Yeungnam Univ J Med.  2020 Jul;37(3):149-158. 10.12701/yujm.2020.00157.

Current perspectives in stem cell therapies for osteoarthritis of the knee

• Kim GB
• Shon OJ

• KMID: 2506513
• DOI: http://doi.org/10.12701/yujm.2020.00157

Abstract

Mesenchymal stem cells (MSCs) are emerging as an attractive option for osteoarthritis (OA) of the knee joint, due to their marked disease-modifying ability and chondrogenic potential. MSCs can be isolated from various organ tissues, such as bone marrow, adipose tissue, synovium, umbilical cord blood, and articular cartilage with similar phenotypic characteristics but different proliferation and differentiation potentials. They can be differentiated into a variety of connective tissues such as bone, adipose tissue, cartilage, intervertebral discs, ligaments, and muscles. Although several studies have reported on the clinical efficacy of MSCs in knee OA, the results lack consistency. Furthermore, there is no consensus regarding the proper cell dosage and application method to achieve the optimal effect of stem cells. Therefore, the purpose of this study is to review the characteristics of various type of stem cells in knee OA, especially MSCs. Moreover, we summarize the clinical issues faced during the application of MSCs.

Keyword

Knee joint; Mesenchymal stem cells; Osteoarthritis; Stem cells

Figure

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  Fig. 1. Molecular mechanisms of osteoarthritis (OA). TNF, tumor necrosis factor; IL, interleukin.

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  Fig. 2. Considerations for clinical application of MSCs. BMAC, bone marrow aspirate concentrate; MSC, mesenchymal stem cell; BM, bone marrow-derived; AD, adipose tissue-derived; S, synovium-derived; hUCB, human umbilical cord blood-derived.

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  Fig. 3. (A, B) Kellgren-Lawrence grade III osteoarthritis is observed in the left knee anteroposterior and 45° flexion standing radiographs in a 49-year-old woman. (C) The scanography image shows neutral alignment of the both lower extremities. (D, E) Coronal T2-weighted fat suppressed magnetic resonance image (MRI) and arthroscopy show the focal chondral defects of International Cartilage Repair Society (ICRS) grade IV in the lateral femoral condyle and lateral tibial plateau. (F) Surgical implantation is performed using a commercialized mixture of human umbilical cord blood-derived mesenchymal stem cells and hyaluronic acid gel (Cartistem). (G, H) The coronal T2-weighted fat suppressed MRI and second-look arthroscopy confirm regenerated cartilage at 18 months after surgery.

Reference

References

1. Gupta S, Hawker GA, Laporte A, Croxford R, Coyte PC. The economic burden of disabling hip and knee osteoarthritis (OA) from the perspective of individuals living with this condition. Rheumatology (Oxford). 2005; 44:1531–7.

2. de Lange-Brokaar BJ, Ioan-Facsinay A, van Osch GJ, Zuurmond AM, Schoones J, Toes RE, et al. Synovial inflammation, immune cells and their cytokines in osteoarthritis: a review. Osteoarthritis Cartilage. 2012; 20:1484–99.

3. Vincenti MP, Brinckerhoff CE. Transcriptional regulation of collagenase (MMP-1, MMP-13) genes in arthritis: integration of complex signaling pathways for the recruitment of gene-specific transcription factors. Arthritis Res. 2002; 4:157–64.

4. Roach HI, Yamada N, Cheung KS, Tilley S, Clarke NM, Oreffo RO, et al. Association between the abnormal expression of matrix-degrading enzymes by human osteoarthritic chondrocytes and demethylation of specific CpG sites in the promoter regions. Arthritis Rheum. 2005; 52:3110–24.

5. Martin JA, Buckwalter JA. The role of chondrocyte senescence in the pathogenesis of osteoarthritis and in limiting cartilage repair. J Bone Joint Surg Am. 2003; 85A(Suppl 2):106–10.

6. Chevalier X, Eymard F, Richette P. Biologic agents in osteoarthritis: hopes and disappointments. Nat Rev Rheumatol. 2013; 9:400–10.

7. Guler-Yuksel M, Allaart CF, Watt I, Goekoop-Ruiterman YP, de Vries-Bouwstra JK, van Schaardenburg D, et al. Treatment with TNF-α inhibitor infliximab might reduce hand osteoarthritis in patients with rheumatoid arthritis. Osteoarthritis Cartilage. 2010; 18:1256–62.

8. Hawker GA, Mian S, Bednis K, Stanaitis I. Osteoarthritis year 2010 in review: non-pharmacologic therapy. Osteoarthritis Cartilage. 2011; 19:366–74.

9. Goyal D, Keyhani S, Lee EH, Hui JH. Evidence-based status of microfracture technique: a systematic review of level I and II studies. Arthroscopy. 2013; 29:1579–88.

10. Mithoefer K, McAdams T, Williams RJ, Kreuz PC, Mandelbaum BR. Clinical efficacy of the microfracture technique for articular cartilage repair in the knee: an evidence-based systematic analysis. Am J Sports Med. 2009; 37:2053–63.

11. Niemeyer P, Porichis S, Steinwachs M, Erggelet C, Kreuz PC, Schmal H, et al. Long-term outcomes after first-generation autologous chondrocyte implantation for cartilage defects of the knee. Am J Sports Med. 2014; 42:150–7.

12. Martincic D, Radosavljevic D, Drobnic M. Ten-year clinical and radiographic outcomes after autologous chondrocyte implantation of femoral condyles. Knee Surg Sports Traumatol Arthrosc. 2014; 22:1277–83.

13. Gudas R, Gudaite A, Mickevicius T, Masiulis N, Simonaityte R, Cekanauskas E, et al. Comparison of osteochondral autologous transplantation, microfracture, or debridement techniques in articular cartilage lesions associated with anterior cruciate ligament injury: a prospective study with a 3-year follow-up. Arthroscopy. 2013; 29:89–97.

14. 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; 32:1254–66.

15. Freitag J, Bates D, Boyd R, Shah K, Barnard A, Huguenin L, et al. Mesenchymal stem cell therapy in the treatment of osteoarthritis: reparative pathways, safety and efficacy. A review. BMC Musculoskelet Disord. 2016; 17:230.

16. Barry F, Murphy M. Mesenchymal stem cells in joint disease and repair. Nat Rev Rheumatol. 2013; 9:584–94.

17. Vezina Audette R, Lavoie-Lamoureux A, Lavoie JP, Laverty S. Inflammatory stimuli differentially modulate the transcription of paracrine signaling molecules of equine bone marrow multipotent mesenchymal stromal cells. Osteoarthritis Cartilage. 2013; 21:1116–24.

18. Jeong SY, Kim DH, Ha J, Jin HJ, Kwon SJ, Chang JW, et al. Thrombospondin-2 secreted by human umbilical cord blood-derived mesenchymal stem cells promotes chondrogenic differentiation. Stem Cells. 2013; 31:2136–48.

19. 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; 99:1681–90.

20. Martin DR, Cox NR, Hathcock TL, Niemeyer GP, Baker HJ. Isolation and characterization of multipotential mesenchymal stem cells from feline bone marrow. Exp Hematol. 2002; 30:879–86.

21. Johnson MH, McConnell JM. Lineage allocation and cell polarity during mouse embryogenesis. Semin Cell Dev Biol. 2004; 15:583–97.

22. Airenne KJ, Hu YC, Kost TA, Smith RH, Kotin RM, Ono C, et al. Baculovirus: an insect-derived vector for diverse gene transfer applications. Mol Ther. 2013; 21:739–49.

23. Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, et al. Multilineage potential of adult human mesenchymal stem cells. Science. 1999; 284:143–7.

24. De Bari C, Dell'Accio F, Tylzanowski P, Luyten FP. Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum. 2001; 44:1928–42.

25. Guilak F, Estes BT, Diekman BO, Moutos FT, Gimble JM. 2010 Nicolas Andry Award: Multipotent adult stem cells from adipose tissue for musculoskeletal tissue engineering. Clin Orthop Relat Res. 2010; 468:2530–40.

26. Trubiani O, Orsini G, Caputi S, Piatelli A. Adult mesenchymal stem cells in dental research: a new approach for tissue engineering. Int J Immunopathol Pharmacol. 2006; 19:451–60.

27. 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; 8:315–7.

28. Ra JC, Shin IS, Kim SH, Kang SK, Kang BC, Lee HY, et al. Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem cells in animals and humans. Stem Cells Dev. 2011; 20:1297–308.

29. Danisovic L, Lesny P, Havlas V, Teyssler P, Syrova Z, Kopani M, et al. Chondrogenic differentiation of human bone marrow and adipose tissue-derived mesenchymal stem cells. J Appl Biomed. 2007; 5:139–50.

30. Koga H, Shimaya M, Muneta T, Nimura A, Morito T, Hayashi M, et al. Local adherent technique for transplanting mesenchymal stem cells as a potential treatment of cartilage defect. Arthritis Res Ther. 2008; 10:R84.

31. 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; 95:1535–41.

32. Wong KL, Lee KB, Tai BC, Law P, Lee EH, Hui JH. 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 2 years' follow-up. Arthroscopy. 2013; 29:2020–8.

33. Wakitani S, Okabe T, Horibe S, Mitsuoka T, Saito M, Koyama T, et al. Safety of autologous bone marrow-derived mesenchymal stem cell transplantation for cartilage repair in 41 patients with 45 joints followed for up to 11 years and 5 months. J Tissue Eng Regen Med. 2011; 5:146–50.

34. Davatchi F, Abdollahi BS, Mohyeddin M, Shahram F, Nikbin B. Mesenchymal stem cell therapy for knee osteoarthritis. Preliminary report of four patients. Int J Rheum Dis. 2011; 14:211–5.

35. 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; 19:219–25.

36. Medical Advisory Secretariat. Osteogenic protein-1 for long bone nonunion: an evidence-based analysis. Ont Health Technol Assess Ser. 2005; 5:1–57.

37. Madry H, Gao L, Eichler H, Orth P, Cucchiarini M. Bone marrow aspirate concentrate-enhanced marrow stimulation of chondral defects. Stem Cells Int. 2017; 2017:1609685.

38. Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006; 98:1076–84.

39. Hernigou P, Mathieu G, Poignard A, Manicom O, Beaujean F, Rouard H. Percutaneous autologous bone-marrow grafting for nonunions: surgical technique. J Bone Joint Surg Am. 2006; 88(1 Suppl 2):322–7.

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.

41. Sampson S, Smith J, Vincent H, Aufiero D, Zall M, Botto-van-Bemden A. Intra-articular bone marrow concentrate injection protocol: short-term efficacy in osteoarthritis. Regen Med. 2016; 11:511–20.

42. Shapiro SA, Kazmerchak SE, Heckman MG, Zubair AC, O'Connor MI. A prospective, single-blind, placebo-controlled trial of bone marrow aspirate concentrate for knee osteoarthritis. Am J Sports Med. 2017; 45:82–90.

43. Jin YZ, Lee JH. Mesenchymal stem cell therapy for bone regeneration. Clin Orthop Surg. 2018; 10:271–8.

44. Raposio E, Bonomini S, Calderazzi F. Isolation of autologous adipose tissue-derived mesenchymal stem cells for bone repair. Orthop Traumatol Surg Res. 2016; 102:909–12.

45. Bourin P, Bunnell BA, Casteilla L, Dominici M, Katz AJ, March KL, et al. Stromal cells from the adipose tissue-derived stromal vascular fraction and culture expanded adipose tissue-derived stromal/stem cells: a joint statement of the International Federation for Adipose Therapeutics and Science (IFATS) and the International Society for Cellular Therapy (ISCT). Cytotherapy. 2013; 15:641–8.

46. Patrikoski M, Juntunen M, Boucher S, Campbell A, Vemuri MC, Mannerström B, et al. Development of fully defined xeno-free culture system for the preparation and propagation of cell therapy-compliant human adipose stem cells. Stem Cell Res Ther. 2013; 4:27.

47. Thirumala S, Gimble JM, Devireddy RV. Cryopreservation of stromal vascular fraction of adipose tissue in a serum-free freezing medium. J Tissue Eng Regen Med. 2010; 4:224–32.

48. Baer PC, Geiger H. Adipose-derived mesenchymal stromal/stem cells: tissue localization, characterization, and heterogeneity. Stem Cells Int. 2012; 2012:812693.

49. Gentile P, Calabrese C, De Angelis B, Pizzicannella J, Kothari A, Garcovich S. Impact of the different preparation methods to obtain human adipose-derived stromal vascular fraction cells (AD-SVFs) and human adipose-derived mesenchymal stem cells (AD-MSCs): enzymatic digestion versus mechanical centrifugation. Int J Mol Sci. 2019; 20:5471.

50. Lee WS, Kim HJ, Kim KI, Kim GB, Jin W. Intra-articular injection of autologous adipose tissue-derived mesenchymal stem cells for the treatment of knee osteoarthritis: a phase IIb, randomized, placebo-controlled clinical trial. Stem Cells Transl Med. 2019; 8:504–11.

51. Pak J, Chang JJ, Lee JH, Lee SH. Safety reporting on implantation of autologous adipose tissue-derived stem cells with platelet-rich plasma into human articular joints. BMC Musculoskelet Disord. 2013; 14:337.

52. 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; 5:847–56.

53. 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; 43:2738–46.

54. 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 orthopaedics. Knee Surg Sports Traumatol Arthrosc. 2013; 21:1717–29.

55. Zimmerlin L, Donnenberg VS, Pfeifer ME, Meyer EM, Paault B, Rubin JP, et al. Stromal vascular progenitors in adult human adipose tissue. Cytometry A. 2010; 77:22–30.

56. Yokota N, Hattori M, Ohtsuru T, Otsuji M, Lyman S, Shimomura K, et al. Comparative clinical outcomes after intra-articular injection with adipose-derived cultured stem cells or noncultured stromal vascular fraction for the treatment of knee osteoarthritis. Am J Sports Med. 2019; 47:2577–83.

57. Fodor PB, Paulseth SG. Adipose derived stromal cell (ADSC) injections for pain management of osteoarthritis in the human knee joint. Aesthet Surg J. 2016; 36:229–36.

58. Kubosch EJ, Lang G, Furst D, Kubosch D, Izadpanah K, Rolauffs B, et al. The potential for synovium-derived stem cells in cartilage repair. Curr Stem Cell Res Ther. 2018; 13:174–84.

59. Sasaki A, Mizuno M, Ozeki N, Katano H, Otabe K, Tsuji K, et al. Canine mesenchymal stem cells from synovium have a higher chondrogenic potential than those from infrapatellar fat pad, adipose tissue, and bone marrow. PLoS One. 2018; 13:e0202922.

60. Kurth TB, Dell'accio F, Crouch V, Augello A, Sharpe PT, De Bari C. Functional mesenchymal stem cell niches in adult mouse knee joint synovium in vivo. Arthritis Rheum. 2011; 63:1289–300.

61. Koga H, Muneta T, Ju YJ, Nagase T, Nimura A, Mochizuki T, et al. Synovial stem cells are regionally specified according to local microenvironments after implantation for cartilage regeneration. Stem Cells. 2007; 25:689–96.

62. Shimomura K, Yasui Y, Koizumi K, Chijimatsu R, Hart DA, Yonetani Y, et al. First-in-human pilot study of implantation of a scaffold-free tissue-engineered construct generated from autologous synovial mesenchymal stem cells for repair of knee chondral lesions. Am J Sports Med. 2018; 46:2384–93.

63. Klontzas ME, Kenanidis EI, Heliotis M, Tsiridis E, Mantalaris A. Bone and cartilage regeneration with the use of umbilical cord mesenchymal stem cells. Expert Opin Biol Ther. 2015; 15:1541–52.

64. Jin HJ, Bae YK, Kim M, Kwon SJ, Jeon HB, Choi SJ, et al. Comparative analysis of human mesenchymal stem cells from bone marrow, adipose tissue, and umbilical cord blood as sources of cell therapy. Int J Mol Sci. 2013; 14:17986–8001.

65. Park YB, Ha CW, Lee CH, Yoon YC, Park YG. Cartilage regeneration in osteoarthritic patients by a composite of allogeneic umbilical cord blood-derived mesenchymal stem cells and hyaluronate hydrogel: results from a clinical trial for safety and proof-of-concept with 7 years of extended follow-up. Stem Cells Transl Med. 2017; 6:613–21.

66. Matas J, Orrego M, Amenabar D, Infante C, Tapia-Limonchi R, Cadiz MI, et al. Umbilical cord-derived mesenchymal stromal cells (MSCs) for knee osteoarthritis: repeated MSC dosing is superior to a single MSC dose and to hyaluronic acid in a controlled randomized Phase I/II trial. Stem Cells Transl Med. 2019; 8:215–24.

67. Ha CW, Park YB, Chung JY, Park YG. Cartilage repair using composites of human umbilical cord blood-derived mesenchymal stem cells and hyaluronic acid hydrogel in a minipig model. Stem Cells Transl Med. 2015; 4:1044–51.

68. Grigolo B, Lisignoli G, Piacentini A, Fiorini M, Gobbi P, Mazzotti G, et al. Evidence for redifferentiation of human chondrocytes grown on a hyaluronan-based biomaterial (HYAff 11): molecular, immunohistochemical and ultrastructural analysis. Biomaterials. 2002; 23:1187–95.

69. Kon E, Verdonk P, Condello V, Delcogliano M, Dhollander A, Filardo G, et al. Matrix-assisted autologous chondrocyte transplantation for the repair of cartilage defects of the knee: systematic clinical data review and study quality analysis. Am J Sports Med. 2009; 37(Suppl 1):156S–166S.

70. Rai V, Dilisio MF, Dietz NE, Agrawal DK. Recent strategies in cartilage repair: a systemic review of the scaffold development and tissue engineering. J Biomed Mater Res A. 2017; 105:2343–54.

71. Breitbach M, Bostani T, Roell W, Xia Y, Dewald O, Nygren JM, et al. Potential risks of bone marrow cell transplantation into infarcted hearts. Blood. 2007; 110:1362–9.

72. Zhu Y, Wu X, Liang Y, Gu H, Song K, Zou X, et al. Repair of cartilage defects in osteoarthritis rats with induced pluripotent stem cell derived chondrocytes. BMC Biotechnol. 2016; 16:78.

73. Miao Q, Shim W, Tee N, Lim SY, Chung YY, Ja KP, et al. iPSC-derived human mesenchymal stem cells improve myocardial strain of infarcted myocardium. J Cell Mol Med. 2014; 18:1644–54.

74. Sareen D, Gowing G, Sahabian A, Staggenborg K, Paradis R, Avalos P, et al. Human induced pluripotent stem cells are a novel source of neural progenitor cells (iNPCs) that migrate and integrate in the rodent spinal cord. J Comp Neurol. 2014; 522:2707–28.

75. Trokovic R, Weltner J, Nishimura K, Ohtaka M, Nakanishi M, Salomaa V, et al. Advanced feeder-free generation of induced pluripotent stem cells directly from blood cells. Stem Cells Transl Med. 2014; 3:1402–9.

76. Park JS, Suryaprakash S, Lao YH, Leong KW. Engineering mesenchymal stem cells for regenerative medicine and drug delivery. Methods. 2015; 84:3–16.

77. Lien CY, Chih-Yuan Ho K, Lee OK, Blunn GW, Su Y. Restoration of bone mass and strength in glucocorticoid-treated mice by systemic transplantation of CXCR4 and cbfa-1 co-expressing mesenchymal stem cells. J Bone Miner Res. 2009; 24:837–48.

78. Cho SW, Sun HJ, Yang JY, Jung JY, An JH, Cho HY, et al. Transplantation of mesenchymal stem cells overexpressing RANK-Fc or CXCR4 prevents bone loss in ovariectomized mice. Mol Ther. 2009; 17:1979–87.