Stem Cell Reviews and Reports

, Volume 14, Issue 3, pp 346–369 | Cite as

Mesenchymal Stem Cells in the Musculoskeletal System: From Animal Models to Human Tissue Regeneration?

  • Klemen Čamernik
  • Ariana Barlič
  • Matej Drobnič
  • Janja Marc
  • Matjaž Jeras
  • Janja Zupan


The musculoskeletal system includes tissues that have remarkable regenerative capabilities. Bone and muscle sustain micro-damage throughout the lifetime, yet they continue to provide the body with the support that is needed for everyday activities. Our current understanding is that the regenerative capacity of the musculoskeletal system can be attributed to the mesenchymal stem/ stromal cells (MSCs) that reside within its different anatomical compartments. These MSCs can replenish various tissues with progenitor cells to form functional cells, such as osteoblasts, chondrocytes, myocytes, and others. However, with aging and in certain disorders of the musculoskeletal system such as osteoarthritis or osteoporosis, this regenerative capacity of MSCs appears to be lost or diverted for the production of other non-functional cell types, such as adipocytes and fibroblasts. In this review, we shed light on the tissue sources and subpopulations of MSCs in the musculoskeletal system that have been identified in animal models, discuss the mechanisms of their anti-inflammatory action as a prerequisite for their tissue regeneration and their current applications in regenerative medicine. While providing up-to-date evidence of the role of MSCs in different musculoskeletal pathologies, in particular in osteoporosis and osteoarthritis, we share some thoughts on their potential as diagnostic markers in musculoskeletal health and disease.


Musculoskeletal system Mesenchymal stem cells Bone Muscles Synovium Regenerative medicine Osteoarthritis Osteoporosis 



The authors acknowledge Chris Berrie for scientific English editing of the manuscript. J. Zupan was funded by UK Arthritis Research as a Postdoctoral Research Fellow at the University of Aberdeen (2014–2016) and by P3-0298 research program of Slovenian Research Agency (2009–2014 and since 2016) as Researcher at the University of Ljubljana. Figures were created using the Mind the Graph platform (

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Walmsley, G. G., Ransom, R. C., Zielins, E. R., et al. (2015). Stem cells in bone regeneration. Stem Cell Reviews and Reports. Scholar
  2. 2.
    Tedesco, F. S., Dellavalle, A., Diaz-Manera, J., Messina, G., & Cossu, G. (2010). Repairing skeletal muscle: regenerative potential of skeletal muscle stem cells. Journal of Clinical Investigation. Scholar
  3. 3.
    Friedenstein, A. J., Chailakhjan, R. K., & Lalykina, K. S. (1970). The development of a fibroblast colonies in monolayer cultures of guinea pig bone marrow and spleen cells. Cell Proliferation. Scholar
  4. 4.
    Pittenger, M., Mackay, A., Beck, S., et al. (1999). Multilineage potential of adult human mesenchymal stem cells. Science. Scholar
  5. 5.
    Hass, R., Kasper, C., Böhm, S., & Jacobs, R. (2011). Different populations and sources of human mesenchymal stem cells (MSCs): a comparison of adult and neonatal tissue-derived MSC. Cell Communication and Signaling: CCS. Scholar
  6. 6.
    Grcevic, D., Pejda, S., Matthews, B. G., et al. (2012). In vivo fate mapping identifies mesenchymal progenitor cells. Stem Cells. Scholar
  7. 7.
    Tuli, R., Seghatoleslami, M. R., Tuli, S., et al. (2003). A simple, high-yield method for obtaining multipotential mesenchymal progenitor cells from trabecular bone. Molecular Biotechnology. Scholar
  8. 8.
    Worthley, D. L., Churchill, M., Compton, J. T., et al. (2015). Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential. Cell. Scholar
  9. 9.
    Méndez-Ferrer, S., Michurina, T. V., Ferraro, F., et al. (2010). Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature. Scholar
  10. 10.
    Zhou, B. O., Yue, R., Murphy, M. M., Peyer, J. G., & Morrison, S. J. (2014). Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell. Scholar
  11. 11.
    Chan, C. K. F., Seo, E. Y., Chen, J. Y., et al. (2015). Identification and specification of the mouse skeletal stem cell. Cell. Scholar
  12. 12.
    De Bari, C., Dell’Accio, F., Tylzanowski, P., Luyten, F. P. (2001) Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis and Rheumatism,<1928::AID-ART331>3.0.CO;2-P Google Scholar
  13. 13.
    Sakaguchi, Y., Sekiya, I., Yagishita, K., & Muneta, T. (2005). Comparison of human stem cells derived from various mesenchymal tissues: superiority of synovium as a cell source. Arthritis and Rheumatism. Scholar
  14. 14.
    Roelofs, A. J., Zupan, J., Riemen, A. H. K., et al. (2017). Joint morphogenetic cells in the adult synovium. Nature Communications. Scholar
  15. 15.
    Kurth, T. B., Dell’Accio, F., Crouch, V., Augello, A., Sharpe, P. T., & De Bari, C. (2011). Functional mesenchymal stem cell niches in adult mouse knee joint synovium in vivo. Arthritis and Rheumatism. Scholar
  16. 16.
    Tan, Q., Lui, P. P., Rui, Y. F., & Wong, Y. M. (2012). Comparison of potentials of stem cells isolated from tendon and bone marrow for musculoskeletal tissue engineering. Tissue Engineering Part A. Scholar
  17. 17.
    Lui, P. P. (2015). Markers for the identification of tendon-derived stem cells in vitro and tendon stem cells in situ – update and future development. Stem Cell Research & Therapy. Scholar
  18. 18.
    Sienkiewicz, D., Kulak, W., Okurowska-Zawada, B., Paszko-Patej, G., Kawnik, K (2015). Duchenne muscular dystrophy: current cell therapies. Therapeutic Advances in Neurological Disorders. Scholar
  19. 19.
    De Bari, C., Dell’Accio, F., Vandenabeele, F., Vermeesch, J. R., Raymackers, J. M., & Luyten, F. P. (2003). Skeletal muscle repair by adult human mesenchymal stem cells from synovial membrane. The Journal of Cell Biology. Scholar
  20. 20.
    Chen, C., Qu, Z., Yin, X., et al. (2016). Efficacy of umbilical cord-derived mesenchymal stem cell-based therapy for osteonecrosis of the femoral head: a three-year follow-up study. Molecular Medicine Reports. Scholar
  21. 21.
    Daltro, G. C., Fortuna, V., de Souza, E. S., et al. (2012). Efficacy of autologous stem cell-based therapy for osteonecrosis of the femoral head in sickle cell disease: a five-year follow-up study. Stem Cell Research & Therapy. Scholar
  22. 22.
    Aoyama, T., Goto, K., Kakinoki, R., et al. (2014). An exploratory clinical trial for idiopathic osteonecrosis of femoral head by cultured autologous multipotent mesenchymal stromal cells augmented with vascularized bone grafts. Tissue Engineering Part B. Scholar
  23. 23.
    Rastogi, S., Sankineani, S. R., Nag, H. L., et al. (2013). Intralesional autologous mesenchymal stem cells in management of osteonecrosis of femur: a preliminary study. Musculoskeletal Surgery. Scholar
  24. 24.
    Zhao, D., Cui, D., Wang, B., et al. (2012). Treatment of early stage osteonecrosis of the femoral head with autologous implantation of bone marrow-derived and cultured mesenchymal stem cells. Bone. Scholar
  25. 25.
    Weel, H., Mallee, W. H., van Dijk, C. N., et al. (2015). The effect of concentrated bone marrow aspirate in operative treatment of fifth metatarsal stress fractures; a double-blind randomized controlled trial. BMC Musculoskeletal Disorders. Scholar
  26. 26.
    Wong, K. L., Lee, K. B., Tai, B. C., Law, P., Lee, E. H., & Hui, J. H. (2013). Injectable cultured bone marrow-derived mesenchymal stem cells in varus knees with cartilage defects undergoing high tibial osteotomy: a prospective, randomized controlled clinical trial with two years’ follow-up. Arthroscopy. Scholar
  27. 27.
    Pers, Y.-M., Rackwitz, L., Ferreira, R., et al. (2016). Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial. Stem Cells Translational Medicine. Scholar
  28. 28.
    Orozco, L., Munar, A., Soler, R., et al. (2013). Treatment of knee osteoarthritis with autologous mesenchymal stem cells. Transplantation. Scholar
  29. 29.
    Freitag, J., Ford, J., Bates, D., et al. (2015). Adipose derived mesenchymal stem cell therapy in the treatment of isolated knee chondral lesions: design of a randomised controlled pilot study comparing arthroscopic microfracture versus arthroscopic microfracture combined with postoperative mesenchymal. British Medical Journal Open. Scholar
  30. 30.
    Jo, C., Lee, Y., & Shin, W. (2014). Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem Cells. Scholar
  31. 31.
    Davatchi, F., Sadeghi Abdollahi, B., Mohyeddin, M., Nikbin, B. (2016). Mesenchymal stem cell therapy for knee osteoarthritis: five years follow-up of three patients. International Journal Rheumatic Diseases. Scholar
  32. 32.
    Davatchi, F., Abdollahi, B. S., Mohyeddin, M., Shahram, F., & Nikbin, B. (2011). Mesenchymal stem cell therapy for knee osteoarthritis. Preliminary report of four patients. International Journal Rheumatic Diseases. Scholar
  33. 33.
    Vega, A., Martín-Ferrero, M. A., Del Canto, F., et al. (2015). Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells. Transplantation. Scholar
  34. 34.
    Vangsness, C. T., Farr, J., Boyd, J., Dellaero, D. T., Mills, C. R., & LeRoux-Williams, M. (2014). Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial menisectomy. The Journal of Bone and Joint Surgery. Scholar
  35. 35.
    Centeno, C. J., Al-Sayegh, H., Bashir, J., Goodyear, S. H., & Freeman, M. D. (2015). A prospective multi-Site registry study of a specific protocol of autologous bone marrow concentrate for the treatment of shoulder rotator cuff tears and osteoarthritis. Journal of Pain Research. Scholar
  36. 36.
    Centeno, C. J., Busse, D., Kisiday, J., et al. (2008). Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells. Pain Physician, 11(3), 343–353.PubMedGoogle Scholar
  37. 37.
    Akgun, I., Unlu, M. C., Erdal, O. A., et al. (2015). Matrix-induced autologous mesenchymal stem cell implantation versus matrix-induced autologous chondrocyte implantation in the treatment of chondral defects of the knee: a 2-year randomized study. Archives of Orthopaedic and Trauma Surgery. Scholar
  38. 38.
    Koh, Y.-G., Kwon, O.-R., Kim, Y.-S., Choi, Y.-J., & Tak, D.-H. (2016). Adipose-derived mesenchymal stem cells with microfracture versus microfracture alone: two-year follow-up of a prospective randomized trial. Arthroscopy. Scholar
  39. 39.
    Chamberlain, C. S., Saether, E. E., Aktas, E., & Vanderby, R. (2017). Mesenchymal stem cell therapy on tendon/ ligament healing. Journal of Cytokine Biology, 2(1), 112.PubMedPubMedCentralGoogle Scholar
  40. 40.
    Lee, S. Y., Kim, W., Lim, C., & Chung, S. G. (2015). Treatment of lateral epicondylosis by using allogenic adipose-derived mesenchymal stem cells: a pilot study. Stem Cells. Scholar
  41. 41.
    Kim, S. J., Song, D. H., Park, J. W., Park, S., & Kim, S. J. (2017). Effect of bone marrow aspirate concentrate-platelet-rich plasma on tendon-derived stem cells and rotator cuff tendon tear. Cell Transplantation. Scholar
  42. 42.
    Alsalameh, S., Amin, R., Gemba, T., & Lotz, M. (2004). Identification of mesenchymal progenitor cells in normal and osteoarthritic human articular cartilage. Arthritis and Rheumatism. Scholar
  43. 43.
    Pretzel, D., Linss, S., Rochler, S., et al. (2011). Relative percentage and zonal distribution of mesenchymal progenitor cells in human osteoarthritic and normal cartilage. Arthritis Research and Therapy. Scholar
  44. 44.
    Williams, R., Khan, I. M., Richardson, K., et al. (2010). Identification and clonal characterisation of a progenitor cell sub-population in normal human articular cartilage. PLoS One. Scholar
  45. 45.
    Sacchetti, B., Funari, A., Remoli, C., et al. (2016). No identical “mesenchymal stem cells” at different times and sites: human committed progenitors of distinct origin and differentiation potential are incorporated as adventitial cells in microvessels. Stem Cell Reports. Scholar
  46. 46.
    Al-Nbaheen, M., Vishnubalaji, R., Ali, D., et al. (2013). Human stromal (mesenchymal) stem cells from bone marrow, adipose tissue and skin exhibit differences in molecular phenotype and differentiation potential. Stem Cell Reviews and Reports. Scholar
  47. 47.
    Crisan, M., Yap, S., Casteilla, L., Chen, C. W., et al. (2008). A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell. Scholar
  48. 48.
    Guimarães-Camboa, N., Cattaneo, P., Sun, Y., et al. (2017). Pericytes of multiple organs do not behave as mesenchymal stem cells in vivo. Cell Stem Cell. Scholar
  49. 49.
    Murphy, J. M., Dixon, K., Beck, S., Fabian, D., Feldman, A., & Barry, F. (2002). Reduced chondrogenic and adipogenic activity of mesenchymal stem cells from patients with advanced osteoarthritis. Arthritis and Rheumatism. Scholar
  50. 50.
    Sakaguchi, Y., Sekiya, I., Yagishita, K., Ichinose, S., Shinomiya, K., & Muneta, T. (2009). Suspended cells from trabecular bone by collagenase digestion become virtually identical to mesenchymal stem cells obtained from marrow. Stem Cells. Scholar
  51. 51.
    Latil, M., Rocheteau, P., Châtre, L., et al. (2012). Skeletal muscle stem cells adopt a dormant cell state post mortem and retain regenerative capacity. Nature Communications. Scholar
  52. 52.
    Valente, S., Alviano, F., Ciavarella, C., et al. (2014). Human cadaver multipotent stromal/stem cells isolated from arteries stored in liquid nitrogen for 5 years. Stem Cell Research & Therapy. Scholar
  53. 53.
    Baustian, C., Hanley, S., & Ceredig, R. (2012). Isolation, selection and culture methods to enhance clonogenicity of mouse bone marrow derived mesenchymal stromal cell precursors. Stem Cell Research & Therapy. Scholar
  54. 54.
    Futami, I., Ishijima, M., Kaneko, H., et al. (2012). Isolation and characterization of multipotential mesenchymal cells from the mouse synovium. PLoS One. Scholar
  55. 55.
    Zhu, H., Guo, Z.-K., Jiang, X.-X., et al. (2010). A protocol for isolation and culture of mesenchymal stem cells from mouse compact bone. Nature Protocols. Scholar
  56. 56.
    Tsai, C.-C., Yew, T.-L., Yang, D.-C., Huang, W.-H., & Hung, S.-C. (2012) Benefits of hypoxic culture on bone marrow multipotent stromal cells. American Journal of Blood Research.Google Scholar
  57. 57.
    Dominici, M., Le Blanc, K., Mueller, I., et al. (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. Scholar
  58. 58.
    Fuchs, E., & Horsley, V. (2011). Ferreting out stem cells from their niches. Nature Cell Biology. Scholar
  59. 59.
    Morikawa, S., Mabuchi, Y., Kubota, Y., et al. (2009). Prospective identification, isolation, and systemic transplantation of multipotent mesenchymal stem cells in murine bone marrow. The Journal of Experimental Medicine. Scholar
  60. 60.
    Pinho, S., Lacombe, J., Hanoun, M., et al. (2013). PDGFRa and CD51 mark human Nestin + sphere-forming mesenchymal stem cells capable of hematopoietic progenitor cell expansion. The Journal of Experimental Medicine. Scholar
  61. 61.
    Park, D., Spencer, J. A., Koh, B. I., et al. (2012). Cell stem cell endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration. Stem Cell. Scholar
  62. 62.
    Mizoguchi, T., Pinho, S., Ahmed, J., et al. (2014). Osterix marks distinct waves of primitive and definitive stromal progenitors during bone marrow development. Developmental Cell. Scholar
  63. 63.
    Liu, Y., Strecker, S., Wang, L., et al. (2013). Osterix-Cre labeled progenitor cells contribute to the formation and maintenance of the bone marrow stroma. PLoS One. Scholar
  64. 64.
    Marecic, O., Tevlin, R., McArdle, A., et al. (2015). Identification and characterization of an injury-induced skeletal progenitor. Proceedings of the National Academy of Sciences. Scholar
  65. 65.
    Tanaka, K. K., Hall, J. K., Troy, A. A., Cornelison, D. D. W., Majka, S. M., & Olwin, B. B. (2009). Syndecan-4-expressing muscle progenitor cells in the SP engraft as satellite cells during muscle regeneration. Cell Stem Cell. Scholar
  66. 66.
    Doyle, M. J., Zhou, S., Tanaka, K. K., et al. (2011). Abcg2 labels multiple cell types in skeletal muscle and participates in muscle regeneration. The Journal of Cell Biology. Scholar
  67. 67.
    Meeson, A. P., Hawke, T. J., Graham, S., et al. (2004). Cellular and molecular regulation of skeletal muscle side population cells. Stem Cells. Scholar
  68. 68.
    Penton, C. M., Thomas-Ahner, J. M., Johnson, E. K., McAllister, C., & Montanaro, F. (2013). Muscle side population cells from dystrophic or injured muscle adopt a fibro-adipogenic fate. PLoS One. Scholar
  69. 69.
    Pannérec, A., Formicola, L., Besson, V., Marazzi, G., & Sassoon, D. A. (2013). Defining skeletal muscle resident progenitors and their cell fate potentials. Development. Scholar
  70. 70.
    Cottle, B. J., Lewis, F. C., Shone, V., & Ellison-Hughes, G. M. (2017). Skeletal muscle-derived interstitial progenitor cells (PICs) display stem cell properties, being clonogenic, self-renewing, and multi-potent in vitro and in vivo. Stem Cell Research & Therapy. Scholar
  71. 71.
    Mitchell, K. J., Pannerec, A., Cadot, B., et al. (2010). Identification and characterization of a non-satellite cell muscle resident progenitor during postnatal development. Nature Cell Biol. Scholar
  72. 72.
    Lewis, F. C., Henning, B. J., Marazzi, G., Sassoon, D., Ellison, G. M., & Nadal-Ginard, B. (2014). Porcine skeletal-muscle-derived multipotent PW1 pos /Pax7 neg interstitial cells: isolation, characterization, and long-term culture. Stem Cells Transational Medicine. Scholar
  73. 73.
    Bosnakovski, D., Xu, Z., Li, W., et al. (2008). Prospective isolation of skeletal muscle stem cells with a Pax7 reporter. Stem Cells. Scholar
  74. 74.
    Seale, P., Sabourin, L. A., Girgis-Gabardo, A., Mansouri, A., Gruss, P., & Rudnicki, M. A. (2000) Pax7 is required for the specification of myogenic satellite cells skeletal muscle. Cell, 102(6), 777–786.PubMedGoogle Scholar
  75. 75.
    Xu, X., Wilschut, K. J., Kouklis, G., et al. (2015). Human satellite cell transplantation and regeneration from diverse skeletal muscles. Stem Cell Reports. Scholar
  76. 76.
    Morosetti, R., Mirabella, M., Gliubizzi, C., et al. (2007). Isolation and characterization of mesoangioblasts from facioscapulohumeral muscular dystrophy muscle biopsies. Stem Cells. Scholar
  77. 77.
    Bonfanti, C., Rossi, G., Tedesco, F. S., et al. (2015). ARTICLE PW1/Peg3 expression regulates key properties that determine mesoangioblast stem cell competence. Nature Communications. Scholar
  78. 78.
    Morosetti, R., Mirabella, M., Gliubizzi, C., et al. (2006). MyoD expression restores defective myogenic differentiation of human mesoangioblasts from inclusion-body myositis muscle. Proceeding of the National Academy of Sciences. Scholar
  79. 79.
    Dellavalle, A., Maroli, G., Covarello, D., et al. (2011). Pericytes resident in postnatal skeletal muscle differentiate into muscle fibres and generate satellite cells. Nature Communications. Scholar
  80. 80.
    Birbrair, A., Zhang, T., Wang, Z. M., et al. (2013). Role of pericytes in skeletal muscle regeneration and fat accumulation. Stem Cells and Development. Scholar
  81. 81.
    Dellavalle, A., Sampaolesi, M., Tonlorenzi, R., et al. (2007) Pericytes of human skeletal muscle are myogenic precursors distinct from satellite cells. Nature Cell Biology, Scholar
  82. 82.
    Uezumi, A., Ito, T., Morikawa, D., et al. (2011). Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle. Journal of Cell Science. Scholar
  83. 83.
    Uezumi, A., Fukada, S., Yamamoto, N., Takeda, S., & Tsuchida, K. (2010). Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nature Cell Biology. Scholar
  84. 84.
    Uezumi, A., Fukada, S., Yamamoto, N., et al. (2014). Identification and characterization of PDGFRa + mesenchymal progenitors in human skeletal muscle. Cell Death & Disease. Scholar
  85. 85.
    Arrighi, N., Moratal, C., Clément, N., et al. (2015). Characterization of adipocytes derived from fibro/adipogenic progenitors resident in human skeletal muscle. Cell Death & Disease. Scholar
  86. 86.
    Joe, A. W., Yi, L., Natarajan, A., et al. (2010). Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nature Cell Biology. Scholar
  87. 87.
    Xu, W., Sun, Y., Zhang, J., et al. (2015). Perivascular-derived stem cells with neural crest characteristics are involved in tendon repair. Stem Cells and Development. Scholar
  88. 88.
    Runesson, E., Ackermann, P., Karlsson, J., & Eriksson, B. I. (2015). A randomised controlled trial of percutaneous fixation with kirschner wires versus volar locking-plate fixation in the treatment of adult patients with a dorsally displaced fracture of the distal radius. BMC Musculoskeletal Disorders. Scholar
  89. 89.
    Donahue, T., Gregersen, C., Hull, M., et al. (2015). Harnessing endogenous stem/progenitor cells for tendon regeneration. Journal of Biomechanical Engineering. Scholar
  90. 90.
    Dyment, N. A., Hagiwara, Y., Matthews, B. G., Li, Y., Kalajzic, I., & Rowe, D. W. (2014). Lineage tracing of resident tendon progenitor cells during growth and natural healing. PLoS One. Scholar
  91. 91.
    Fukada, S., Higuchi, S., Segawa, M., et al. (2004). Purification and cell-surface marker characterization of quiescent satellite cells from murine skeletal muscle by a novel monoclonal antibody. Experimental Cell Research. Scholar
  92. 92.
    Kuyinu, E. L., Narayanan, G., Nair, L. S., & Laurencin, C. T. (2016). Animal models of osteoarthritis: classification, update, and measurement of outcomes. Journal of Orthopaedic Surgery and Research. Scholar
  93. 93.
    Mills, L. A., & Simpson, A. H. (2012). In vivo models of bone repair. Bone Joint and Journal. Scholar
  94. 94.
    Hardy, D., Besnard, A., Latil, M., et al. (2016). Comparative study of injury models for studying muscle regeneration in mice. PLoS One. Scholar
  95. 95.
    Carpenter, J. E., & Hankenson, K. D. (2004). Animal models of tendon and ligament injuries for tissue engineering applications. Biomaterials. Scholar
  96. 96.
    Docheva, D., Müller, S. A., Majewski, M., & Evans, C. H. (2015). Biologics for tendon repair. Advanced Drug Delivery Reviews. Scholar
  97. 97.
    Hast, M. W., Zuskov, A., & Soslowsky, L. J. (2014). The role of animal models in tendon research. Bone and Joint Research. Scholar
  98. 98.
    Kfoury, Y., & Scadden, D. T. (2015). Cell stem cell mesenchymal cell contributions to the stem cell niche. Stem Cells. Scholar
  99. 99.
    Omatsu, Y., Seike, M., Sugiyama, T., Kume, T., & Nagasawa, T. (2014). Foxc1 is a critical regulator of haematopoietic stem/ progenitor cell niche formation. Nature. Scholar
  100. 100.
    Isern, J., Martín-Antonio, B., Ghazanfari, R., et al. (2013). Self-renewing human bone marrow mesenspheres promote hematopoietic stem cell expansion. Cell Reports. Scholar
  101. 101.
    Ding, L., Saunders, T. L., Enikolopov, G., & Morrison, S. J. (2012). Endothelial and perivascular cells maintain haematopoietic stem cells. Nature. Scholar
  102. 102.
    Kunisaki, Y., Bruns, I., Scheiermann, C., et al. (2013). Arteriolar niches maintain haematopoietic stem cell quiescence. Nature. Scholar
  103. 103.
    Fernandez-Moure, J. S., Corradetti, B., Chan, P., et al. (2015). Enhanced osteogenic potential of mesenchymal stem cells from cortical bone: a comparative analysis. Stem Cell Research & Therapy. Scholar
  104. 104.
    Li, H., Ghazanfari, R., Zacharaki, D., et al. (2014). Low/ negative expression of PDGFR-α identifies the candidate primary mesenchymal stromal cells in adult human bone marrow. Stem Cell Reports. Scholar
  105. 105.
    Campbell, T. M., Churchman, S. M., Gomez, A., et al. (2016). Mesenchymal stem cell alterations in bone marrow lesions in patients with hip osteoarthritis. Arthritis & Rheumatology. Scholar
  106. 106.
    Lee, W. C., Shi, H., Poon, Z., et al. (2014). Multivariate biophysical markers predictive of mesenchymal stromal cell multipotency. Proceedings of the National Academy of Science. Scholar
  107. 107.
    Johnson, K., Zhu, S., Tremblay, M. S., et al. (2013). A stem-cell–based approach to cartilage repair. Science. Scholar
  108. 108.
    Mauro, A. (1961). Satellite cell of skeletal muscle fibers. The Journal of Biophysical and Biochemical Cytology. Scholar
  109. 109.
    Muir, A. R., Kanji, A. H., & Allbrook, D. (1965). The structure of the satellite cells in skeletal muscle. Journal of Anatomy, 99(Pt 3), 435–444.PubMedPubMedCentralGoogle Scholar
  110. 110.
    Goodell, M. A., Brose, K., Paradis, G., Conner, A. S., & Mulligan, R. C. (1996). Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. The Journal of Experimental Medicine. Scholar
  111. 111.
    Montanaro, F., Liadaki, K., Schienda, J., Flint, A., Gussoni, E., & Kunkel, L. M. (2004). Demystifying SP cell purification: Viability, yield, and phenotype are defined by isolation parameters. Experimental Cell Research. Scholar
  112. 112.
    Uezumi, A., Ojima, K., Fukada, S., et al. (2006). Functional heterogeneity of side population cells in skeletal muscle. Biochemical and Biophysical Research Communications. Scholar
  113. 113.
    Zhou, S., Schuetz, J. D., Bunting, K. D., et al. (2001). The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nature Medicine. Scholar
  114. 114.
    Asakura, A., Seale, P., Girgis-Gabardo, A., & Rudnicki, M. A. (2002). Myogenic specification of side population cells in skeletal muscle. The Journal of Cell Biology. Scholar
  115. 115.
    Sampaolesi, M., Torrente, Y., Innocenzi, A., et al. (2003). Cell therapy of α-sarcoglycan-null dystrophic mice through intra-arterial delivery of mesoangioblasts. Science. Scholar
  116. 116.
    Galvez, B. G., Sampaolesi, M., Brunelli, S., et al. (2006). Complete repair of dystrophic skeletal muscle by mesoangioblasts with enhanced migration ability. The Journal of Cell Biology. Scholar
  117. 117.
    Sampaolesi, M., Blot, S., D’Antona, G., et al. (2006). Mesoangioblast stem cells ameliorate muscle function in dystrophic dogs. Nature. Scholar
  118. 118.
    Cossu, G., Previtali, S. C., Napolitano, S., et al. (2015). Intra-arterial transplantation of HLA-matched donor mesoangioblasts in Duchenne muscular dystrophy. EMBO Molecular Medicine. Scholar
  119. 119.
    Relaix, F., & Zammit, P. S. (2012). Satellite cells are essential for skeletal muscle regeneration: the cell on the edge returns centre stage. Development. Scholar
  120. 120.
    Sambasivan, R., Yao, R., Kissenpfennig, A., Van Wittenberghe, L., et al. (2011). Pax7-expressing satellite cells are indispensable for adult skeletal muscle regeneration. Development. Scholar
  121. 121.
    Hernandez-Torres, F., Rodríguez-Outeiriño, L., Franco, D., & Aranega, A. E. (2017). Pitx2 in embryonic and adult myogenesis. Frontiers in Cell and Development Biology. Scholar
  122. 122.
    Zhang, J., & Wang, J. (2013). Human tendon stem cells better maintain their stemness in hypoxic culture conditions. PLoS One. Scholar
  123. 123.
    Bi, Y., Ehirchiou, D., Kilts, T. M., et al. (2007). Identification of tendon stem/progenitor cells and the role of the extracellular matrix in their niche. Nature Medicine. Scholar
  124. 124.
    Po, P., & Lui, Y. (2015). Stem cell technology for tendon regeneration: current status, challenges, and future research directions. Stem Cells Cloning: Advances and Applications. Scholar
  125. 125.
    Zhang, X., Lin, Y. C., Rui, Y. F., et al. (2016). Therapeutic roles of tendon stem/ progenitor cells in tendinopathy. Stem Cells International. Scholar
  126. 126.
    Lee, K. J., Clegg, P. D., Comerford, E. J., & Canty-Laird, E. G. (2017). Ligament-derived stem cells: identification, characterisation, and therapeutic application. Stem Cells International. Scholar
  127. 127.
    Cheng, M. T., Yang, H. W., Chen, T. H., & Lee, O. K. (2009). Isolation and characterization of multipotent stem cells from human cruciate ligaments. Cell Proliferation. Scholar
  128. 128.
    de Sousa, E., Casado, P., Neto, V., Duarte, M. E., & Aguiar, D. (2014). Synovial fluid and synovial membrane mesenchymal stem cells: latest discoveries and therapeutic perspectives. Stem Cell Research & Therapy. Scholar
  129. 129.
    Spees, J. L., Lee, R. H., & Gregory, C. A. (2016). Mechanisms of mesenchymal stem/stromal cell function. Stem Cell Research & Therapy. Scholar
  130. 130.
    Zachar, L., Bačenková, D., & Rosocha, J. (2016). Activation, homing, and role of the mesenchymal stem cells in the inflammatory environment. Journal of Inflammation Research. Scholar
  131. 131.
    Schepers, K., & Fibbe, W. E. (2016). Unraveling mechanisms of mesenchymal stromal cell-mediated immunomodulation through patient monitoring and product characterization. Annals of the New York Academy of Sciences. Scholar
  132. 132.
    Zhao, Q., Ren, H., & Han, Z. (2016). Mesenchymal stem cells: Immunomodulatory capability and clinical potential in immune diseases. Journal of Cellular Immunotherapy. Scholar
  133. 133.
    Regulski, M. J. (2017). Mesenchymal stem cells: “guardians of inflammation.” Wounds, 29, 20–27.PubMedGoogle Scholar
  134. 134.
    Nishizawa, K., & Seki, R. (2016). Mechanisms of immunosuppression by mesenchymal stromal cells: a review with a focus on molecules. Biomedical Research and Clinical Practice. Scholar
  135. 135.
    Glenn, J. D. (2014). Mesenchymal stem cells: emerging mechanisms of immunomodulation and therapy. World Journal of Stem Cells. Scholar
  136. 136.
    Gruh, I., & Martin, U. (2009). Transdifferentiation of stem cells: a critical view. Engineering of Stem Cells. Scholar
  137. 137.
    Prockop, D. J., & Oh, J. Y. (2012). Medical therapies with adult stem/progenitor cells (MSCs): a backward journey from dramatic results in vivo to the cellular and molecular explanations. Journal of Cellular Biochemistry. Scholar
  138. 138.
    Sottile, F., Aulicino, F., Theka, I., & Cosma, M. P. (2016). Mesenchymal stem cells generate distinct functional hybrids in vitro via cell fusion or entosis. Scientific Reports. Scholar
  139. 139.
    Usunier, B., Benderitter, M., Tamarat, R., & Chapel, A. (2014). Management of fibrosis: the mesenchymal stromal cells breakthrough. Stem Cells International. Scholar
  140. 140.
    Islam, M. N., Das, S. R., Emin, M. T., et al. (2012). Mitochondrial transfer from bone marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nature Medicine. Scholar
  141. 141.
    Chinnery, H. R., Pearlman, E., & McMenamin, P. G. (2008). Cutting edge: Membrane nanotubes in vivo: a feature of MHC class II + cells in the mouse cornea. Journal of Immunology, 180(9), 5779–5783.Google Scholar
  142. 142.
    Liu, K., Ji, K., Guo, L., et al. (2014). Mesenchymal stem cells rescue injured endothelial cells in an in vitro ischemia–reperfusion model via tunneling nanotube like structure-mediated mitochondrial transfer. Microvascular Research. Scholar
  143. 143.
    Valadi, H., Ekström, K., Bossios, A., Sjöstrand, M., Lee, J. J., & Lötvall, J. O. (2007). Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nature Cell Biology. Scholar
  144. 144.
    Viganò, M., Sansone, V., d’Agostino, M. C., Romeo, P., Perucca Orfei, C., & de Girolamo, L. (2016). Mesenchymal stem cells as therapeutic target of biophysical stimulation for the treatment of musculoskeletal disorders. Journal of Orthopaedic Surgery and Research. Scholar
  145. 145.
    Coelho, M. B., Cabral, J. M. S., & Karp, J. M. (2012). Intraoperative stem cell therapy. Annual Review of Biomedical Engineering. Scholar
  146. 146.
    Veronesi, F., Giavaresi, G., Tschon, M., Borsari, V., Nicoli Aldini, N., & Fini, M. (2013). Clinical use of bone marrow, bone marrow concentrate, and expanded bone marrow mesenchymal stem cells in cartilage disease. Stem Cells and Development. Scholar
  147. 147.
    Hernigou, P., Homma, Y., Flouzat Lachaniette, C.H., et al (2013). Benefits of small volume and small syringe for bone marrow aspirations of mesenchymal stem cells. International Orthopaedics.
  148. 148.
    Otsuru, S., Hofmann, T. J., Olson, T. S., Dominici, M., & Horwitz, E. M. (2013). Improved isolation and expansion of bone marrow mesenchymal stromal cells using a novel marrow filter device. Cytotherapy. Scholar
  149. 149.
    Ito, K., Aoyama, T., Fukiage, K., et al. (2010). A novel method to isolate mesenchymal stem cells from bone marrow in a closed system using a device made by nonwoven fabric. Tissue Engineering Part C Methods. Scholar
  150. 150.
    Zuk, P. A., Zhu, M., Mizuno, H., et al. (2001). Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Engineering. Scholar
  151. 151.
    Lendeckel, S., Jödicke, A., Christophis, P., et al. (2004). Autologous stem cells (adipose) and fibrin glue used to treat widespread traumatic calvarial defects: case report. Journal of Cranio-Maxillofacial Surgery. Scholar
  152. 152.
    Baer, P. C., & Geiger, H. (2012). Adipose-derived mesenchymal stromal/stem cells: tissue localization, characterization, and heterogeneity. Stem Cells International. Scholar
  153. 153.
    Fraser, J. K., Zhu, M., Wulur, I., & Alfonso, Z. (2008). Adipose-derived stem cells. Methods in Molecular Biology. Scholar
  154. 154.
    Pak, J., Lee, J. H., Park, K. S., Park, M., Kang, L. W., & Lee, S. H. (2017). Current use of autologous adipose tissue-derived stromal vascular fraction cells for orthopedic applications. Journal of Biomedical Sciences. Scholar
  155. 155.
    Ancans, J. (2012). Cell therapy medicinal product regulatory framework in Europe and its application for MSC-based therapy development. Frontiers in Immunology. Scholar
  156. 156.
    Kristjánsson, B., & Honsawek, S. (2014). Current perspectives in mesenchymal stem cell therapies for osteoarthritis. Stem Cells International. Scholar
  157. 157.
    Reissis, D., Tang, Q. O., Cooper, N. C., et al. (2016). Current clinical evidence for the use of mesenchymal stem cells in articular cartilage repair. Expert Opinion on Biological Therapy. Scholar
  158. 158.
    Centeno, C. J., Al-Sayegh, H., Freeman, M. D., Smith, J., Murrell, W. D., & Bubnov, R. (2016). A multi-center analysis of adverse events among two thousand, three hundred and seventy two adult patients undergoing adult autologous stem cell therapy for orthopaedic conditions. International Orthopaedics. Scholar
  159. 159.
    Deng, Z., Jin, J., Zhao, J., & Xu, H. (2016). Cartilage defect treatments: With or without cells? Mesenchymal stem cells or chondrocytes? Traditional or matrix-assisted? A systematic review and meta-analyses. Stem Cells International. Scholar
  160. 160.
    Kon, E., Roffi, A., Filardo, G., Tesei, G., & Marcacci, M. (2015). Scaffold-based cartilage treatments: with or without cells? A systematic review of preclinical and clinical evidence. Arthroscopy. Scholar
  161. 161.
    Merlos-Suárez, A., Barriga, F. M., Jung, P., et al. (2011). The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse. Cell Stem Cell. Scholar
  162. 162.
    Cao, C., Dong, Y., & Dong, Y. (2005). [Study on culture and in vitro osteogenesis of blood-derived human mesenchymal stem cells]. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi, 19, 642–647.PubMedGoogle Scholar
  163. 163.
    Kassis, I., Zangi, L., Rivkin, R., et al. (2006). Isolation of mesenchymal stem cells from G-CSF-mobilized human peripheral blood using fibrin microbeads. Bone Marrow Transplant. Scholar
  164. 164.
    Pino, A. M., Rosen, C. J., & Rodríguez, J. P. (2012). In Osteoporosis, differentiation of mesenchymal stem cells (MSCs) improves bone marrow adipogenesis. Biological Research. Scholar
  165. 165.
    Rodríguez, J. P., Garat, S., Gajardo, H., Pino, A. M., & Seitz, G. (1999). Abnormal osteogenesis in osteoporotic patients is reflected by altered mesenchymal stem cells dynamics. Journal of Cellular Biochemistry.<414::AID-JCB7>3.0.CO;2-C Google Scholar
  166. 166.
    Rosen, C. J., & Bouxsein, M. L. (2006). Mechanisms of disease: is osteoporosis the obesity of bone? Nature Clinical Practice Rheumatology. Scholar
  167. 167.
    D’Ippolito, G., Schiller, P. C., Ricordi, C., Roos, B. A., & Howard, G. A. (1999). Age-related osteogenic potential of mesenchymal stromal stem cells from human vertebral bone marrow. Journal of Bone and Mineral Research. Scholar
  168. 168.
    Gunawardene, P., Bermeo, S., Vidal, C., et al. (2016). Association between circulating osteogenic progenitor cells and disability and frailty in older persons: the Nepean osteoporosis and frailty study. The Journals of Gerontology Series A, Biological Sciences and Medical Sciences. Scholar
  169. 169.
    Yu, B., & Wang, C. Y. (2016). Osteoporosis: the result of an “aged” bone microenvironment. Trends Mol Med. Scholar
  170. 170.
    Benisch, P., Schilling, T., Klein-Hitpass, L., et al. (2012). The transcriptional profile of mesenchymal stem cell populations in primary osteoporosis is distinct and shows overexpression of osteogenic inhibitors. PLoS One. Scholar
  171. 171.
    Marco, F., Milena, F., Gianluca, G., & Vittoria, O. (2005). Peri-implant osteogenesis in health and osteoporosis. Micron. Scholar
  172. 172.
    Heilmeier, U., Hackl, M., Skalicky, S., et al. (2016). Serum miRNA signatures are indicative of skeletal fractures in postmenopausal women with and without type 2 diabetes and influence of osteogenic and adipogenic differentiation of adipose-tissue-derived mesenchymal stem cells in vitro. Journal of Bone and Mineral Research. Scholar
  173. 173.
    Barry, F., & Murphy, M. (2013). Mesenchymal stem cells in joint disease and repair. Nature Reviews Rheumatology. Scholar
  174. 174.
    Hermida-Gómez, T., Fuentes-Boquete, I., Gimeno-Longas, M. J., et al. (2011). Quantification of cells expressing mesenchymal stem cell markers in healthy and osteoarthritic synovial membranes. The Journal of Rheumatology. Scholar
  175. 175.
    Findlay, D. M., & Kuliwaba, J. S. (2016). Bone–cartilage crosstalk: a conversation for understanding osteoarthritis. Bone Research. Scholar
  176. 176.
    Kalinkovich, A., & Livshits, G. (2015). Sarcopenia–The search for emerging biomarkers. Ageing Research Reviews. Scholar
  177. 177.
    Sousa-Victor, P., & Muñoz-Cánoves, P. (2016). Regenerative decline of stem cells in sarcopenia. Molecular Aspects of Medicine. Scholar
  178. 178.
    Sousa-Victor, P., Gutarra, S., García-Prat, L., et al. (2014). Geriatric muscle stem cells switch reversible quiescence into senescence. Nature. Scholar
  179. 179.
    Fry, C. S., Lee, J. D., Mula, J., et al. (2015). Inducible depletion of satellite cells in adult, sedentary mice impairs muscle regenerative capacity without affecting sarcopenia. Nature Medicine. Scholar
  180. 180.
    Dennison, E. M., Sayer, A. A., & Cooper, C. (2017). Epidemiology of sarcopenia and insight into possible therapeutic targets. Nature Reviews Rheumatology. Scholar
  181. 181.
    Snijders, T., Verdijk, L. B., & van Loon, L. J. C. (2009). The impact of sarcopenia and exercise training on skeletal muscle satellite cells. Ageing Research Reviews. Scholar
  182. 182.
    Emery, A. E. H. (1991). Population frequencies of inherited neuromuscular diseases-A world survey. Neuromuscular Disorders. Scholar
  183. 183.
    Song, Y., Yao, S., Liu, Y., et al. (2017). Expression levels of TGF-β1 and CTGF are associated with the severity of Duchenne muscular dystrophy. Experimental and Therapeutic Medicine. Scholar
  184. 184.
    Almeida, C. F., Martins, P. C., & Vainzof, M. (2016). Comparative transcriptome analysis of muscular dystrophy models Largemyd, Dmdmdx/Largemyd and Dmdmdx: what makes them different? European Journal of Human Genetics. Scholar
  185. 185.
    Dumont, N. A., Xin Wang, Y., & von Maltzahn, J. (2015). Dystrophin expression in muscle stem cells regulates their polarity and asymmetric division. Nature Medicine. Scholar
  186. 186.
    Marg, A., Escobar, H., Gloy, S., et al. (2014). Human satellite cells have regenerative capacity and are genetically manipulable. Journal of Clinical Investigation. Scholar
  187. 187.
    Wang, Y., Han, Z., Song, Y., & Han, Z. C. (2012). Safety of mesenchymal stem cells for clinical application. Stem Cells International. Scholar
  188. 188.
    Lu, X., & Zhao, T. (2013). Clinical Therapy using iPSCs: Hopes and Challenges. Genomics, Proteomics & Bioinformatics. Scholar
  189. 189.
    Liu, X., Li, W., Fu, X., & Xu, Y. (2017). The immunogenicity and immune tolerance of pluripotent stem cell derivatives. Frontiers in Immunology. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Faculty of PharmacyUniversity of LjubljanaLjubljanaSlovenia
  2. 2.EDUCELL Cell Therapy ServiceTrzinSlovenia
  3. 3.Department of Orthopaedic SurgeryUniversity Medical Centre LjubljanaLjubljanaSlovenia

Personalised recommendations