34+Lin− hematopoietic stem cells using cell surface markers AC133 and CD7. Blood 2000; 95: 2813–2820.

    CAS  PubMed  Google Scholar 

  55. Corbeil D, Roper K, Hellwig A, Tavian M, Miraglia S, Watt SM et al. The human AC133 hematopoietic stem cell antigen is also expressed in epithelial cells and targeted to plasma membrane protrusions. J Biol Chem 2000; 275: 5512–5520.

    Article  CAS  Google Scholar 

  56. Torrente Y, Tremblay JP, Pisati F, Belicchi M, Rossi B, Sironi M et al. Intraarterial injection of muscle-derived CD34+Sca-1+ stem cells restored dystrophin in mdx mice. J Cell Biol 2001; 152: 335–348.

    Article  CAS  Google Scholar 

  57. Ito CY, Li CYJ, Bernstein A, Dick JE, Stanford WL . Hematopoietic stem cell and progenitor defects in Sca-1/Ly-6A null mice. Blood 2003; 101: 517–523.

    Article  CAS  Google Scholar 

  58. Enver T, Heyworth CM, Dexter TM . Do stem cells play dice? Blood 1998; 92: 348–351.

    CAS  Google Scholar 

  59. Badorff C, Brandes RP, Popp R, Rupp S, Urbich C, Aicher A et al. Transdifferentiation of blood-derived human adult endothelial progenitor cells into functionally active cardiomyocytes. Circulation 2003; 107: 1024–1032.

    Article  Google Scholar 

  60. Spees JL, Olson SD, Ylostalo J, Lynch PJ, Smith J, Perry A et al. Differentiation, cell fusion, and nuclear fusion during ex vivo repair of epithelium by human adult stem cells from bone marrow stroma. Proc Natl Acad Sci USA 2003; 100: 2397–2402.

    Article  CAS  Google Scholar 

  61. Chesney J, Bacher M, Bender A, Bucala R . The peripheral blood fibrocyte is a potent antigen-presenting cell capable of priming naïve T cells in situ. Proc Natl Acad Sci USA 1997; 94: 6307–6312.

    Article  CAS  Google Scholar 

  62. Lin F, Cordes K, Li L, Hood L, Couser WG, Shankland SJ et al. Hematopoietic stem cells contribute to the regeneration of renal tubules after renal ischemia–reperfusion injury in mice. J Am Soc Nephrol 2003; 14: 1188–1199.

    Article  Google Scholar 

  63. 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: 1355–1356.

    Article  Google Scholar 

  64. Asakura A, Seale P, Girgis-Gabardo A, Rudnicki MA . Myogenic specification of side population cells in skeletal muscle. J Cell Biol 2002; 159: 123–134.

    Article  CAS  Google Scholar 

  65. Forbes SJ, Poulsom R, Wright NA . Hepatic and renal differentiation from blood-borne stem cells. Gene Ther 2002; 197: 419–423.

    Google Scholar 

  66. Weimann JM, Charlton CA, Brazelton TR, Hackman RC, Blau HM . Contribution of transplanted bone marrow cells to Purkinje neurons in human adult brains. Proc Natl Acad Sci USA 2003; 100: 2088–2093.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

Supported by NIH grant R01 HL61796-01, EU grant QLK3-CT-2002-30307 and KBN grant PBZ-501/Z/B/1/2002 to MZR.

Author information

Authors and Affiliations

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

    M Z Ratajczak, M Kucia, R Reca & J Ratajczak

  2. European Stem Cell Therapeutic Excellence Center, Medical College, Jagiellonian University, Cracow, Poland

    M Z Ratajczak, M Kucia & M Majka

  3. University of Alberta and Canadian Blood Services, Edmonton, Canada

    A Janowska-Wieczorek

Authors
  1. M Z Ratajczak
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Kucia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. R Reca
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M Majka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A Janowska-Wieczorek
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Ratajczak
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

This paper was presented as an oral presentation at the 32nd Annual Meeting of the International Society for Experimental Hematology, Paris, France, July 5–8, 2003

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ratajczak, M., Kucia, M., Reca, R. et al. Stem cell plasticity revisited: CXCR4-positive cells expressing mRNA for early muscle, liver and neural cells ‘hide out’ in the bone marrow. Leukemia 18, 29–40 (2004). https://doi.org/10.1038/sj.leu.2403184

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403184

Keywords

This article is cited by

Search

Advanced search

Quick links