Abstract
Adult tissues are reservoirs of rare populations of cells known as mesenchymal stem/stromal cells (MSCs) that have tissue-regenerating features retained from embryonic development. As well as building up the musculoskeletal system in early life, MSCs also replenish and repair tissues in adult life, such as bone, cartilage, muscle, and adipose tissue. Cells that show regenerative features at least in vitro have been identified from several connective tissues. Bone marrow and adipose tissue are the most well recognized sources of MSCs that are already used widely in clinical practice. Regenerative medicine aims to exploit MSCs and their tissue regeneration even though the underlying mechanisms for their beneficial effects are largely unknown. Despite many studies that have used various tissue-derived MSCs, the most effective tissue source for orthopedic procedures still remains to be identified. Another question that needs to be addressed is how to evaluate autologous MSCs (i.e., patient derived). Previous studies have suggested the features of bone-marrow-derived MSCs can differ widely between individuals, and can be changed in particular in patients suffering from some forms of degenerative disorder, such as osteoarthritis. The synovium is a thin membrane that protects the synovial joints, and it is a rich source of MSCs that show great potential for regenerative medicine. Here, we review synovium-derived MSCs from reports on basic and clinical studies. We discuss their potential to treat cartilage defects caused by either degeneration or trauma, and what needs to be done in further research toward their better exploitation for joint regeneration.
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References
Arthritis Research UK. (2018). State of musculoskeletal health 2018
Baboolal TG, Khalil-Khan A, Theodorides AA, Wall O, Jones E, McGonagle D (2018) A novel arthroscopic technique for intraoperative mobilization of synovial mesenchymal stem cells. Am J Sports Med 46:1–9. https://doi.org/10.1177/0363546518803757
Bianco P, Cao X, Frenette PS, Mao JJ, Robey PG, Simmons PJ, Wang CY (2013) The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat Med 19:35–42. https://doi.org/10.1038/nm.3028
Čamernik K, Barlič A, Drobnič M, Marc J, Jeras M, Zupan J (2018) Mesenchymal stem cells in the musculoskeletal system: from animal models to human tissue regeneration? Stem Cell Rev Rep 14(3):346–369. https://doi.org/10.1007/s12015-018-9800-6
Campbell TM, Churchman SM, Gomez A, Mcgonagle D, Conaghan PG, Ponchel F, Jones E (2016) Mesenchymal stem cell alterations in bone narrow lesions in patients with hip osteoarthritis. Arthritis Rheumatol 68:1648–1659. https://doi.org/10.1002/art.39622
Caplan AI (2017) Mesenchymal stem cells: time to change the name! Stem Cells Transl Med 6:1445–1451. https://doi.org/10.1002/sctm.17-0051
Chan CKF, Gulati GS, Sinha R, Tompkins JV, Lopez M, Carter AC, Ransom RC, Reinisch A, Wearda T, Murphy M, Brewer RE, Koepke LS, Marecic O, Manjunath A, Seo EY, Leavitt T, Lu W-J, Nguyen A, Conley SD, Salhotra A, Ambrosi TH, Borrelli MR, Siebel T, Chan K, Schallmoser K, Seita J, Sahoo D, Goodnough H, Bishop J, Gardner M, Majeti R, Wan DC, Goodman S, Weissman IL, Chang HY, Longaker MT (2018) Identification of the human skeletal stem cell. Cell 175:43–56.e21. https://doi.org/10.1016/j.cell.2018.07.029
Coelho MB, Cabral JMS, Karp JM (2012) Intraoperative stem cell therapy. Annu Rev Biomed Eng 14:325–349. https://doi.org/10.1146/annurev-bioeng-071811-150041
De Bari C, Roelofs AJ (2018) Stem cell-based therapeutic strategies for cartilage defects and osteoarthritis. Curr Opin Pharmacol 40:74–80. https://doi.org/10.1016/J.COPH.2018.03.009
De Bari C, Dell’Accio F, Tylzanowski P, Luyten FP (2001) Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum 44:1928–1942. https://doi.org/10.1002/1529-0131(200108)44:8<1928::AID-ART331>3.0.CO;2-P
de Sousa E, Casado P, Neto V, Duarte ME, Aguiar D (2014) Synovial fluid and synovial membrane mesenchymal stem cells: latest discoveries and therapeutic perspectives. Stem Cell Res Ther 5:112. https://doi.org/10.1186/scrt501
Delgado-Enciso I, Paz-Garcia J, Valtierra-Alvarez J, Preciado-Ramirez J, Almeida-Trinidad R, Guzman-Esquivel J, Mendoza-Hernandez MA, Garcia-Vega A, Soriano-Hernandez AD, Cortes-Bazan JL, Galvan-Salazar HR, Cabrera-Licona A, Rodriguez-Sanchez IP, Martinez-Fierro ML, Delgado-Enciso J, Paz-Michel B (2018) A phase I-II controlled randomized trial using a promising novel cell-free formulation for articular cartilage regeneration as treatment of severe osteoarthritis of the knee. Eur J Med Res 23(1):52. https://doi.org/10.1186/s40001-018-0349-2
Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop D, Horwitz E (2006) Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 8:315–317. https://doi.org/10.1080/14653240600855905
Enomoto T, Akagi R, Ogawa Y, Yamaguchi S, Hoshi H, Sasaki T, Sato Y, Nakagawa R, Kimura S, Ohtori S, Sasho T (2018) Timing of intra-articular injection of synovial mesenchymal stem cells affects cartilage restoration in a partial thickness cartilage defect model in rats. Cartilage:194760351878654. https://doi.org/10.1177/1947603518786542
Ermis A, Henn W, Remberger K, Hopf C, Hopf T, Zang KD (1995) Proliferation enhancement by spontaneous multiplication of chromosome 7 in rheumatic synovial cells in vitro. Hum Genet 96(6):651–654
Fellows CR, Matta C, Zakany R, Khan IM, Mobasheri A (2016) Adipose, bone marrow and synovial joint-derived mesenchymal stem cells for cartilage repair. Front Genet 7:1–20. https://doi.org/10.3389/fgene.2016.00213
Ferro T, Santhagunam A, Madeira C, Salgueiro JB, da Silva CL, Cabral JMS (2019) Successful isolation and ex-vivo expansion of human mesenchymal stem/ stromal cells obtained from different synovial tissue-derived (biopsy) samples. J Cell Physiol 234(4):3973–3984. https://doi.org/10.1002/jcp.27202
Friedenstein AJ, Chailakhjan RK, Lalykina KS (1970) The development of fibroblast colonies in monolayer cultures of Guinea-pig bone marrow and spleen cells. Cell Prolif 3:393–403. https://doi.org/10.1111/j.1365-2184.1970.tb00347.x
Fuchs E, Horsley V (2011) Ferreting out stem cells from their niches. Nat Cell Biol 13:513–518. https://doi.org/10.1038/ncb0511-513
Futami I, Ishijima M, Kaneko H, Tsuji K, Ichikawa-Tomikawa N, Sadatsuki R, Muneta T, Arikawa-Hirasawa E, Sekiya I, Kaneko K (2012) Isolation and characterization of multipotential mesenchymal cells from the mouse synovium. PLoS One 7(9):e45517. https://doi.org/10.1371/journal.pone.0045517
Garcia J, Wright K, Roberts S, Kuiper JH, Mangham C, Richardson J, Mennan C (2016) Characterisation of synovial fluid and infrapatellar fat-pad-derived mesenchymal stromal cells: the influence of tissue source and inflammatory stimulus. Sci Rep 6:24295. https://doi.org/10.1038/srep24295
Ha CW, Park YB, Kim SH, Lee HJ (2019) Intra-articular mesenchymal stem cells in osteoarthritis of the knee: a systematic review of clinical outcomes and evidence of cartilage repair. Arthroscopy 35(1):277–288.e2. https://doi.org/10.1016/j.arthro.2018.07.028
Harrell CR, Markovic BS, Fellabaum C, Arsenijevic A, Volarevic V (2019) Mesenchymal stem cell-based therapy of osteoarthritis: current knowledge and future perspectives. Biomed Pharmacother 109:2318–2326. https://doi.org/10.1016/j.biopha.2018.11.099
Heck BE, Park JJ, Makani V, Kim EC, Kim DH (2017) PPAR-δ agonist with mesenchymal stem cells induces type II collagen-producing chondrocytes in human arthritic synovial fluid. Cell Transplant 26:1405–1417. https://doi.org/10.1177/0963689717720278
Hermida-Gómez T, Fuentes-Boquete I, Gimeno-Longas MJ, Muiños-López E, Díaz-Prado S, De Toro FJ, Blanco FJ (2011) Quantification of cells expressing mesenchymal stem cell markers in healthy and osteoarthritic synovial membranes. J Rheumatol 38:339–349. https://doi.org/10.3899/jrheum.100614
Im GI, Shin YW, Lee KB (2005) Do adipose tissue-derived mesenchymal stem cells have the same osteogenic and chondrogenic potential as bone marrow-derived cells? Osteoarthr Cartil 13(10):845–853. https://doi.org/10.1016/j.joca.2005.05.005
Jia Z, Liang Y, Li X, Xu X, Xiong J, Wang D, Duan L (2018a) Magnetic-activated cell sorting strategies to isolate and purify synovial-fluid-derived mesenchymal stem cells from a rabbit model. J Vis Exp:e57466–e57466. https://doi.org/10.3791/57466
Jia Z, Liu Q, Liang Y, Li X, Xu X, Ouyang K, Xiong J, Wang D, Duan L (2018b) Repair of articular cartilage defects with intra-articular injection of autologous rabbit synovial fluid-derived mesenchymal stem cells. J Transl Med 16:123. https://doi.org/10.1186/s12967-018-1485-8
Jo CH, Ahn HJ, Kim HJ, Seong SC, Lee MC (2007) Surface characterization and chondrogenic differentiation of mesenchymal stromal cells derived from synovium. Cytotherapy 9:316–327. https://doi.org/10.1080/14653240701291620
Johnson K, Zhu S, Tremblay MS, Payette JN, Wang J, Bouchez LC, Meeusen S, Althage A, Cho CY, Wu X, Schultz PG (2012) A stem-cell-based approach to cartilage repair. Science 336:717–721. https://doi.org/10.1126/science.1215157
Katagiri K, Matsukura Y, Muneta T, Ozeki N, Mizuno M, Katano H, Sekiya I (2017) Fibrous synovium releases higher numbers of mesenchymal stem cells than adipose synovium in a suspended synovium culture model. Arthrosc J Arthrosc Relat Surg 33:800–810. https://doi.org/10.1016/J.ARTHRO.2016.09.033
Koga H, Muneta T, Nagase T, Nimura A, Ju Y-J, Mochizuki T, Sekiya I (2008) Comparison of mesenchymal tissues-derived stem cells for in-vivo chondrogenesis: suitable conditions for cell therapy of cartilage defects in rabbit. Cell Tissue Res 333:207–215. https://doi.org/10.1007/s00441-008-0633-5
Kohno Y, Mizuno M, Ozeki N, Katano H, Komori K, Fujii S, Otabe K, Horie M, Koga H, Tsuji K, Matsumoto M, Kaneko H, Takazawa Y, Muneta T, Sekiya I (2017) Yields and chondrogenic potential of primary synovial mesenchymal stem cells are comparable between rheumatoid arthritis and osteoarthritis patients. Stem Cell Res Ther 8:1–5. https://doi.org/10.1186/s13287-017-0572-8
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. Arthrosc J Arthrosc Relat Surg 31:767–775. https://doi.org/10.1016/J.ARTHRO.2014.11.017
Kurth TB, Dell’Accio F, Crouch V, Augello A, Sharpe PT, De Bari C (2011) Functional mesenchymal stem cell niches in adult mouse knee joint synovium in vivo. Arthritis Rheum 63:1289–1300. https://doi.org/10.1002/art.30234
Kuyinu EL, Narayanan G, Nair LS, Laurencin CT (2016) Animal models of osteoarthritis: classification, update, and measurement of outcomes. J Orthop Surg Res 11:19. https://doi.org/10.1186/s13018-016-0346-5
Lee WY, Wang B (2017) Cartilage repair by mesenchymal stem cells: clinical trial update and perspectives. J Orthop Transl 9:76–88. https://doi.org/10.1016/J.JOT.2017.03.005
Lv F-J, Tuan RS, Cheung KMC, Leung VYL (2014) Concise review: the surface markers and identity of human mesenchymal stem cells. Stem Cells 32:1408–1419. https://doi.org/10.1002/stem.1681
Mak J, Jablonski CL, Leonard CA, Dunn JF, Raharjo E, Matyas JR, Biernaskie J, Krawetz RJ (2016) Intra-articular injection of synovial mesenchymal stem cells improves cartilage repair in a mouse injury model. Sci Rep 6:23076. https://doi.org/10.1038/srep23076
Matsukura Y, Muneta T, Tsuji K, Koga H, Sekiya I (2014) Mesenchymal stem cells in synovial fluid increase after meniscus injury. Clin Orthop Relat Res 472:1357–1364. https://doi.org/10.1007/s11999-013-3418-4
Mizuno M, Katano H, Mabuchi Y, Ogata Y, Ichinose S, Fujii S, Otabe K, Komori K, Ozeki N, Koga H, Tsuji K, Akazawa C, Muneta T, Sekiya I (2018) Specific markers and properties of synovial mesenchymal stem cells in the surface, stromal, and perivascular regions. Stem Cell Res Ther 9:123. https://doi.org/10.1186/s13287-018-0870-9
Morito T, Muneta T, Hara K, Ju Y-J, Mochizuki T, Makino H, Umezawa A, Sekiya I (2008) Synovial-fluid-derived mesenchymal stem cells increase after intra-articular ligament injury in humans. Rheumatology 47:1137–1143. https://doi.org/10.1093/rheumatology/ken114
Murata Y, Uchida S, Utsunomiya H, Hatakeyama A, Nakashima H, Chang A, Sekiya I, Sakai A (2018) Synovial mesenchymal stem cells derived from the cotyloid fossa synovium have higher self-renewal and differentiation potential than those from the paralabral synovium in the hip joint. Am J Sports Med 46:2942–2953. https://doi.org/10.1177/0363546518794664
Murphy JM, 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 Rheum 46(3):704–713. https://doi.org/10.1002/art.10118
Nakamura T, Sekiya I, Muneta T, Hatsushika D, Horie M, Tsuji K, Kawarasaki T, Watanabe A, Hishikawa S, Fujimoto Y, Tanaka H, Kobayashi E (2012) Arthroscopic, histological and MRI analyses of cartilage repair after a minimally invasive method of transplantation of allogeneic synovial mesenchymal stromal cells into cartilage defects in pigs. Cytotherapy 14:327–338. https://doi.org/10.3109/14653249.2011.638912
Neybecker P, Henrionnet C, Pape E, Mainard D, Galois L, Loeuille D, Gillet P, Pinzano A (2018) In-vitro and in-vivo potentialities for cartilage repair from human advanced knee osteoarthritis synovial fluid-derived mesenchymal stem cells. Stem Cell Res Ther 9:329. https://doi.org/10.1186/s13287-018-1071-2
Nimura A, Muneta T, Koga H, Mochizuki T, Suzuki K, Makino H, Umezawa A, Sekiya I (2008) Increased proliferation of human synovial mesenchymal stem cells with autologous human serum: comparisons with bone marrow mesenchymal stem cells and with fetal bovine serum. Arthritis Rheum 58(2):501–510. https://doi.org/10.1002/art.23219
Ogata Y, Mabuchi Y, Yoshida M, Suto EG, Suzuki N, Muneta T, Sekiya I, Akazawa C (2015) Purified human synovium mesenchymal stem cells as a good resource for cartilage regeneration. PLoS One 10(6):e0129096. https://doi.org/10.1371/journal.pone.0129096
Ozeki N, Muneta T, Koga H, Nakagawa Y, Mizuno M, Tsuji K, Mabuchi Y, Akazawa C, Kobayashi E, Matsumoto K, Futamura K, Saito T, Sekiya I (2016) Not single but periodic injections of synovial mesenchymal stem cells maintain viable cells in knees and inhibit osteoarthritis progression in rats. Osteoarthr Cartil 24:1061–1070. https://doi.org/10.1016/J.JOCA.2015.12.018
Partridge L, Deelen J, Slagboom PE (2018) Facing up to the global challenges of ageing. Nature 561:45–56. https://doi.org/10.1038/s41586-018-0457-8
Reissis D, Tang QO, Cooper NC, Carasco CF, Gamie Z, Mantalaris A, Tsiridis E (2016) Current clinical evidence for the use of mesenchymal stem cells in articular cartilage repair. Expert Opin Biol Ther 16:535–557. https://doi.org/10.1517/14712598.2016.1145651
Roelofs AJ, Zupan J, Riemen AHK, Kania K, Ansboro S, White N, Clark SM, De Bari C (2017) Joint morphogenetic cells in the adult mammalian synovium. Nat Commun 8:15040. https://doi.org/10.1038/ncomms15040
Roffi A, Nakamura N, Sanchez M, Cucchiarini M, Filardo G (2018) Injectable systems for Intra-Articular Delivery of mesenchymal stromal cells for cartilage treatment: a systematic review of preclinical and clinical evidence. Int J Mol Sci 25(19):11. https://doi.org/10.3390/ijms19113322.
Sacchetti B, Funari A, Remoli C, Giannicola G, Kogler G, Liedtke S, Cossu G, Serafini M, Sampaolesi M, Tagliafico E, Tenedini E, Saggio I, Robey PG, Riminucci M, Bianco P (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 Rep 6:897–913. https://doi.org/10.1016/j.stemcr.2016.05.011
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 Rheum 52:2521–2529. https://doi.org/10.1002/art.21212
Sekiya I, Muneta T, Horie M, Koga H (2015) Arthroscopic transplantation of synovial stem cells improves clinical outcomes in knees with cartilage defects. Clin Orthop Relat Res 473:2316–2326. https://doi.org/10.1007/s11999-015-4324-8
Shimomura K, Yasui Y, Koizumi K, Chijimatsu R, Hart DA, Yonetani Y, Ando W, Nishii T, Kanamoto T, Horibe S, Yoshikawa H, Nakamura N, Sakaue M, Sugita N, Moriguchi Y (2018) 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 46:2384–2393. https://doi.org/10.1177/0363546518781825
Sipp D, Robey PG, Turner L (2018) Clear up this stem-cell mess. Nature 561:455–457
Smith MD (2011) The normal synovium. Open Rheumatol J 5:100–106. https://doi.org/10.2174/1874312901105010100
Vangsness CT Jr, Farr J 2nd, Boyd J, Dellaero DT, Mills CR, LeRoux-Williams M (2014) 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 96(2):90–98. https://doi.org/10.2106/JBJS.M.00058
Viganò M, Sansone V, d’Agostino MC, Romeo P, Perucca Orfei C, de Girolamo L (2016) Mesenchymal stem cells as therapeutic target of biophysical stimulation for the treatment of musculoskeletal disorders. J Orthop Surg Res 11(1):163. https://doi.org/10.1186/s13018-016-0496-5
Waldner M, Zhang W, James IB, Allbright K, Havis E, Bliley JM, Almadori A, Schweizer R, Plock JA, Washington KM, Gorantla VS, Solari MG, Marra KG, Rubin JP (2018) Characteristics and Immunomodulating functions of adipose-derived and bone marrow-derived mesenchymal stem cells across defined human leukocyte antigen barriers. Front Immunol 24(9):1642. https://doi.org/10.3389/fimmu.2018.01642
Worthley DL, Churchill M, Compton JT, Tailor Y, Rao M, Si Y, Levin D, Schwartz MG, Uygur A, Hayakawa Y, Gross S, Renz BW, Setlik W, Martinez AN, Chen X, Nizami S, Lee HG, Kang HP, Caldwell JM, Asfaha S, Westphalen CB, Graham T, Jin G, Nagar K, Wang H, Kheirbek MA, Kolhe A, Carpenter J, Glaire M, Nair A, Renders S, Manieri N, Muthupalani S, Fox JG, Reichert M, Giraud AS, Schwabe RF, Pradere JP, Walton K, Prakash A, Gumucio D, Rustgi AK, Stappenbeck TS, Friedman RA, Gershon MD, Sims P, Grikscheit T, Lee FY, Karsenty G, Mukherjee S, Wang TC (2015) Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential. Cell 160:269–284. https://doi.org/10.1016/j.cell.2014.11.042
Xing D, Kwong J, Yang Z, Hou Y, Zhang W, Ma B, Lin J (2018) Intra-articular injection of mesenchymal stem cells in treating knee osteoarthritis: a systematic review of animal studies. Osteoarthr Cartil 26:445–461. https://doi.org/10.1016/j.joca.2018.01.010
Yan M, Liu X, Dang Q, Huang H, Yang F, Li Y (2017) Intra-articular injection of human synovial membrane-derived mesenchymal stem cells in murine collagen-induced arthritis: assessment of immunomodulatory capacity in vivo. Stem Cells Int 2017:9198328. https://doi.org/10.1155/2017/9198328
Yao Y, Li ZY, Zhang H, Zheng YH, Mai LX, Liu WJ, Zhang ZG, Sun YP (2018) Synovial fluid-derived synovial fragments represent an improved source of synovial mesenchymal stem cells in the temporomandibular joint. Int J Mol Med 41:173–183. https://doi.org/10.3892/ijmm.2017.3210
Yasui Y, Hart DA, Sugita N, Chijimatsu R, Koizumi K, Ando W, Moriguchi Y, Shimomura K, Myoui A, Yoshikawa H, Nakamura N (2018) Time-dependent recovery of human synovial membrane mesenchymal stem cell function after high-dose steroid therapy: case report and laboratory study. Am J Sports Med 46:695–701. https://doi.org/10.1177/0363546517741307
Zayed M, Newby S, Misk N, Donnell R, Dhar M (2018) Xenogenic implantation of equine synovial fluid-derived mesenchymal stem cells leads to articular cartilage regeneration. Stem Cells Int 2018:1–9. https://doi.org/10.1155/2018/1073705
Zhou BO, Yue R, Murphy MM, Peyer JG, Morrison SJ (2014) Leptin-receptor-expressing mesenchymal stromal cells represent the main source of bone formed by adult bone marrow. Cell Stem Cell 15:154–168. https://doi.org/10.1016/j.stem.2014.06.008
Acknowledgments
Janja Zupan was funded by UK Arthritis Research (2016–2018) and is currently part of the P3-0298 Research Programme ‘Genes, hormones and personality changes in metabolic disorders’, funded by the Slovenian Research Agency, and ARTE Project EU INTERREG Italia-Slovenija 2014–2020. The authors would like to thank Chris Berrie for scientific English editing of the manuscript.
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Zupan, J., Drobnič, M., Stražar, K. (2019). Synovium-Derived Mesenchymal Stem/Stromal Cells and their Promise for Cartilage Regeneration. In: Turksen, K. (eds) Cell Biology and Translational Medicine, Volume 6. Advances in Experimental Medicine and Biology(), vol 1212. Springer, Cham. https://doi.org/10.1007/5584_2019_381
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