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Potency Assay Considerations for Cartilage Repair, Osteoarthritis and Use of Extracellular Vesicles

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Potency Assays for Advanced Stem Cell Therapy Medicinal Products

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1420))

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Abstract

Articular cartilage covers the ends of bones in synovial joints acting as a shock absorber that helps movement of bones. Damage of the articular cartilage needs treatment as it does not repair itself and the damage can progress to osteoarthritis. In osteoarthritis all the joint tissues are involved with characteristic progressive cartilage degradation and inflammation. Autologous chondrocyte implantation is a well-proven cell-based treatment for cartilage defects, but a main downside it that it requires two surgeries. Multipotent, aka mesenchymal stromal cell (MSC)-based cartilage repair has gained attention as it can be used as a one-step treatment. It is proposed that a combination of immunomodulatory and regenerative capacities make MSC attractive for the treatment of osteoarthritis. Furthermore, since part of the paracrine effects of MSCs are attributed to extracellular vesicles (EVs), small membrane enclosed particles secreted by cells, EVs are currently being widely investigated for their potential therapeutic effects. Although MSCs have entered clinical cartilage treatments and EVs are used in in vivo efficacy studies, not much attention has been given to determine their potency and to the development of potency assays. This chapter provides considerations and suggestions for the development of potency assays for the use of MSCs and MSC-EVs for the treatment of cartilage defects and osteoarthritis.

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References

  1. Acharya C, Adesida A, Zajac P, Mumme M, Riesle J, Martin I, Barbero A (2012) Enhanced chondrocyte proliferation and mesenchymal stromal cells chondrogenesis in coculture pellets mediate improved cartilage formation. J Cell Physiol 227:88–97. https://doi.org/10.1002/jcp.22706

    Article  CAS  PubMed  Google Scholar 

  2. Adachi N, Ochi M, Deie M, Ito Y (2005) Transplant of mesenchymal stem cells and hydroxyapatite ceramics to treat severe osteochondral damage after septic arthritis of the knee. J Rheumatol 32:1615–1618

    PubMed  Google Scholar 

  3. Bartz C, Meixner M, Giesemann P, Roël G, Bulwin GC, Smink JJ (2016) An ex vivo human cartilage repair model to evaluate the potency of a cartilage cell transplant. J Transl Med 14:1–15. https://doi.org/10.1186/s12967-016-1065-8

    Article  CAS  Google Scholar 

  4. Bekkers JEJ, Tsuchida AI, Van Rijen MHP, Vonk LA, Dhert WJA, Creemers LB, Saris DBF (2013) Single-stage cell-based cartilage regeneration using a combination of chondrons and mesenchymal stromal cells: comparison with microfracture. Am J Sports Med 41:2158–2166. https://doi.org/10.1177/0363546513494181

    Article  PubMed  Google Scholar 

  5. Blázquez R, Sánchez-Margallo FM, Álvarez V, Usón A, Marinaro F, Casado JG (2018) Fibrin glue mesh fixation combined with mesenchymal stem cells or exosomes modulates the inflammatory reaction in a murine model of incisional hernia. Acta Biomater 71:318–329. https://doi.org/10.1016/j.actbio.2018.02.014

    Article  CAS  PubMed  Google Scholar 

  6. Boreström C, Simonsson S, Enochson L, Bigdeli N, Brantsing C, Ellerström C, Hyllner J, Lindahl A (2014) Footprint-free human induced pluripotent stem cells from articular cartilage with redifferentiation capacity: a first step toward a clinical-grade cell source. Stem Cells Transl Med 3:433–447. https://doi.org/10.5966/sctm.2013-0138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Bravery CA, Carmen J, Fong T, Oprea W, Hoogendoorn KH, Woda J, Burger SR, Rowley JA, Bonyhadi ML, Van’T Hof W (2013) Potency assay development for cellular therapy products: an ISCT* review of the requirements and experiences in the industry. Cytotherapy 15:9–19. https://doi.org/10.1016/j.jcyt.2012.10.008

    Article  PubMed  Google Scholar 

  8. Brittberg M, Lindahl A, Nilsson A, Ohlsson C, Isaksson O, Peterson L (1994) Treatment of deep cartilage defects in the knee with autologous chondrocyte transplantation. N Engl J Med 331:889–895

    Article  CAS  PubMed  Google Scholar 

  9. Brittberg M, Recker D, Ilgenfritz J, Saris DBF (2018) Matrix-applied characterized autologous cultured chondrocytes versus microfracture: five-year follow-up of a prospective randomized trial. Am J Sports Med 46:1343–1351. https://doi.org/10.1177/0363546518756976

    Article  PubMed  Google Scholar 

  10. Callahan CM, Drake BG, Heck DA, Dittus RS (1994) Patient outcomes following tricompartmental total knee replacement: a meta-analysis. JAMA 271:1349–1357. https://doi.org/10.1001/jama.1994.03510410061034

    Article  CAS  PubMed  Google Scholar 

  11. Caplan AI, Dennis JE (2006) Mesenchymal stem cells as trophic mediators. J Cell Biochem 98:1076–1084. https://doi.org/10.1002/jcb.20886

    Article  CAS  PubMed  Google Scholar 

  12. Chahal J, Gómez-Aristizábal A, Shestopaloff K, Bhatt S, Chaboureau A, Fazio A, Chisholm J, Weston A, Chiovitti J, Keating A, Kapoor M, Ogilvie-Harris DJ, Syed KA, Gandhi R, Mahomed NN, Marshall KW, Sussman MS, Naraghi AM, Viswanathan S (2019) Bone marrow mesenchymal stromal cells in patients with osteoarthritis results in overall improvement in pain and symptoms and reduces synovial inflammation. Stem Cells Transl Med 8:746–757. https://doi.org/10.1002/sctm.18-0183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Chen W, Huang Y, Han J, Yu L, Li Y, Lu Z, Li H, Liu Z, Shi C, Duan F, Xiao Y (2016) Immunomodulatory effects of mesenchymal stromal cells-derived exosome. Immunol Res 64:831–840. https://doi.org/10.1007/s12026-016-8798-6

    Article  CAS  PubMed  Google Scholar 

  14. Chen WH, Lai MT, Wu ATH, Wu CC, Gelovani JG, Lin CT, Hung SC, Chiu WT, Deng WP (2009) In vitro stage-specific chondrogenesis of mesenchymal stem cells committed to chondrocytes. Arthritis Rheum 60:450–459. https://doi.org/10.1002/art.24265

    Article  CAS  PubMed  Google Scholar 

  15. Choi H, Lee RH, Bazhanov N, Oh JY, Prockop DJ (2011) Anti-inflammatory protein TSG-6 secreted by activated MSCs attenuates zymosan-induced mouse peritonitis by decreasing TLR2/NF-κB signaling in resident macrophages. Blood 118:330–338. https://doi.org/10.1182/blood-2010-12-327353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Civinini R, Carulli C, Matassi F, Cozzi Lepri A, Sirleo L, Innocenti M (2017) The survival of total knee arthroplasty: current data from registries on tribology: review article. HSS J 13:28–31. https://doi.org/10.1007/s11420-016-9513-9

    Article  PubMed  Google Scholar 

  17. Conforti A, Scarsella M, Starc N, Giorda E, Biagini S, Proia A, Carsetti R, Locatelli F, Bernardo ME (2014) Microvescicles derived from mesenchymal stromal cells are not as effective as their cellular counterpart in the ability to modulate immune responses in vitro. Stem Cells Dev 23:2591–2599. https://doi.org/10.1089/scd.2014.0091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dale TP, De Castro A, Kuiper NJ, Parkinson EK, Forsyth NR (2015) Immortalisation with hTERT impacts on sulphated glycosaminoglycan secretion and immunophenotype in a variable and cell specific manner. PLoS One 10. https://doi.org/10.1371/journal.pone.0133745

  19. Darling EM, Athanasiou KA (2005) Rapid phenotypic changes in passaged articular chondrocyte subpopulations. J Orthop Res 23:425–432. https://doi.org/10.1016/j.orthres.2004.08.008

    Article  CAS  PubMed  Google Scholar 

  20. Davatchi F, Sadeghi Abdollahi B, Mohyeddin M, Nikbin B (2016) Mesenchymal stem cell therapy for knee osteoarthritis: 5 years follow-up of three patients. Int J Rheum Dis 19:219–225. https://doi.org/10.1111/1756-185X.12670

    Article  PubMed  Google Scholar 

  21. Delco ML, Goodale M, Talts JF, Pownder SL, Koff MF, Miller AD, Nixon B, Bonassar LJ, Lundgren-Åkerlund E, Fortier LA (2020) Integrin α10β1-selected mesenchymal stem cells mitigate the progression of osteoarthritis in an equine Talar Impact model. Am J Sports Med 036354651989908. https://doi.org/10.1177/0363546519899087

  22. Dell’Accio F, De Bari C, Luyten FP (2001) Molecular markers predictive of the capacity of expanded human articular chondrocytes to form stable cartilage in vivo. Arthritis Rheum 44:1608–1619. https://doi.org/10.1002/1529

    Article  PubMed  Google Scholar 

  23. Diaz-Romero J, Kürsener S, Kohl S, Nesic D (2017) S100B + A1 CELISA: a novel potency assay and screening tool for redifferentiation stimuli of human articular chondrocytes. J Cell Physiol 232:1559–1570. https://doi.org/10.1002/jcp.25682

    Article  CAS  PubMed  Google Scholar 

  24. 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

    Article  CAS  PubMed  Google Scholar 

  25. Emadedin M, Aghdami N, Taghiyar L, Fazeli R, Moghadasali R, Jahangir S, Farjad R, Eslaminejad MB (2012) Intra-articular injection of autologous mesenchymal stem cells in six patients with knee osteoarthritis. Arch Iran Med 15:422–428. 012157/AIM.0010

    PubMed  Google Scholar 

  26. Emadedin M, Liastani MG, Fazeli R, Mohseni F, Moghadasali R, Mardpour S, Hosseini SE, Niknejadi M, Moeininia F, Fanni AA, Eslaminejhad RB, Dizaji AV, Labibzadeh N, Bafghi AM, Baharvand H, Aghdami N (2015) Long-term follow-up of intra-articular injection of autologous mesenchymal stem cells in patients with knee, ankle, or hip osteoarthritis. Arch Iran Med 18:336–344. 015186/AIM.003

    PubMed  Google Scholar 

  27. Enomoto T, Akagi R, Ogawa Y, Yamaguchi S, Hoshi H, Sasaki T, Sato Y, Nakagawa R, Kimura S, Ohtori S, Sasho T (2020) Timing of intra-articular injection of synovial mesenchymal stem cells affects cartilage restoration in a partial thickness cartilage defect model in rats. Cartilage 11:122–129. https://doi.org/10.1177/1947603518786542

    Article  PubMed  Google Scholar 

  28. Forsberg MH, Kink JA, Hematti P, Capitini CM (2020) Mesenchymal stromal cells and exosomes: progress and challenges. Front Cell Dev Biol 8:1–11. https://doi.org/10.3389/fcell.2020.00665

    Article  Google Scholar 

  29. Galipeau J (2021) Macrophages at the nexus of mesenchymal stromal cell potency: the emerging role of chemokine cooperativity. Stem Cells 1–10. https://doi.org/10.1002/stem.3380

  30. Gardner OFW, Fahy N, Alini M, Stoddart MJ (2016) Differences in human mesenchymal stem cell secretomes during chondrogenic induction. Eur Cells Mater 31:221–235. https://doi.org/10.22203/eCM.v031a15

    Article  CAS  Google Scholar 

  31. Gimona M, Brizzi MF, Choo ABH, Dominici M, Davidson SM, Grillari J, Hermann DM, Hill AF, de Kleijn D, Lai RC, Lai CP, Lim R, Monguió-Tortajada M, Muraca M, Ochiya T, Ortiz LA, Toh WS, Yi YW, Witwer KW, Giebel B, Lim SK (2021) Critical considerations for the development of potency tests for therapeutic applications of mesenchymal stromal cell-derived small extracellular vesicles. Cytotherapy 000. https://doi.org/10.1016/j.jcyt.2021.01.001

  32. Gimona M, Pachler K, Laner-Plamberger S, Schallmoser K, Rohde E (2017) Manufacturing of human extracellular vesicle-based therapeutics for clinical use. Int J Mol Sci 18. https://doi.org/10.3390/ijms18061190

  33. Goldberg A, Mitchell K, Soans J, Kim L, Zaidi R (2017) The use of mesenchymal stem cells for cartilage repair and regeneration : a systematic review. J Orthop Surg Res 12:39. https://doi.org/10.1186/s13018-017-0534-y

    Article  PubMed  PubMed Central  Google Scholar 

  34. Gouveia De Andrade AV, Bertolino G, Riewaldt J, Bieback K, Karbanová J, Odendahl M, Bornhäuser M, Schmitz M, Corbeil D, Tonn T (2015) Extracellular vesicles secreted by bone marrow- and adipose tissue-derived mesenchymal stromal cells fail to suppress lymphocyte proliferation. Stem Cells Dev 24:1374–1376. https://doi.org/10.1089/scd.2014.0563

    Article  CAS  PubMed  Google Scholar 

  35. Griffin TM, Scanzello CR (2019) Innate inflammation and synovial macrophages in osteoarthritis pathophysiology. Clin Exp Rheumatol 37:57–63

    PubMed  PubMed Central  Google Scholar 

  36. Gupta PK, Chullikana A, Rengasamy M, Shetty N, Pandey V, Agarwal V, Wagh SY, Vellotare PK, Damodaran D, Viswanathan P, Thej C, Balasubramanian S, Sen MA (2016) Efficacy and safety of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (Stempeucel®): preclinical and clinical trial in osteoarthritis of the knee joint. Arthritis Res Ther 18:1–18. https://doi.org/10.1186/s13075-016-1195-7

    Article  CAS  Google Scholar 

  37. Hamilton DF, Howie CR, Burnett R, Simpson AHRW, Patton JT (2015) Dealing with the predicted increase in demand for revision total knee arthroplasty: challenges, risks and opportunities. Bone Jt J 97-B:723–728. https://doi.org/10.1302/0301-620X.97B6.35185

    Article  Google Scholar 

  38. 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

    Article  CAS  PubMed  Google Scholar 

  39. Hennig T, Lorenz H, Thiel A, Goetzke K, Dickhut A, Geiger F, Richter W (2007) Reduced chondrogenic potential of adipose tissue derived stromal cells correlates with an altered TGFb receptor and BMP profile and is overcome by BMP-6. J Cell Physiol 211:682–691. https://doi.org/10.1002/JCP

    Article  CAS  PubMed  Google Scholar 

  40. Hoburg A, Niemeyer P, Laute V, Zinser W, Becher C, Kolombe T, Fay J, Pietsch S, Kuźma T, Widuchowski W, Fickert S (2020) Matrix-associated autologous chondrocyte implantation with spheroid technology is superior to arthroscopic microfracture at 36 months regarding activities of daily living and sporting activities after treatment. Cartilage Adv. https://doi.org/10.1177/1947603519897290

  41. Jaime P, García-guerrero N, Estella R, Pardo J, García-Alvarez F, Martinez-Lostao L (2017) CD56+/CD16- Natural Killer cells expressing the inflammatory protease granzyme A are enriched in synovial fluid from patients with osteoarthritis. Osteoarthr Cartil 25:1708–1718. https://doi.org/10.1016/j.joca.2017.06.007

    Article  CAS  Google Scholar 

  42. Jeon JE, Vaquette C, Theodoropoulos C, Klein TJ, Hutmacher DW (2014) Multiphasic construct studied in an ectopic osteochondral defect model. J R Soc Interface 11. https://doi.org/10.1098/rsif.2014.0184

  43. Jo CH, Chai JW, Jeong EC, Oh S, Shin JS, Shim H, Yoon KS (2017) Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a 2-year follow-up study. Am J Sports Med 45:2774–2783. https://doi.org/10.1177/0363546517716641

    Article  PubMed  Google Scholar 

  44. Johnstone B, Hering TM, Caplan AI, Goldberg VM, Yoo JU (1998) In vitro Chondrogenesis of bone marrow-derived mesenchymal progenitor cells. Exp Cell Res 238:265–272

    Article  CAS  PubMed  Google Scholar 

  45. Jones KJ, Kelley BV, Arshi A, McAllister DR, Fabricant PD (2019) Comparative effectiveness of cartilage repair with respect to the minimal clinically important difference. Am J Sports Med 47:3284–3293. https://doi.org/10.1177/0363546518824552

    Article  PubMed  Google Scholar 

  46. Kordelas L, Rebmann V, Ludwig AK, Radtke S, Ruesing J, Doeppner TR, Epple M, Horn PA, Beelen DW, Giebel B (2014) MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia 28:970–973. https://doi.org/10.1038/leu.2014.41

    Article  CAS  PubMed  Google Scholar 

  47. Korpershoek JV, Rikkers M, Wallis F, Dijkstra K, Saris DBF, Vonk LA (2022) Mitochondrial transport between chondrocytes and mesenchymal stromal cells. In: International Cartilage Regeneration and Joint Preservation Society, Berlin

    Google Scholar 

  48. Kuroda R, Ishida K, Matsumoto T, Akisue T, Fujioka H, Mizuno K, Ohgushi H, Wakitani S, Kurosaka M (2007) Treatment of a full-thickness articular cartilage defect in the femoral condyle of an athlete with autologous bone-marrow stromal cells. Osteoarthr Cartil 15:226–231. https://doi.org/10.1016/j.joca.2006.08.008

    Article  CAS  Google Scholar 

  49. Lamo-Espinosa JM, Mora G, Blanco JF, Granero-Moltó F, Núñez-Córdoba JM, López-Elío S, Andreu E, Sánchez-Guijo F, Aquerreta JD, Bondía JM, Valentí-Azcárate A, Consuelo del Cañizo M, Villarón EM, Valentí-Nin JR, Prósper F (2018) Intra-articular injection of two different doses of autologous bone marrow mesenchymal stem cells versus hyaluronic acid in the treatment of knee osteoarthritis: long-term follow up of a multicenter randomized controlled clinical trial (phase I/II). J Transl Med 16:1–5. https://doi.org/10.1186/s12967-018-1591-7

    Article  CAS  Google Scholar 

  50. Lee KBL, Hui JHP, Song IC, Ardany L, Lee EH (2007) Injectable mesenchymal stem cell therapy for large cartilage defects-A Porcine model. Stem Cells 25:2964–2971. https://doi.org/10.1634/stemcells.2006-0311

    Article  PubMed  Google Scholar 

  51. Li M, Luo X, Lv X, Liu V, Zhao G, Zhang X, Cao W, Wang R, Wang W (2016) In vivo human adipose-derived mesenchymal stem cell tracking after intra-articular delivery in a rat osteoarthritis model. Stem Cell Res Ther 7:1–13. https://doi.org/10.1186/s13287-016-0420-2

    Article  CAS  Google Scholar 

  52. Madel RJ, Börger V, Dittrich R, Bremer M, Tertel T, Thi Phuong NN, Baba HA, Kordelas L, Buer J, Horn PA, Westendorf AM, Brandau S, Kirschning CJ, Giebel B (2020) Independent human mesenchymal stromal cell-derived extracellular vesicle preparations differentially affect symptoms in an advanced murine Graft-versus-Host-Disease model. bioRxiv. https://doi.org/10.1101/2020.12.21.423658

  53. 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 6:1–12. https://doi.org/10.1038/srep23076

    Article  CAS  Google Scholar 

  54. Mandelbaum BR, Browne JE, Fu F, Micheli L, Mosely JB, Erggelet C, Minas T, Peterson L (1998) Articular cartilage lesions of the knee. Am J Sports Med 26:853–861. https://doi.org/10.1177/03635465980260062201

    Article  CAS  PubMed  Google Scholar 

  55. Marquina M, Collado JA, Pérez-Cruz M, Fernández-Pernas P, Fafián-Labora J, Blanco FJ, Mánez R, Arufe MC, Costa C (2017) Biodistribution and immunogenicity of allogeneic mesenchymal stem cells in a Rat Model of intraarticular chondrocyte xenotransplantation. Front Immunol 8:1465. https://doi.org/10.3389/fimmu.2017.01465

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Nejadnik H, Hui JH, Feng Choong EP, Tai B-C, Lee EH (2010) Autologous bone marrow-derived mesenchymal stem cells versus autologous chondrocyte implantation: an observational cohort study. Am J Sports Med 38:1110–1116. https://doi.org/10.1177/0363546509359067

    Article  PubMed  Google Scholar 

  57. Németh K, Leelahavanichkul A, Yuen PST, Mayer B, Parmelee A, Doi K, Robey PG, Leelahavanichkul K, Koller BH, Brown JM, Hu X, Jelinek I, Star RA, Mezey É (2009) Bone marrow stromal cells attenuate sepsis via prostaglandin E 2-dependent reprogramming of host macrophages to increase their interleukin-10 production. Nat Med 15:42–49. https://doi.org/10.1038/nm.1905

    Article  CAS  PubMed  Google Scholar 

  58. Oberbauer E, Steffenhagen C, Feichtinger G, Hildner F, Hacobian A, Danzer M, Gabriel C, Redl H, Wolbank S (2016) A Luciferase-based quick potency assay to predict chondrogenic differentiation. Tissue Eng Part C Methods 22:487–495. https://doi.org/10.1089/ten.tec.2015.0435

    Article  CAS  PubMed  Google Scholar 

  59. Orozco L, Munar A, Soler R, Alberca M, Soler F, Huguet M, Sentís J, Sánchez A, García-Sancho J (2013) Treatment of knee osteoarthritis with autologous mesenchymal stem cells: a pilot study. Transplantation 95:1535–1541. https://doi.org/10.1097/TP.0b013e318291a2da

    Article  CAS  PubMed  Google Scholar 

  60. Pachler K, Ketterl N, Desgeorges A, Dunai ZA, Laner-Plamberger S, Streif D, Strunk D, Rohde E, Gimona M (2017) An in vitro potency assay for monitoring the immunomodulatory potential of stromal cell-derived extracellular vesicles. Int J Mol Sci 18:1–11. https://doi.org/10.3390/ijms18071413

    Article  CAS  Google Scholar 

  61. Pacienza N, Lee RH, Bae EH, Kim D, Ki LQ, Prockop DJ, Yannarelli G (2019) In vitro macrophage assay predicts the in vivo anti-inflammatory potential of exosomes from human mesenchymal stromal cells. Mol Ther Methods Clin Dev 13:67–76. https://doi.org/10.1016/j.omtm.2018.12.003

    Article  CAS  PubMed  Google Scholar 

  62. Paggi CA, Dudakovic A, Fu Y, Garces CG, Hevesi M, Galeano Garces D, Dietz AB, van Wijnen A, Karperien M (2020) Autophagy is involved in mesenchymal stem cell death in Coculture with chondrocytes. Cartilage. https://doi.org/10.1177/1947603520941227

  63. Park YB, Ha CW, Kim JA, Han WJ, Rhim JH, Lee HJ, Kim KJ, Park YG, Chung JY (2017) Single-stage cell-based cartilage repair in a rabbit model: cell tracking and in vivo chondrogenesis of human umbilical cord blood-derived mesenchymal stem cells and hyaluronic acid hydrogel composite. Osteoarthr Cartil 25:570–580. https://doi.org/10.1016/j.joca.2016.10.012

    Article  CAS  Google Scholar 

  64. Pearle AD, Warren RF, Rodeo SA (2005) Basic science of articular cartilage and osteoarthritis. Clin Sports Med 24:1–12. https://doi.org/10.1016/j.csm.2004.08.007

    Article  PubMed  Google Scholar 

  65. Pers YM, Quentin J, Feirreira R, Espinoza F, Abdellaoui N, Erkilic N, Cren M, Dufourcq-Lopez E, Pullig O, Nöth U, Jorgensen C, Louis-Plence P (2018) Injection of adipose-derived stromal cells in the knee of patients with severe osteoarthritis has a systemic effect and promotes an anti-inflammatory phenotype of circulating immune cells. Theranostics 8:5519–5528. https://doi.org/10.7150/thno.27674

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Pigott JH, Ishihara A, Wellman ML, Russell DS, Bertone AL (2013) Investigation of the immune response to autologous, allogeneic, and xenogeneic mesenchymal stem cells after intra-articular injection in horses. Vet Immunol Immunopathol 156:99–106. https://doi.org/10.1016/j.vetimm.2013.09.003

    Article  CAS  PubMed  Google Scholar 

  67. Rapko S, Parker A, Mortelliti C, Duguay SJ (2007) P192 Aggrecan gene expression as a potency marker for matrix-induced autologous chondroctye implantation (MACI). Osteoarthr Cartil 15:B136. https://doi.org/10.1016/s1063-4584(07)61547-7

    Article  Google Scholar 

  68. Rohde E, Pachler K, Gimona M (2019) Manufacturing and characterization of extracellular vesicles from umbilical cord–derived mesenchymal stromal cells for clinical testing. Cytotherapy 21:581–592. https://doi.org/10.1016/j.jcyt.2018.12.006

    Article  PubMed  Google Scholar 

  69. Saris DBF, de Windt TS, Vonk LA, Krych AJ, Terzic A (2018) Regenerative musculoskeletal care: ensuring practice implementation. Clin Pharmacol Ther 103:50–53. https://doi.org/10.1002/cpt.883

    Article  PubMed  Google Scholar 

  70. Saris TFF, de Windt TS, Kester EC, Vonk LA, Custers RJH, Saris DBF (2021) Five-year outcome of 1-stage cell-based cartilage repair using recycled autologous Chondrons and allogenic mesenchymal stromal cells: a first-in-human clinical trial. Am J Sports Med 49:941–947. https://doi.org/10.1177/0363546520988069

    Article  PubMed  Google Scholar 

  71. Satué M, Schüler C, Ginner N, Erben RG (2019) Intra-articularly injected mesenchymal stem cells promote cartilage regeneration, but do not permanently engraft in distant organs. Sci Rep 9:1–10. https://doi.org/10.1038/s41598-019-46554-5

    Article  CAS  Google Scholar 

  72. Schubert T, Anders S, Neumann E, Schölmerich J, Hofstädter F, Grifka J, Libera J, Schedel J (2009) Long-term effects of chondrospheres on cartilage lesions in an autologous chondrocyte implantation model as investigated in the SCID mouse model. Int J Mol Med 23:455–460. https://doi.org/10.3892/ijmm_00000151

    Article  CAS  PubMed  Google Scholar 

  73. Shim G, Lee S, Han J, Kim G, Jin H, Miao W, Yi TG, Cho YK, Song SU, Oh YK (2015) Pharmacokinetics and in vivo fate of intra-articularly transplanted human bone marrow-derived clonal mesenchymal stem cells. Stem Cells Dev 24:1124–1132. https://doi.org/10.1089/scd.2014.0240

    Article  CAS  PubMed  Google Scholar 

  74. lo Sicco C, Reverberi D, Balbi C, Ulivi V, Principi E, Pascucci L, Becherini P, Bosco MC, Varesio L, Franzin C, Pozzobon M, Cancedda R, Tasso R (2017) Mesenchymal stem cell-derived extracellular vesicles as mediators of anti-inflammatory effects: endorsement of macrophage polarization. Stem Cells Transl Med 6:1018–1028

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Soler R, Orozco L, Munar A, Huguet M, López R, Vives J, Coll R, Codinach M, Garcia-Lopez J (2016) 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 23:647–654. https://doi.org/10.1016/j.knee.2015.08.013

    Article  PubMed  Google Scholar 

  76. Tan SHS, Kwan YT, Neo WJ, Chong JY, Kuek TYJ, See JZF, Wong KL, Toh WS, Hui JHP (2021) Intra-articular injections of mesenchymal stem cells without adjuvant therapies for knee osteoarthritis: a systematic review and meta-analysis. Am J Sports Med 49:3113–3124. https://doi.org/10.1177/0363546520981704

    Article  PubMed  Google Scholar 

  77. Teng X, Chen L, Chen W, Yang J, Yang Z, Shen Z (2015) Mesenchymal stem cell-derived exosomes improve the microenvironment of infarcted myocardium contributing to angiogenesis and anti-inflammation. Cell Physiol Biochem 37:2415–2424. https://doi.org/10.1159/000438594

    Article  CAS  PubMed  Google Scholar 

  78. The Committee for Advanced Therapies (CAT) (2010) Reflection paper on in-vitro cultured chondrocyte containing products for cartilage repair of the knee Reflection paper on in-vitro cultured chondrocyte containing products for cartilage repair of the knee. EMA/CAT/CPWP/568181/2009

    Google Scholar 

  79. Théry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, Antoniou A, Arab T, Archer F, Atkin-Smith GK, Ayre DC, Bach JM, Bachurski D, Baharvand H, Balaj L, Baldacchino S, Bauer NN, Baxter AA, Bebawy M, Beckham C, Bedina Zavec A, Benmoussa A, Berardi AC, Bergese P, Bielska E, Blenkiron C, Bobis-Wozowicz S, Boilard E, Boireau W, Bongiovanni A, Borràs FE, Bosch S, Boulanger CM, Breakefield X, Breglio AM, Brennan M, Brigstock DR, Brisson A, Broekman MLD, Bromberg JF, Bryl-Górecka P, Buch S, Buck AH, Burger D, Busatto S, Buschmann D, Bussolati B, Buzás EI, Byrd JB, Camussi G, Carter DRF, Caruso S, Chamley LW, Chang YT, Chaudhuri AD, Chen C, Chen S, Cheng L, Chin AR, Clayton A, Clerici SP, Cocks A, Cocucci E, Coffey RJ, Cordeiro-da-Silva A, Couch Y, Coumans FAW, Coyle B, Crescitelli R, Criado MF, D’Souza-Schorey C, Das S, de Candia P, De Santana EF, De Wever O, del Portillo HA, Demaret T, Deville S, Devitt A, Dhondt B, Di Vizio D, Dieterich LC, Dolo V, Dominguez Rubio AP, Dominici M, Dourado MR, Driedonks TAP, Duarte FV, Duncan HM, Eichenberger RM, Ekström K, Andaloussi ELS, Elie-Caille C, Erdbrügger U, Falcón-Pérez JM, Fatima F, Fish JE, Flores-Bellver M, Försönits A, Frelet-Barrand A, Fricke F, Fuhrmann G, Gabrielsson S, Gámez-Valero A, Gardiner C, Gärtner K, Gaudin R, Gho YS, Giebel B, Gilbert C, Gimona M, Giusti I, Goberdhan DCI, Görgens A, Gorski SM, Greening DW, Gross JC, Gualerzi A, Gupta GN, Gustafson D, Handberg A, Haraszti RA, Harrison P, Hegyesi H, Hendrix A, Hill AF, Hochberg FH, Hoffmann KF, Holder B, Holthofer H, Hosseinkhani B, Hu G, Huang Y, Huber V, Hunt S, AGE I, Ikezu T, Inal JM, Isin M, Ivanova A, Jackson HK, Jacobsen S, Jay SM, Jayachandran M, Jenster G, Jiang L, Johnson SM, Jones JC, Jong A, Jovanovic-Talisman T, Jung S, Kalluri R, Ichi KS, Kaur S, Kawamura Y, Keller ET, Khamari D, Khomyakova E, Khvorova A, Kierulf P, Kim KP, Kislinger T, Klingeborn M, Klinke DJ, Kornek M, Kosanović MM, Kovács ÁF, Krämer-Albers EM, Krasemann S, Krause M, Kurochkin IV, Kusuma GD, Kuypers S, Laitinen S, Langevin SM, Languino LR, Lannigan J, Lässer C, Laurent LC, Lavieu G, Lázaro-Ibáñez E, Le Lay S, Lee MS, Lee YXF, Lemos DS, Lenassi M, Leszczynska A, ITS L, Liao K, Libregts SF, Ligeti E, Lim R, Lim SK, Linē A, Linnemannstöns K, Llorente A, Lombard CA, Lorenowicz MJ, Lörincz ÁM, Lötvall J, Lovett J, Lowry MC, Loyer X, Lu Q, Lukomska B, Lunavat TR, SLN M, Malhi H, Marcilla A, Mariani J, Mariscal J, Martens-Uzunova ES, Martin-Jaular L, Martinez MC, Martins VR, Mathieu M, Mathivanan S, Maugeri M, LK MG, MJ MV, Meckes DG, Meehan KL, Mertens I, Minciacchi VR, Möller A, Møller Jørgensen M, Morales-Kastresana A, Morhayim J, Mullier F, Muraca M, Musante L, Mussack V, Muth DC, Myburgh KH, Najrana T, Nawaz M, Nazarenko I, Nejsum P, Neri C, Neri T, Nieuwland R, Nimrichter L, Nolan JP, Nolte-‘t Hoen ENM, Noren Hooten N, O’Driscoll L, O’Grady T, O’Loghlen A, Ochiya T, Olivier M, Ortiz A, Ortiz LA, Osteikoetxea X, Ostegaard O, Ostrowski M, Park J, Pegtel DM, Peinado H, Perut F, Pfaffl MW, Phinney DG, Pieters BCH, Pink RC, Pisetsky DS, Pogge von Strandmann E, Polakovicova I, Poon IKH, Powell BH, Prada I, Pulliam L, Quesenberry P, Radeghieri A, Raffai RL, Raimondo S, Rak J, Ramirez MI, Raposo G, Rayyan MS, Regev-Rudzki N, Ricklefs FL, Robbins PD, Roberts DD, Rodrigues SC, Rohde E, Rome S, Rouschop KMA, Rughetti A, Russell AE, Saá P, Sahoo S, Salas-Huenuleo E, Sánchez C, Saugstad JA, Saul MJ, Schiffelers RM, Schneider R, Schøyen TH, Scott A, Shahaj E, Sharma S, Shatnyeva O, Shekari F, Shelke GV, Shetty AK, Shiba K, PRM S, Silva AM, Skowronek A, Snyder OL, Soares RP, Sódar BW, Soekmadji C, Sotillo J, Stahl PD, Stoorvogel W, Stott SL, Strasser EF, Swift S, Tahara H, Tewari M, Timms K, Tiwari S, Tixeira R, Tkach M, Toh WS, Tomasini R, Torrecilhas AC, Tosar JP, Toxavidis V, Urbanelli L, Vader P, van Balkom BWM, Van der Grein SG, van Deun J, van Herwijnen MJC, Van Keuren-Jensen K, van Niel G, van Royen ME, van Wijnen AJ, Vasconcelos MH, Vechetti IJ, Veit TD, Vella LJ, Velot É, Verweij FJ, Vestad B, Viñas JL, Visnovitz T, Vukman KV, Wahlgren J, Watson DC, Wauben MHM, Weaver A, Webber JP, Weber V, Wehman AM, Weiss DJ, Welsh JA, Wendt S, Wheelock AM, Wiener Z, Witte L, Wolfram J, Xagorari A, Xander P, Xu J, Yan X, Yáñez-Mó M, Yin H, Yuana Y, Zappulli V, Zarubova J, Žėkas V, Ye ZJ, Zhao Z, Zheng L, Zheutlin AR, Zickler AM, Zimmermann P, Zivkovic AM, Zocco D, Zuba-Surma EK (2018) Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles 7. https://doi.org/10.1080/20013078.2018.1535750

  80. Toupet K, Maumus M, Luz-Crawford P, Lombardo E, Lopez-Belmonte J, Van Lent P, Garin MI, Van Den Berg W, Dalemans W, Jorgensen C, Noël D (2015) Survival and biodistribution of xenogenic adipose mesenchymal stem cells is not affected by the degree of inflammation in arthritis. PLoS One 10:1–13. https://doi.org/10.1371/journal.pone.0114962

    Article  CAS  Google Scholar 

  81. Toupet K, Maumus M, Peyrafitte JA, Bourin P, Van Lent PLEM, Ferreira R, Orsetti B, Pirot N, Casteilla L, Jorgensen C, Noël D (2013) Long-term detection of human adipose-derived mesenchymal stem cells after intraarticular injection in SCID mice. Arthritis Rheum 65:1786–1794. https://doi.org/10.1002/art.37960

    Article  CAS  PubMed  Google Scholar 

  82. Di Trapani M, Bassi G, Midolo M, Gatti A, Kamga PT, Cassaro A, Carusone R, Adamo A, Krampera M (2016) Differential and transferable modulatory effects of mesenchymal stromal cell-derived extracellular vesicles on T, B and NK cell functions. Sci Rep 6:1–13. https://doi.org/10.1038/srep24120

    Article  CAS  Google Scholar 

  83. Vainieri ML, Lolli A, Kops N, D’Atri D, Eglin D, Yayon A, Alini M, Grad S, Sivasubramaniyan K, van Osch GJVM (2020) Evaluation of biomimetic hyaluronic-based hydrogels with enhanced endogenous cell recruitment and cartilage matrix formation. Acta Biomater 101:293–303. https://doi.org/10.1016/j.actbio.2019.11.015

    Article  CAS  PubMed  Google Scholar 

  84. Valencia J, Blanco B, Yáñez R, Vázquez M, Herrero Sánchez C, Fernández-García M, Rodríguez Serrano C, Pescador D, Blanco JF, Hernando-Rodríguez M, Sánchez-Guijo F, Lamana ML, Segovia JC, Vicente Á, Del Cañizo C, Zapata AG (2016) Comparative analysis of the immunomodulatory capacities of human bone marrow– and adipose tissue–derived mesenchymal stromal cells from the same donor. Cytotherapy 18:1297–1311. https://doi.org/10.1016/j.jcyt.2016.07.006

    Article  CAS  PubMed  Google Scholar 

  85. Vanlauwe J, Saris DBF, Victor J, Almqvist KF, Bellemans J (2011) Five-year outcome of characterized chondrocyte implantation versus microfracture for symptomatic cartilage defects of the knee early treatment matters. Am J Sports Med 39:2566–2574. https://doi.org/10.1177/0363546511422220

    Article  PubMed  Google Scholar 

  86. Varderidou-Minasian S, Lorenowicz MJ (2020) Mesenchymal stromal/stem cell-derived extracellular vesicles in tissue repair: challenges and opportunities. Theranostics 10:5979–5997. https://doi.org/10.7150/thno.40122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Vega A, Martín-Ferrero MA, Del CF, Alberca M, García V, Munar A, Orozco L, Soler R, Fuertes JJ, Huguet M, Sánchez A, García-Sancho J (2015) Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation 99:1681–1690. https://doi.org/10.1097/TP.0000000000000678

    Article  CAS  PubMed  Google Scholar 

  88. Vonk LA, van Dooremalen SFJ, Liv N, Klumperman J, Coffer PJ, Saris DBF, Lorenowicz MJ (2018) Mesenchymal stromal/stem cell-derived extracellular vesicles promote human cartilage regeneration in vitro. Theranostics 8:906–920. https://doi.org/10.7150/thno.20746

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Vonk LA, De Windt TS, Slaper-Cortenbach ICM, Saris DBF (2015) Autologous, allogeneic, induced pluripotent stem cell or a combination stem cell therapy? Where are we headed in cartilage repair and why: a concise review. Stem Cell Res Ther 6:94

    Article  PubMed  PubMed Central  Google Scholar 

  90. De Vries-Van Melle ML, Narcisi R, Kops N, Koevoet WJLM, Bos PK, Murphy JM, Verhaar JAN, Van Der Kraan PM, Van Osch GJVM (2014) Chondrogenesis of mesenchymal stem cells in an osteochondral environment is mediated by the subchondral bone. Tissue Eng Part A 20:23–33. https://doi.org/10.1089/ten.tea.2013.0080

    Article  CAS  PubMed  Google Scholar 

  91. Wakitani S, Mitsuoka T, Nakamura N, Toritsuka Y, Nakamura Y, Horibe S (2004) Autologous bone marrow stromal cell transplantation for repair of full-thickness articular cartilage defects in human patellae: two case reports. Cell Transplant 13:595–600. https://doi.org/10.3727/000000004783983747

    Article  PubMed  Google Scholar 

  92. Wang R, Maimaitijuma T, Ma Y, Jiao Y, Cao Y (2021) Mitochondrial transfer from bone-marrow-derived mesenchymal stromal cells to chondrocytes protects against cartilage degenerative mitochondrial dysfunction in rats chondrocytes. Chin Med J 134:212–218. https://doi.org/10.1097/CM9.0000000000001057

    Article  CAS  Google Scholar 

  93. Weber AE, Bolia IK, Trasolini NA (2021) Biological strategies for osteoarthritis: from early diagnosis to treatment. Int Orthop 45:335–344. https://doi.org/10.1007/s00264-020-04838-w

    Article  PubMed  Google Scholar 

  94. Willis GR, Fernandez-Gonzalez A, Anastas J, Vitali SH, Liu X, Ericsson M, Kwong A, Mitsialis SA, Kourembanas S (2018) Mesenchymal stromal cell exosomes ameliorate experimental bronchopulmonary dysplasia and restore lung function through macrophage immunomodulation. Am J Respir Crit Care Med 197:104–116. https://doi.org/10.1164/rccm.201705-0925OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. de Windt TS, Hendriks JAA, Zhao X, Vonk LA, Creemers LB, Dhert WJA, Randolph MA, Saris DBF (2014) Concise review: unraveling stem cell cocultures in regenerative medicine: which cell interactions steer cartilage regeneration and how? Stem Cells Transl Med 3:723–733. https://doi.org/10.5966/sctm.2013-0207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. De Windt TS, Saris DBF, Slaper-Cortenbach ICM, Van Rijen MHP, Gawlitta D, Creemers LB, De Weger RA, Dhert WJA, Vonk LA (2015) Direct cell–cell contact with chondrocytes is a key mechanism in multipotent mesenchymal stromal cell-mediated chondrogenesis. Tissue Eng Part A 21:2536–2547. https://doi.org/10.1089/ten.tea.2014.0673

    Article  CAS  PubMed  Google Scholar 

  97. de Windt TS, Vonk LA, Slaper-Cortenbach ICM, van den Broek MPH, Nizak R, van Rijen MHPP, De Weger RA, Dhert WJA, Saris DBF (2017) 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 35:256–264. https://doi.org/10.1002/stem.2475

    Article  CAS  PubMed  Google Scholar 

  98. de Windt TS, Vonk LA, Slaper-Cortenbach ICM, Nizak R, van Rijen MHP, Saris DBF (2017) Allogeneic MSCs and recycled autologous Chondrons mixed in a one-stage cartilage cell transplantion: a first-in-man trial in 35 patients. Stem Cells 35:1984–1993. https://doi.org/10.1002/stem.2657

    Article  CAS  PubMed  Google Scholar 

  99. Witwer KW, Van Balkom BWM, Bruno S, Choo A, Dominici M, Gimona M, Hill AF, De Kleijn D, Koh M, Lai RC, Mitsialis SA, Ortiz LA, Rohde E, Asada T, Toh WS, Weiss DJ, Zheng L, Giebel B, Lim SK (2019) Defining mesenchymal stromal cell (MSC)-derived small extracellular vesicles for therapeutic applications. J Extracell Vesicles 8. https://doi.org/10.1080/20013078.2019.1609206

  100. Witwer KW, Buzás EI, Bemis LT, Bora A, Lässer C, Lötvall J, Nolte-’t Hoen EN, Piper MG, Sivaraman S, Skog J, Théry C, Wauben MH, Hochberg F (2013) Standardization of sample collection, isolation and analysis methods in extracellular vesicle research. J Extracell Vesicles 2. https://doi.org/10.3402/jev.v2i0.20360

  101. Witwer KW, Théry C (2019) Extracellular vesicles or exosomes? On primacy, precision, and popularity influencing a choice of nomenclature. J Extracell Vesicles 8. https://doi.org/10.1080/20013078.2019.1648167

  102. de Wolf C, van de Bovenkamp M, Hoefnagel M (2017) Regulatory perspective on in vitro potency assays for human mesenchymal stromal cells used in immunotherapy. Cytotherapy 19:784–797. https://doi.org/10.1016/j.jcyt.2017.03.076

    Article  CAS  PubMed  Google Scholar 

  103. Woodell-May JE, Sommerfeld SD (2020) Role of inflammation and the immune system in the progression of osteoarthritis. J Orthop Res 38:253–257. https://doi.org/10.1002/jor.24457

    Article  PubMed  Google Scholar 

  104. Wu L, Leijten J, Van Blitterswijk CA, Karperien M (2013) Fibroblast growth factor-1 is a mesenchymal stromal cell-secreted factor stimulating proliferation of osteoarthritic chondrocytes in co-culture. Stem Cells Dev 22:2356–2367. https://doi.org/10.1089/scd.2013.0118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Wu L, Leijten JCH, Georgi N, Post JN, van Blitterswijk CA, Karperien M (2011) Trophic effects of mesenchymal stem cells increase chondrocyte proliferation and matrix formation. Tissue Eng Part A 17:1425–1436. https://doi.org/10.1089/ten.tea.2010.0517

    Article  CAS  PubMed  Google Scholar 

  106. Wu L, Prins H-JJ, Helder MN, van Blitterswijk CA, Karperien M (2012) Trophic effects of mesenchymal stem cells in chondrocyte co-cultures are independent of culture conditions and cell sources. Tissue Eng Part A 18:1542–1551. https://doi.org/10.1089/ten.tea.2011.0715

    Article  CAS  PubMed  Google Scholar 

  107. Xia H, Liang C, Luo P, Huang J, He J, Wang Z, Cao X, Peng C, Wu S (2018) Pericellular collagen i coating for enhanced homing and chondrogenic differentiation of mesenchymal stem cells in direct intra-articular injection. Stem Cell Res Ther 9:1–12. https://doi.org/10.1186/s13287-018-0916-z

    Article  CAS  Google Scholar 

  108. 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

    Article  PubMed  Google Scholar 

  109. Zha K, Sun Z, Yang Y, Chen M, Gao C, Fu L, Li H, Sui X, Guo Q, Liu S (2021) Recent developed strategies for enhancing chondrogenic differentiation of MSC: impact on MSC-based therapy for cartilage regeneration. Stem Cells Int 2021:1–15. https://doi.org/10.1155/2021/8830834

    Article  CAS  Google Scholar 

  110. Zhang H, Lin C, Zeng C, Wang Z, Wang H, Lu J, Liu X, Shao Y, Zhao C, Pan J, Xu S, Zhang Y, Xie D, Cai D, Bai X (2018) Synovial macrophage M1 polarisation exacerbates experimental osteoarthritis partially through R-spondin-2. Ann Rheum Dis 77:1524–1534. https://doi.org/10.1136/annrheumdis-2018-213450

    Article  CAS  PubMed  Google Scholar 

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  1. Department of Orthopaedics, University Medical Center Utrecht, Utrecht, The Netherlands

    Lucienne A. Vonk

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    Jorge S. Burns

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Vonk, L.A. (2023). Potency Assay Considerations for Cartilage Repair, Osteoarthritis and Use of Extracellular Vesicles. In: Burns, J.S. (eds) Potency Assays for Advanced Stem Cell Therapy Medicinal Products. Advances in Experimental Medicine and Biology, vol 1420. Springer, Cham. https://doi.org/10.1007/978-3-031-30040-0_5

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