The Role of MSCs for Nonsurgical Treatment of OA

  • Silvia Lopa
  • Matteo Moretti
  • Laura de GirolamoEmail author


Osteoarthritis (OA) is the most common form of arthritis, representing a social and economic burden worldwide. The scarce efficacy of the traditional conservative treatments is among the main reasons for the increasing demand of knee and hip replacement, as well as for the increasing interest for stem cell-based treatments, due to their anti-inflammatory, immunomodulatory, and regenerative potential and to their ability to influence positively the articular environment.

Among adult stem cells, mesenchymal stem cells or, as more recently proposed, also known as medicinal signaling cells (MSCs), are the most widely used in the OA context. MSCs are mainly derived from bone marrow and adipose tissue and can be used either expanded or freshly isolated. On average, the current literature shows very promising results deriving from injective treatment with MSCs, although some data are still conflicting in terms of the best cell type, dose, and duration of the therapeutic effect.

In this chapter, we will describe the main variables that can be considered when designing a MSC-based therapy in the context of OA treatment and will provide an updated report of the studies focusing on the intraarticular injection of MSCs for the nonsurgical treatment of this pathology.


Osteoarthritis Inflammation Mesenchymal stem cell Intraarticular injection Articular cartilage Bone marrow concentrate Stromal vascular fraction 



Amniotic suspension allograft


Adipose-derived mesenchymal stem cells


Bone marrow concentrate


Bone marrow-derived mesenchymal stem cells


Hyaluronic acid


Infrapatellar fat pad-derived mesenchymal stem cell


Magnetic resonance imaging


Mesenchymal stem cell




Platelet-rich plasma


Stromal vascular fraction


Visual analog scale


Western Ontario and McMaster Universities osteoarthritis index


  1. 1.
    Woolf AD, Pfleger B. Burden of major musculoskeletal conditions. Bull World Health Organ. 2003;81(9):646–56.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Glyn-Jones S, Palmer AJ, Agricola R, Price AJ, Vincent TL, Weinans H, et al. Osteoarthritis. Lancet. 2015;386(9991):376–87.CrossRefGoogle Scholar
  3. 3.
    Hiligsmann M, Cooper C, Arden N, Boers M, Branco JC, Luisa Brandi M, et al. Health economics in the field of osteoarthritis: an expert’s consensus paper from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). Semin Arthritis Rheum. 2013;43(3):303–13.CrossRefPubMedGoogle Scholar
  4. 4.
    Paxton EW, Namba RS, Maletis GB, Khatod M, Yue EJ, Davies M, et al. A prospective study of 80,000 total joint and 5000 anterior cruciate ligament reconstruction procedures in a community-based registry in the United States. J Bone Joint Surg Am. 2010;92(Suppl 2):117–32.CrossRefPubMedGoogle Scholar
  5. 5.
    Barry F, Murphy M. Mesenchymal stem cells in joint disease and repair. Nat Rev Rheumatol. 2013;9(10):584–94.CrossRefPubMedGoogle Scholar
  6. 6.
    de Girolamo L, Kon E, Filardo G, Marmotti AG, Soler F, Peretti GM, et al. Regenerative approaches for the treatment of early OA. Knee Surg Sports Traumatol Arthrosc. 2016;24(6):1826–35.CrossRefPubMedGoogle Scholar
  7. 7.
    Filardo G, Madry H, Jelic M, Roffi A, Cucchiarini M, Kon E. Mesenchymal stem cells for the treatment of cartilage lesions: from preclinical findings to clinical application in orthopedics. Knee Surg Sports Traumatol Arthrosc. 2013;21(8):1717–29.CrossRefPubMedGoogle Scholar
  8. 8.
    Caplan AI. Mesenchymal stem cells. J Orthop Res. 1991;9(5):641–50.CrossRefPubMedGoogle Scholar
  9. 9.
    Caplan AI. The mesengenic process. Clin Plast Surg. 1994;21(3):429–35.PubMedGoogle Scholar
  10. 10.
    Caplan AI. Adult mesenchymal stem cells: when, where, and how. Stem Cells Int. 2015;2015:628767.CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Caplan AI. MSCs: the sentinel and safe-guards of injury. J Cell Physiol. 2016;231(7):1413–6.CrossRefPubMedGoogle Scholar
  12. 12.
    Crisan M, Yap S, Casteilla L, Chen CW, Corselli M, Park TS, et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell. 2008;3(3):301–13.CrossRefPubMedGoogle Scholar
  13. 13.
    Kean TJ, Lin P, Caplan AI, Dennis JE. MSCs: delivery routes and engraftment, cell-targeting strategies, and immune modulation. Stem Cells Int. 2013;2013:732742.CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Caplan AI, Correa D. The MSC: an injury drugstore. Cell Stem Cell. 2011;9(1):11–5.CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Goldring MB, Goldring SR. Articular cartilage and subchondral bone in the pathogenesis of osteoarthritis. Ann N Y Acad Sci. 2010;1192:230–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Ruiz M, Cosenza S, Maumus M, Jorgensen C, Noel D. Therapeutic application of mesenchymal stem cells in osteoarthritis. Expert Opin Biol Ther. 2016;16(1):33–42.CrossRefPubMedGoogle Scholar
  17. 17.
    de Girolamo L, Lucarelli E, Alessandri G, Avanzini MA, Bernardo ME, Biagi E, et al. Mesenchymal stem/stromal cells: a new “cells as drugs” paradigm. Efficacy and critical aspects in cell therapy. Curr Pharm Des. 2013;19(13):2459–73.CrossRefPubMedCentralPubMedGoogle Scholar
  18. 18.
    Horwitz EM, Le Blanc K, Dominici M, Mueller I, Slaper-Cortenbach I, Marini FC, et al. Clarification of the nomenclature for MSC: the International Society for Cellular Therapy position statement. Cytotherapy. 2005;7(5):393–5.CrossRefPubMedGoogle Scholar
  19. 19.
    Caplan AI. What’s in a name? Tissue Eng Part A. 2010;16(8):2415–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Dragoo JL, Chang W. Arthroscopic harvest of adipose-derived mesenchymal stem cells from the infrapatellar fat pad. Am J Sports Med. 2017;45(13):3119-3127.CrossRefPubMedGoogle Scholar
  21. 21.
    Lopa S, Colombini A, Stanco D, de Girolamo L, Sansone V, Moretti M. Donor-matched mesenchymal stem cells from knee infrapatellar and subcutaneous adipose tissue of osteoarthritic donors display differential chondrogenic and osteogenic commitment. Eur Cell Mater. 2014;27:298–311.CrossRefPubMedGoogle Scholar
  22. 22.
    Vines JB, Aliprantis AO, Gomoll AH, Farr J. Cryopreserved amniotic suspension for the treatment of knee osteoarthritis. J Knee Surg. 2016;29(6):443–50.CrossRefPubMedGoogle Scholar
  23. 23.
    Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 2006;8(4):315–7.CrossRefGoogle Scholar
  24. 24.
    Vangsness CT Jr, Farr J 2nd, Boyd J, Dellaero DT, Mills CR, LeRoux-Williams M. Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: a randomized, double-blind, controlled study. J Bone Joint Surg Am. 2014;96(2):90–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Beane OS, Fonseca VC, Cooper LL, Koren G, Darling EM. Impact of aging on the regenerative properties of bone marrow-, muscle-, and adipose-derived mesenchymal stem/stromal cells. PLoS One. 2014;9(12):e115963.CrossRefPubMedCentralPubMedGoogle Scholar
  26. 26.
    Cianfarani F, Toietta G, Di Rocco G, Cesareo E, Zambruno G, Odorisio T. Diabetes impairs adipose tissue-derived stem cell function and efficiency in promoting wound healing. Wound Repair Regen. 2013;21(4):545–53.CrossRefPubMedGoogle Scholar
  27. 27.
    Sun Y, Deng W, Geng L, Zhang L, Liu R, Chen W, et al. Mesenchymal stem cells from patients with rheumatoid arthritis display impaired function in inhibiting Th17 cells. J Immunol Res. 2015;2015:284215.CrossRefPubMedCentralPubMedGoogle Scholar
  28. 28.
    Zhang J, Huang X, Wang H, Liu X, Zhang T, Wang Y, et al. The challenges and promises of allogeneic mesenchymal stem cells for use as a cell-based therapy. Stem Cell Res Ther. 2015;6:234.CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    de Windt TS, Vonk LA, Slaper-Cortenbach IC, van den Broek MP, Nizak R, van Rijen MH, et al. Allogeneic mesenchymal stem cells stimulate cartilage regeneration and are safe for single-stage cartilage repair in humans upon mixture with recycled autologous chondrons. Stem Cells. 2017;35(1):256–64.CrossRefPubMedGoogle Scholar
  30. 30.
    de Windt TS, Vonk LA, Slaper-Cortenbach ICM, Nizak R, van Rijen MHP, Saris DBF. Allogeneic MSCs and recycled autologous chondrons mixed in a one-stage cartilage cell transplantion: a first-in-man trial in 35 patients. Stem Cells. 2017;35(8):1984–93.CrossRefPubMedGoogle Scholar
  31. 31.
    Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D. Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells. Pain Physician. 2008;11(3):343–53.PubMedGoogle Scholar
  32. 32.
    Emadedin M, Aghdami N, Taghiyar L, Fazeli R, Moghadasali R, Jahangir S, et al. Intra-articular injection of autologous mesenchymal stem cells in six patients with knee osteoarthritis. Arch Iran Med. 2012;15(7):422–8.PubMedGoogle Scholar
  33. 33.
    Emadedin M, Ghorbani Liastani M, Fazeli R, Mohseni F, Moghadasali R, Mardpour S, et al. Long-term follow-up of intra-articular injection of autologous mesenchymal stem cells in patients with knee, ankle, or hip osteoarthritis. Arch Iran Med. 2015;18(6):336–44.PubMedGoogle Scholar
  34. 34.
    Orozco L, Munar A, Soler R, Alberca M, Soler F, Huguet M, et al. Treatment of knee osteoarthritis with autologous mesenchymal stem cells: a pilot study. Transplantation. 2013;95(12):1535–41.CrossRefPubMedGoogle Scholar
  35. 35.
    Orozco L, Munar A, Soler R, Alberca M, Soler F, Huguet M, et al. Treatment of knee osteoarthritis with autologous mesenchymal stem cells: two-year follow-up results. Transplantation. 2014;97(11):e66–8.CrossRefPubMedGoogle Scholar
  36. 36.
    Soler R, Orozco L, Munar A, Huguet M, Lopez R, Vives J, et al. Final results of a phase I-II trial using ex vivo expanded autologous mesenchymal stromal cells for the treatment of osteoarthritis of the knee confirming safety and suggesting cartilage regeneration. Knee. 2016;23(4):647–54.CrossRefPubMedGoogle Scholar
  37. 37.
    Davatchi F, Sadeghi Abdollahi B, Mohyeddin M, Nikbin B. Mesenchymal stem cell therapy for knee osteoarthritis: 5 years follow-up of three patients. Int J Rheum Dis. 2016;19(3):219–25.CrossRefPubMedGoogle Scholar
  38. 38.
    Lamo-Espinosa JM, Mora G, Blanco JF, Granero-Molto F, Nunez-Cordoba JM, Sanchez-Echenique C, et al. Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: multicenter randomized controlled clinical trial (phase I/II). J Transl Med. 2016;14(1):246.CrossRefPubMedCentralPubMedGoogle Scholar
  39. 39.
    Kim JD, Lee GW, Jung GH, Kim CK, Kim T, Park JH, et al. Clinical outcome of autologous bone marrow aspirates concentrate (BMAC) injection in degenerative arthritis of the knee. Eur J Orthop Surg Traumatol. 2014;24(8):1505–11.CrossRefPubMedGoogle Scholar
  40. 40.
    Centeno C, Pitts J, Al-Sayegh H, Freeman M. Efficacy of autologous bone marrow concentrate for knee osteoarthritis with and without adipose graft. Biomed Res Int. 2014;2014:370621.CrossRefPubMedCentralPubMedGoogle Scholar
  41. 41.
    Vega A, Martin-Ferrero MA, Del Canto F, Alberca M, Garcia V, Munar A, et al. Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation. 2015;99(8):1681–90.CrossRefPubMedGoogle Scholar
  42. 42.
    Gupta PK, Chullikana A, Rengasamy M, Shetty N, Pandey V, Agarwal V, et al. Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel(R)): preclinical and clinical trial in osteoarthritis of the knee joint. Arthritis Res Ther. 2016;18(1):301.CrossRefPubMedCentralPubMedGoogle Scholar
  43. 43.
    Jo CH, Lee YG, Shin WH, Kim H, Chai JW, Jeong EC, et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem Cells. 2014;32(5):1254–66.CrossRefPubMedGoogle Scholar
  44. 44.
    Pers YM, Rackwitz L, Ferreira R, Pullig O, Delfour C, Barry F, et al. Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of the knee: a phase I dose-escalation trial. Stem Cells Transl Med. 2016;5(7):847–56.CrossRefPubMedCentralPubMedGoogle Scholar
  45. 45.
    Kim YS, Kwon OR, Choi YJ, Suh DS, Heo DB, Koh YG. Comparative matched-pair analysis of the injection versus implantation of mesenchymal stem cells for knee osteoarthritis. Am J Sports Med. 2015;43(11):2738–46.CrossRefPubMedGoogle Scholar
  46. 46.
    Pak J. Regeneration of human bones in hip osteonecrosis and human cartilage in knee osteoarthritis with autologous adipose-tissue-derived stem cells: a case series. J Med Case Rep. 2011;5:296.CrossRefPubMedCentralPubMedGoogle Scholar
  47. 47.
    Pak J, Lee JH, Park KS, Jeong BC, Lee SH. Regeneration of cartilage in human knee osteoarthritis with autologous adipose tissue-derived stem cells and autologous extracellular matrix. Biores Open Access. 2016;5(1):192–200.CrossRefPubMedCentralPubMedGoogle Scholar
  48. 48.
    Koh YG, Choi YJ. Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis. Knee. 2012;19(6):902–7.CrossRefPubMedGoogle Scholar
  49. 49.
    Koh YG, Jo SB, Kwon OR, Suh DS, Lee SW, Park SH, et al. Mesenchymal stem cell injections improve symptoms of knee osteoarthritis. Arthroscopy. 2013;29(4):748–55.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Silvia Lopa
    • 1
  • Matteo Moretti
    • 1
    • 2
    • 3
  • Laura de Girolamo
    • 4
    Email author
  1. 1.Cell and Tissue Engineering LaboratoryIRCCS Galeazzi Orthopedic InstituteMilanItaly
  2. 2.Regenerative Medicine Technologies LabEnte Ospedaliero Cantonale (EOC)LuganoSwitzerland
  3. 3.Swiss Institute for Regenerative MedicineLuganoSwitzerland
  4. 4.Orthopedic Biotechnology LaboratoryIRCCS Galeazzi Orthopedic InstituteMilanItaly

Personalised recommendations