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.

  • Opinion
  • Published:

The elusive nature and function of mesenchymal stem cells

Nature Reviews Molecular Cell Biology volume 12, pages 126–131 (2011)Cite this article

Subjects

Abstract

Mesenchymal stem cells (MSCs) are a diverse subset of multipotent precursors present in the stromal fraction of many adult tissues and have drawn intense interest from translational and basic investigators. MSCs have been operationally defined by their ability to differentiate into osteoblasts, adipocytes and chondrocytes after in vitro expansion. Nevertheless, their identity in vivo, heterogeneity, anatomical localization and functional roles in adult tissue homeostasis have remained enigmatic and are only just starting to be uncovered.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: MSCs and multipotent mesenchymal stromal cells.
Figure 2: Proposed biological functions of BM-resident MSCs in vivo.

Similar content being viewed by others

References

  1. Weissman, I. L. Stem cells: units of development, units of regeneration, and units in evolution. Cell 100, 157–168 (2000).

    CAS  PubMed  Google Scholar 

  2. Friedenstein, A. J., Piatetzky-Shapiro, I. I. & Petrakova, K. V. Osteogenesis in transplants of bone marrow cells. J. Embryol. Exp. Morphol. 16, 381–390 (1966).

    CAS  PubMed  Google Scholar 

  3. Tavassoli, M. & Crosby, W. H. Transplantation of marrow to extramedullary sites. Science 161, 54–56 (1968).

    CAS  PubMed  Google Scholar 

  4. Friedenstein, A. J., Chailakhjan, R. K. & Lalykina, K. S. The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet. 3, 393–403 (1970).

    CAS  PubMed  Google Scholar 

  5. Pittenger, M. F. et al. Multilineage potential of adult human mesenchymal stem cells. Science 284, 143–147 (1999).

    Article  CAS  PubMed  Google Scholar 

  6. Caplan, A. I. Mesenchymal stem cells. J. Orthop. Res. 9, 641–650 (1991).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  8. da Silva Meirelles, L., Chagastelles, P. C. & Nardi, N. B. Mesenchymal stem cells reside in virtually all post-natal organs and tissues. J. Cell Sci. 119, 2204–2213 (2006).

    PubMed  Google Scholar 

  9. Kuznetsov, S. A. et al. Circulating skeletal stem cells. J. Cell Biol. 153, 1133–1140 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Mendes, S. C., Robin, C. & Dzierzak, E. Mesenchymal progenitor cells localize within hematopoietic sites throughout ontogeny. Development 132, 1127–1136 (2005).

    CAS  PubMed  Google Scholar 

  11. Javazon, E. H., Beggs, K. J. & Flake, A. W. Mesenchymal stem cells: paradoxes of passaging. Exp. Hematol. 32, 414–425 (2004).

    CAS  PubMed  Google Scholar 

  12. Meirelles Lda, S., Fontes, A. M., Covas, D. T. & Caplan, A. I. Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev. 20, 419–427 (2009).

    PubMed  Google Scholar 

  13. Bianco, P., Robey, P. G., Saggio, I. & Riminucci, M. “Mesenchymal” stem cells in human bone marrow (skeletal stem cells): a critical discussion of their nature, identity, and significance in incurable skeletal disease. Hum. Gene Ther. 21, 1057–1066 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Bianco, P., Robey, P. G. & Simmons, P. J. Mesenchymal stem cells: revisiting history, concepts, and assays. Cell Stem Cell 2, 313–319 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Horwitz, E. M. et al. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy 7, 393–395 (2005).

    CAS  PubMed  Google Scholar 

  16. Dominici, M. et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8, 315–317 (2006).

    CAS  PubMed  Google Scholar 

  17. Haynesworth, S. E., Goshima, J., Goldberg, V. M. & Caplan, A. I. Characterization of cells with osteogenic potential from human marrow. Bone 13, 81–88 (1992).

    CAS  PubMed  Google Scholar 

  18. Ashton, B. A. et al. Formation of bone and cartilage by marrow stromal cells in diffusion chambers in vivo. Clin. Orthop. Relat. Res. 151, 294–307 (1980).

    Google Scholar 

  19. Li, F., Wang, X. & Niyibizi, C. Bone marrow stromal cells contribute to bone formation following infusion into femoral cavities of a mouse model of osteogenesis imperfecta. Bone 47, 546–555 (2010).

    PubMed  PubMed Central  Google Scholar 

  20. Oswald, J. et al. Mesenchymal stem cells can be differentiated into endothelial cells in vitro. Stem Cells 22, 377–384 (2004).

    PubMed  Google Scholar 

  21. Makino, S. et al. Cardiomyocytes can be generated from marrow stromal cells in vitro. J. Clin. Invest. 103, 697–705 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Snykers, S., De Kock, J., Rogiers, V. & Vanhaecke, T. In vitro differentiation of embryonic and adult stem cells into hepatocytes: state of the art. Stem Cells 27, 577–605 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Arthur, A., Rychkov, G., Shi, S., Koblar, S. A. & Gronthos, S. Adult human dental pulp stem cells differentiate toward functionally active neurons under appropriate environmental cues. Stem Cells 26, 1787–1795 (2008).

    CAS  PubMed  Google Scholar 

  24. Phinney, D. G. & Prockop, D. J. Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair — current views. Stem Cells 25, 2896–2902 (2007).

    PubMed  Google Scholar 

  25. Alvarez-Dolado, M. et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature 425, 968–973 (2003).

    CAS  PubMed  Google Scholar 

  26. Bianco, P., Riminucci, M., Gronthos, S. & Robey, P. G. Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells 19, 180–192 (2001).

    CAS  PubMed  Google Scholar 

  27. Muraglia, A., Cancedda, R. & Quarto, R. Clonal mesenchymal progenitors from human bone marrow differentiate in vitro according to a hierarchical model. J. Cell Sci. 113, 1161–1166 (2000).

    CAS  PubMed  Google Scholar 

  28. Colter, D. C., Class, R., DiGirolamo, C. M. & Prockop, D. J. Rapid expansion of recycling stem cells in cultures of plastic-adherent cells from human bone marrow. Proc. Natl Acad. Sci. USA 97, 3213–3218 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Colter, D. C., Sekiya, I. & Prockop, D. J. Identification of a subpopulation of rapidly self-renewing and multipotential adult stem cells in colonies of human marrow stromal cells. Proc. Natl Acad. Sci. USA 98, 7841–7845 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Digirolamo, C. M. et al. Propagation and senescence of human marrow stromal cells in culture: a simple colony-forming assay identifies samples with the greatest potential to propagate and differentiate. Br. J. Haematol. 107, 275–281 (1999).

    CAS  PubMed  Google Scholar 

  31. Kuznetsov, S. A. et al. Single-colony derived strains of human marrow stromal fibroblasts form bone after transplantation in vivo. J. Bone Miner. Res. 12, 1335–1347 (1997).

    CAS  PubMed  Google Scholar 

  32. Sarugaser, R., Hanoun, L., Keating, A., Stanford, W. L. & Davies, J. E. Human mesenchymal stem cells self-renew and differentiate according to a deterministic hierarchy. PLoS ONE 4, e6498 (2009).

    PubMed  PubMed Central  Google Scholar 

  33. Jiang, Y. et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 418, 41–49 (2002).

    CAS  PubMed  Google Scholar 

  34. Kuroda, Y. et al. Unique multipotent cells in adult human mesenchymal cell populations. Proc. Natl Acad. Sci. USA 107, 8639–8643 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Panepucci, R. A. et al. Comparison of gene expression of umbilical cord vein and bone marrow-derived mesenchymal stem cells. Stem Cells 22, 1263–1278 (2004).

    CAS  PubMed  Google Scholar 

  36. Lee, R. H. et al. Characterization and expression analysis of mesenchymal stem cells from human bone marrow and adipose tissue. Cell Physiol. Biochem. 14, 311–324 (2004).

    CAS  PubMed  Google Scholar 

  37. Kaltz, N. et al. Novel markers of mesenchymal stem cells defined by genome-wide gene expression analysis of stromal cells from different sources. Exp. Cell Res. 316, 2609–2617 (2010).

    CAS  PubMed  Google Scholar 

  38. Caplan, A. I. Adult mesenchymal stem cells for tissue engineering versus regenerative medicine. J. Cell. Physiol. 213, 341–347 (2007).

    CAS  PubMed  Google Scholar 

  39. Simmons, P. J. & Torok-Storb, B. Identification of stromal cell precursors in human bone marrow by a novel monoclonal antibody, STRO-1. Blood 78, 55–62 (1991).

    CAS  PubMed  Google Scholar 

  40. Gronthos, S. et al. Molecular and cellular characterisation of highly purified stromal stem cells derived from human bone marrow. J. Cell Sci. 116, 1827–1835 (2003).

    CAS  PubMed  Google Scholar 

  41. Gang, E. J., Bosnakovski, D., Figueiredo, C. A., Visser, J. W. & Perlingeiro, R. C. SSEA-4 identifies mesenchymal stem cells from bone marrow. Blood 109, 1743–1751 (2007).

    CAS  PubMed  Google Scholar 

  42. Jones, E. A. et al. Optimization of a flow cytometry-based protocol for detection and phenotypic characterization of multipotent mesenchymal stromal cells from human bone marrow. Cytometry B Clin. Cytom. 70, 391–399 (2006).

    PubMed  Google Scholar 

  43. Buhring, H. J. et al. Novel markers for the prospective isolation of human MSC. Ann. N. Y. Acad. Sci. 1106, 262–271 (2007).

    PubMed  Google Scholar 

  44. Battula, V. L. et al. Isolation of functionally distinct mesenchymal stem cell subsets using antibodies against CD56, CD271, and mesenchymal stem cell antigen-1. Haematologica 94, 173–184 (2009).

    CAS  PubMed  Google Scholar 

  45. Sacchetti, B. et al. Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment. Cell 131, 324–336 (2007).

    CAS  PubMed  Google Scholar 

  46. Morikawa, S. et al. Prospective identification, isolation, and systemic transplantation of multipotent mesenchymal stem cells in murine bone marrow. J. Exp. Med. 206, 2483–2496 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Mendez-Ferrer, S. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Corselli, M., Chen, C. W., Crisan, M., Lazzari, L. & Peault, B. Perivascular ancestors of adult multipotent stem cells. Arterioscler. Thromb. Vasc. Biol. 30, 1104–1109 (2010).

    CAS  PubMed  Google Scholar 

  49. Hirschi, K. K. & D'Amore, P. A. Pericytes in the microvasculature. Cardiovasc. Res. 32, 687–698 (1996).

    CAS  PubMed  Google Scholar 

  50. Farrington-Rock, C. et al. Chondrogenic and adipogenic potential of microvascular pericytes. Circulation 110, 2226–2232 (2004).

    CAS  PubMed  Google Scholar 

  51. Doherty, M. J. et al. Vascular pericytes express osteogenic potential in vitro and in vivo. J. Bone Miner. Res. 13, 828–838 (1998).

    CAS  PubMed  Google Scholar 

  52. Collett, G. D. & Canfield, A. E. Angiogenesis and pericytes in the initiation of ectopic calcification. Circ. Res. 96, 930–938 (2005).

    CAS  PubMed  Google Scholar 

  53. Shi, S. & Gronthos, S. Perivascular niche of postnatal mesenchymal stem cells in human bone marrow and dental pulp. J. Bone Miner. Res. 18, 696–704 (2003).

    PubMed  Google Scholar 

  54. Schwab, K. E. & Gargett, C. E. Co-expression of two perivascular cell markers isolates mesenchymal stem-like cells from human endometrium. Hum. Reprod. 22, 2903–2911 (2007).

    CAS  PubMed  Google Scholar 

  55. Crisan, M. et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 3, 301–313 (2008).

    CAS  PubMed  Google Scholar 

  56. Kiel, M. J., Yilmaz, O. H., Iwashita, T., Terhorst, C. & Morrison, S. J. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005).

    CAS  PubMed  Google Scholar 

  57. Dellavalle, A. et al. Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells. Nature Cell Biol. 9, 255–267 (2007).

    CAS  PubMed  Google Scholar 

  58. Tang, W. et al. White fat progenitor cells reside in the adipose vasculature. Science 322, 583–586 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Traktuev, D. O. et al. A population of multipotent CD34-positive adipose stromal cells share pericyte and mesenchymal surface markers, reside in a periendothelial location, and stabilize endothelial networks. Circ. Res. 102, 77–85 (2008).

    CAS  PubMed  Google Scholar 

  60. Tintut, Y. et al. Multilineage potential of cells from the artery wall. Circulation 108, 2505–2510 (2003).

    PubMed  Google Scholar 

  61. Hoshino, A., Chiba, H., Nagai, K., Ishii, G. & Ochiai, A. Human vascular adventitial fibroblasts contain mesenchymal stem/progenitor cells. Biochem. Biophys. Res. Commun. 368, 305–310 (2008).

    CAS  PubMed  Google Scholar 

  62. Lo Celso, C. et al. Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Nature 457, 92–96 (2009).

    CAS  PubMed  Google Scholar 

  63. Xie, Y. et al. Detection of functional haematopoietic stem cell niche using real-time imaging. Nature 457, 97–101 (2009).

    CAS  PubMed  Google Scholar 

  64. Kiel, M. J. & Morrison, S. J. Uncertainty in the niches that maintain haematopoietic stem cells. Nature Rev. Immunol. 8, 290–301 (2008).

    CAS  Google Scholar 

  65. Garrett, R. W. & Emerson, S. G. Bone and blood vessels: the hard and the soft of hematopoietic stem cell niches. Cell Stem Cell 4, 503–506 (2009).

    CAS  PubMed  Google Scholar 

  66. Naveiras, O. et al. Bone-marrow adipocytes as negative regulators of the haematopoietic microenvironment. Nature 460, 259–263 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Dexter, T. M., Allen, T. D. & Lajtha, L. G. Conditions controlling the proliferation of haemopoietic stem cells in vitro. J. Cell. Physiol. 91, 335–344 (1977).

    CAS  PubMed  Google Scholar 

  68. Campagnoli, C. et al. Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood 98, 2396–2402 (2001).

    CAS  PubMed  Google Scholar 

  69. Melero-Martin, J. M. et al. Engineering robust and functional vascular networks in vivo with human adult and cord blood-derived progenitor cells. Circ. Res. 103, 194–202 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Sugiyama, T., Kohara, H., Noda, M. & Nagasawa, T. Maintenance of the hematopoietic stem cell pool by CXCL12–CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 25, 977–988 (2006).

    CAS  PubMed  Google Scholar 

  71. Omatsu, Y. et al. The essential functions of adipo-osteogenic progenitors as the hematopoietic stem and progenitor cell niche. Immunity 33, 387–399 (2010).

    CAS  PubMed  Google Scholar 

  72. Katayama, Y. et al. Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124, 407–421 (2006).

    CAS  PubMed  Google Scholar 

  73. Mendez-Ferrer, S., Chow, A., Merad, M. & Frenette, P. S. Circadian rhythms influence hematopoietic stem cells. Curr. Opin. Hematol. 16, 235–242 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Uccelli, A., Moretta, L. & Pistoia, V. Mesenchymal stem cells in health and disease. Nature Rev. Immunol. 8, 726–736 (2008).

    CAS  Google Scholar 

  75. Bernardo, M. E., Locatelli, F. & Fibbe, W. E. Mesenchymal stromal cells. Ann. N. Y. Acad. Sci. 1176, 101–117 (2009).

    CAS  PubMed  Google Scholar 

  76. Pillai, S. & Cariappa, A. The bone marrow perisinusoidal niche for recirculating B cells and the positive selection of bone marrow-derived B lymphocytes. Immunol. Cell Biol. 87, 16–19 (2009).

    CAS  PubMed  Google Scholar 

  77. Sapoznikov, A. et al. Perivascular clusters of dendritic cells provide critical survival signals to B cells in bone marrow niches. Nature Immunol. 9, 388–395 (2008).

    CAS  Google Scholar 

  78. Salem, H. K. & Thiemermann, C. Mesenchymal stromal cells: current understanding and clinical status. Stem Cells 28, 585–596 (2010).

    CAS  PubMed  Google Scholar 

  79. Horwitz, E. M. et al. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: implications for cell therapy of bone. Proc. Natl Acad. Sci. USA 99, 8932–8937 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Horwitz, E. M. et al. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nature Med. 5, 309–313 (1999).

    CAS  PubMed  Google Scholar 

  81. Tolar, J., Le Blanc, K., Keating, A. & Blazar, B. R. Concise review: hitting the right spot with mesenchymal stromal cells. Stem Cells 28, 1446–1455 (2010).

    PubMed  PubMed Central  Google Scholar 

  82. Auletta, J. J., Cooke, K. R., Solchaga, L. A., Deans, R. J. & van't Hof, W. Regenerative stromal cell therapy in allogeneic hematopoietic stem cell transplantation: current impact and future directions. Biol. Blood Marrow Transplant. 16, 891–906 (2010).

    PubMed  Google Scholar 

Download references

Acknowledgements

L.E.S. is supported by grants P01 HL095489 and R01 HL093139, and contract HHSN268201000009C from the National Heart Lung and Blood Institute, USA. J.R. is supported by grant P01 CA78378 from the National Cancer Institute, USA, and grant P01 CA142106 and contract HHSN268201000009C from the National Heart Lung and Blood Institute. C.N-A. is a recipient of Human Frontiers in Science Program long-term fellowship 00194/2008-L.

Author information

Author notes

  1. César Nombela-Arrieta, Jerome Ritz and Leslie E. Silberstein: César Nombela-Arrieta and Leslie E. Silberstein are members of the Joint Program in Transfusion Medicine, Children's Hospital Boston, Boston, Massachusetts 02115, USA.

Authors and Affiliations

  1. Jerome Ritz is at the Division of Haematologic Malignancies, Dana-Farber Cancer Institute, 44 Binney Street, Mayer 530, Boston, Massachusetts 02115, USA.,

    Jerome Ritz

  2. Division of Molecular and Cellular Medicine, Jerome Ritz and Leslie E. Silberstein are also at the Center for Human Cell Therapy, Children's Hospital Boston, Karp Research Building, One Blackfan Circle, Boston, Massachusetts 02115, USA.,

    Jerome Ritz & Leslie E. Silberstein

Authors
  1. César Nombela-Arrieta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jerome Ritz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Leslie E. Silberstein
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Leslie E. Silberstein.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Leslie E. Silberstein's homepage

Jerome Ritz's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nombela-Arrieta, C., Ritz, J. & Silberstein, L. The elusive nature and function of mesenchymal stem cells. Nat Rev Mol Cell Biol 12, 126–131 (2011). https://doi.org/10.1038/nrm3049

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm3049

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing