Clinical application of mesenchymal stem cells for cartilage regeneration

Abstract

Cartilage has the ability to transmit and distribute loads, providing lubrication in the diarthrodial joints. Risk factors including age, gender, genetics, nutrition and bone density may predispose to osteoarthritis (OA) and cartilage defect formation. Appropriate treatment include sufficient rest and medical therapy. Intra-articular injections such as steroids, platelet-rich plasma, visco-supplementation and mesenchymal stem cells (MSCs) injections present as alternative options for non-operative treatments. For cartilage defects, microfracture (MF), osteochondral autograft transplantation (OAT) and autologous chondrocyte implantation (ACI) are the most common treatment procedures. MSCs have been identified as an ideal cell source for OA therapy because they are easily expanded in culture, generally non-tumorigenic, and can be readily obtained from patients. It may be harvested from bone marrow (BMSCs), adipose tissue (ADSCs), synovium (SDSCs) or peripheral blood. BMSCs features the most common source of stem cells, and infrapatellar fat pad (IPFP) is another popular stem cell source. A phase 1 clinical study entitled “Treatment of Knee OA with Autologous Mesenchymal Stromal Cell Product (RegStem®)” was conducted in Taiwan and utilized 5 × 107 IPFP-MSCs in the study for OA therapy. Most of the existing clinical studies have shown that patients receiving MSCs treatment have improved clinical outcome, such as Visual Analogue Scale, International Knee Documentation Committee and Western Ontario and McMaster Universities Arthritis Index (WOMAC) score. Some studies have also found an improvement in cartilage volume by Magnetic Resonance Imaging evaluation. Furthermore, MSCs can also be used for cartilage defect treatment. Clinical outcomes such as IKDC, Lysholm, and Tegner scores showed significant improvement when the cartilage defects were repaired and regenerated by several millions of stem cells. A 10-year follow-up clinical research indicated that there was no apparent increased tumor formation risk when BMSCs were used for cartilage defect treatment. In addition, a BMSCs/collagen gel composite for cartilage repair clinical trial in Taiwan was conducted in 2008, and results suggested that there was an improvement in IKDC and MRI score at 9-years of follow-up. It appears that the use of MSCs for OA and cartilage defect treatment may be a promising method.

Keywords

Mesenchymal stem cell / osteoarthritis / cartilage defect / cartilage regeneration

References

[1] Aigner T.Collagens--major component of the physiological cartilage matrix, major target of cartilage degeneration, major tool in cartilage repair..Adv Drug Deliv Rev2003;55:1569-93

[2] Mow VC.Brandt KD,Lohmander LS.Mechanical properties of normal and osteoarthritic articular cartilage..Osteoarthritis.1998;OxfordOxford University Press108-22

[3] Mauck LR.Pallua N.Engineering cartilage tissue..Tissue Engineering, from lab to clinic.2011;UKSpringer-Verlag Berlin Heidelberg493-520

[4] Bastiaansen-Jenniskens YM,de Bart AC,Zuurmond AM.Contribution of collagen network features to functional properties of engineered cartilage..Osteoarthritis Cartilage2008;16:359-66

[5] Arden N.Osteoarthritis: epidemiology..Best Pract Res Clin Rheumatol2006;20:3-25

[6] Kotlarz H,Fang H.Insurer and out-of-pocket costs of osteoarthritis in the US: evidence from national survey data..Arthritis Rheum2009;60:3546-53

[7] Fransen M,March L,Penserga E.The epidemiology of osteoarthritis in Asia..Int J Rheum Dis2011;14:113-21

[8] Neogi T.Epidemiology of osteoarthritis..Rheum Dis Clin North Am2013;39:1-19 PMCID:PMC3545412

[9] Jo CH,Jeong EC,Shin JS.Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the Knee: a 2-year follow-up study..Am J Sports Med2017;45:2774-83

[10] Saklatvala J.Tumour necrosis factor alpha stimulates resorption and inhibits synthesis of proteoglycan in cartilage..Nature1986;322:547-9 PMCID:PMC7095107

[11] Lefebvre V,Vaes G.Modulation by interleukin 1 and tumor necrosis factor alpha of production of collagenase, tissue inhibitor of metalloproteinases and collagen types in differentiated and dedifferentiated articular chondrocytes..Biochim Biophys Acta1990;22:366-78

[12] Kaneko S,Chiba J,Inoue K.Interleukin-6 and interleukin-8 levels in serum and synovial fluid of patients with osteoarthritis..Cytokines Cell Mol Ther2000;6:71-9

[13] Sokolove J.Role of inflammation in the pathogenesis of osteoarthritis: latest findings and interpretations..Ther Adv Musculoskelet Dis2013;5:77-94 PMCID:PMC3638313

[14] Kapoor M,Lajeunesse D,Fahmi H.Role of proinflammatory cytokines in the pathophysiology of osteoarthritis..Nat Rev Rheumatol2011;7:33-42

[15] Harris DJ.Dragoo JL.Management of knee articular cartilage injuries..Modern Arthroscopy.2011;InTech103-28

[16] Bhatia D,Novo M.Current interventions in the management of knee osteoarthritis..J Pharm Bioallied Sci2013;5:30-8 PMCID:PMC3612336

[17] Jones IA,Wilson ML,Vangsness CT Jr.Intra-articular treatment options for knee osteoarthritis..Nat Rev Rheumatol2019;15:77-90 PMCID:PMC6390843

[18] Rabago D,Mundt M,Grettie J.Dextrose prolotherapy for knee osteoarthritis: a randomized controlled trial..Ann Fam Med2013;11:229-37 PMCID:PMC3659139

[19] Glynn LG,Casey M,Blom J.Platelet-rich plasma (PRP) therapy for knee arthritis: a feasibility study in primary care..Pilot Feasibility Stud2018;4:93 PMCID:PMC6030745

[20] Mancuso P,Glynn A,Murphy JM.Mesenchymal stem cell therapy for osteoarthritis: the critical role of the cell secretome..Front Bioeng Biotechnol2019;7:9 PMCID:PMC6361779

[21] Case JM.Treatment of articular cartilage defects of the knee with microfracture and enhanced microfracture techniques..Sports Med Arthrosc Rev2016;24:63-8

[22] Inderhaug E.Osteochondral autograft transplant (mosaicplasty) for knee articular cartilage defects..JBJS Essent Surg Tech2019;9:e34.1-2 PMCID:PMC6974309

[23] Kim MK,Jeon YM.Clinical, radiological, and histological outcomes after the fibrin-matrix autologous chondrocyte implantation for chondral lesions of the knee in patients more than 50 years old: a prospective case series with minimum 2-year follow-up..J Orthop Surg (Hong Kong)2020;28:2309499019893509

[24] Erickson BJ,Gomoll AH.Indications, techniques, outcomes for matrix-induced autologous chondrocyte implantation (MACI)..Oper Tech Sports Med2018;26:175-82

[25] Pers YM,Noel D.Mesenchymal stem cells for the management of inflammation in osteoarthritis: state of the art and perspectives..Osteoarthritis Cartilage2015;23:2027-35

[26] Dominici M,Mueller I,Marini F.Minimal criteria for defining multipotent mesenchymal stromal cells. The international society for cellular therapy position statement..Cytotherapy2006;8:315-7

[27] Gupta PK,Chullikana A.Mesenchymal stem cells for cartilage repair in osteoarthritis..Stem Cell Res Ther2012;3:25 PMCID:PMC3580463

[28] Chen YC,Chen PL,Shen YS.Donor site morbidity after harvesting of proximal tibia bone..Head Neck2006;28:496-500

[29] Cotter EJ,Yanke AB.Bone marrow aspirate concentrate for cartilage defects of the knee: from bench to bedside evidence..Cartilage2018;9:161-70 PMCID:PMC5871125

[30] Nathan S,Thambyah A,Goh J.Cell-based therapy in the repair of osteochondral defects: a novel use for adipose tissue..Tissue Eng2003;9:733-44

[31] Si Z,Sun C,Xu J.Adipose-derived stem cells: Sources, potency, and implications for regenerative therapies..Biomed Pharmacother2019;114:108765

[32] Baer PC.Adipose-derived mesenchymal stromal/stem cells: tissue localization, characterization, and heterogeneity..Stem Cells Int2012;2012:812693 PMCID:PMC3345279

[33] Pak J,Park KS,Kang LW.Current use of autologous adipose tissue-derived stromal vascular fraction cells for orthopedic applications..J Biomed Sci2017;24:9 PMCID:PMC5282826

[34] De Ugarte DA,Elbarbary A,Zuk PA.Comparison of multi-lineage cells from human adipose tissue and bone marrow..Cells Tissues Organs2003;174:101-9

[35] Xu L,Sun Y,Xiong Y.Tissue source determines the differentiation potentials of mesenchymal stem cells: a comparative study of human mesenchymal stem cells from bone marrow and adipose tissue..Stem Cell Res Ther2017;8:275 PMCID:PMC5718061

[36] Heo JS,Kim HS.Comparison of molecular profiles of human mesenchymal stem cells derived from bone marrow, umbilical cord blood, placenta and adipose tissue..Int J Mol Med2016;37:115-25 PMCID:PMC4687432

[37] Deng M,Liu Z,Ma GE.Endothelial differentiation of human adipose-derived stem cells on polyglycolic acid/polylactic acid mesh..Stem Cells Int2015;2015:350718 PMCID:PMC4464689

[38] Lin J,Huang J,Kuang Y.Hypoxia promotes vascular smooth muscle cell (VSMC) differentiation of adipose-derived stem cell (ADSC) by regulating mettl3 and paracrine factors..Stem Cells Int2020;2020:2830565 PMCID:PMC7053496

[39] Edwards NJ,Christy R,Pollok B.Differentiation of adipose derived stem cells to keratinocyte-like cells on an advanced collagen wound matrix..Tissue Cell2018;53:68-75

[40] Wada Y,Morine Y,Saito Y.The differences in the characteristics of insulin-producing cells using human adipose-tissue derived mesenchymal stem cells from subcutaneous and visceral tissues..Sci Rep2019;9:13204 PMCID:PMC6744430

[41] Gao S,Zhao S,Zhou F.Differentiation of human adipose-derived stem cells into neuron/motoneuron-like cells for cell replacement therapy of spinal cord injury..Cell Death Dis2019;10:597 PMCID:PMC6687731

[42] Tomita K,Sakai Y,Terenghi G.Glial differentiation of human adipose-derived stem cells: implications for cell-based transplantation therapy..Neuroscience2013;236:55-65

[43] Lee RH,Choi I,Choi HS.Characterization and expression analysis of mesenchymal stem cells from human bone marrow and adipose tissue..Cell Physiol Biochem2004;14:311-24

[44] Tsuji W,Marra KG.Adipose-derived stem cells: implications in tissue regeneration..World J Stem Cells2014;6:312-21 PMCID:PMC4131273

[45] Sakaguchi Y,Yagishita K.Comparison of human stem cells derived from various mesenchymal tissues - Superiority of synovium as a cell source..Arthritis Rheum2005;52:2521-9

[46] Mochizuki T,Sakaguchi Y,Yokoyama A.Higher chondrogenic potential of fibrous synovium- and adipose synovium-derived cells compared with subcutaneous fat-derived cells: distinguishing properties of mesenchymal stem cells in humans..Arthritis Rheum2006;54:843-53

[47] Kouroupis D,Willman MA,Colombini A.Infrapatellar fat pad-derived MSC response to inflammation and fibrosis induces an immunomodulatory phenotype involving CD10-mediated Substance P degradation..Sci Rep2019;9:10864 PMCID:PMC6659713

[48] Centeno CJ,Kisiday J,Freeman M.Regeneration of meniscus cartilage in a knee treated with percutaneously implanted autologous mesenchymal stem cells..Med Hypotheses2008;71:900-8

[49] Davatchi F,Mohyeddin M,Nikbin B.Mesenchymal stem cell therapy for knee osteoarthritis. Preliminary report of four patients..Int J Rheum Dis2011;14:211-5

[50] Davatchi F,Mohyeddin M.Mesenchymal stem cell therapy for knee osteoarthritis: 5 years follow-up of three patients..Int J Rheum Dis2016;19:219-25

[51] Orozco L,Soler R,Soler F.Treatment of knee osteoarthritis with autologous mesenchymal stem cells: two-year follow-up results..Transplantation2014;97:e66-8

[52] Soler R,Munar A,Lopez R.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..Knee2016;23:647-54

[53] Chahal J,Shestopaloff K,Chaboureau A.Bone marrow mesenchymal stromal cell treatment in patients with osteoarthritis results in overall improvement in pain and symptoms and reduces synovial inflammation..Stem Cells Transl Med2019;8:746-57 PMCID:PMC6646697

[54] Fodor PB.Adipose derived stromal cell (ADSC) injections for pain management of osteoarthritis in the human knee joint..Aesthet Surg J2016;36:229-36

[55] Yokota N,Ohtsuru T,Lyman S.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 Med2019;47:2577-83

[56] Pers YM,Ferreira R,Delfour C.ADIPOA Consortium. Adipose mesenchymal stromal cell-based therapy for severe osteoarthritis of theknee: a phase I dose-escalation trial..Stem Cells Transl Med2016;5:847-56 PMCID:PMC4922848

[57] Lee WS,Kim KI,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 Med2019;8:504-11 PMCID:PMC6525553

[58] Lu L,Zhang Z,Li S.Treatment of knee osteoarthritis with intra-articular injection of autologous adipose-derived mesenchymal progenitor cells: a prospective, randomized, double-blind, active-controlled, phase IIb clinical trial..Stem Cell Res Ther2019;10:143 PMCID:PMC6528322

[59] Chuckpaiwong B,Kraus VB,Nunley JA.Age-associated increases in the size of the infrapatellar fat pad in knee osteoarthritis as measured by 3T MRI..J Orthop Res2010;28:1149-54 PMCID:PMC3625521

[60] Koh YG.Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis..Knee2012;19:902-7

[61] do Amaral R,Kelly DJ,Kearney CJ.Infrapatellar fat pad stem cells: from developmental biology to cell therapy..Stem Cells Int2017;2017:6843727 PMCID:PMC5606137

[62] Toghraie FS,Gholipour MA,Torabinejad S.Treatment of osteoarthritis with infrapatellar fat pad derived mesenchymal stem cells in Rabbit..Knee2011;18:71-5

[63] Koh YG,Kwon OR,Lee SW.Mesenchymal stem cell injections improve symptoms of knee osteoarthritis..Arthroscopy2013;29:748-55

[64] Spasovski D,Bascarevic Z,Vreca M.Intra-articular injection of autologous adipose-derived mesenchymal stem cells in the treatment of knee osteoarthritis..J Gene Med2018;20:e3002

[65] Wakitani S,Yamamoto T,Murata N.Human autologous culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage defects in osteoarthritic knees..Osteoarthritis Cartilage2002;10:199-206

[66] Nejadnik H,Feng Choong EP,Lee EH.Autologous bone marrow-derived mesenchymal stem cells versus autologous chondrocyte implantation: an observational cohort study..Am J Sports Med2010;38:1110-6

[67] Haleem AM,Sabry D,Rashed LA.The clinical use of human culture-expanded autologous bone marrow mesenchymal stem cells transplanted on platelet-rich fibrin glue in the treatment of articular cartilage defects: a pilot study and preliminary results..Cartilage2010;1:253-61 PMCID:PMC3002255

[68] Teo AQA,Shen L,Toh WS.Equivalent 10-year outcomes after implantation of autologous bone marrow-derived mesenchymal stem cells versus autologous chondrocyte implantation for chondral defects of the knee..Am J Sports Med2019;47:2881-7

[69] Koga H,Muneta T,Morito T.Local adherent technique for transplanting mesenchymal stem cells as a potential treatment of cartilage defect..Arthritis Res Ther2008;10:R84 PMCID:PMC2575632

[70] Sekiya I,Horie M.Arthroscopic transplantation of synovial stem cells improves clinical outcomes in knees with cartilage defects..Clin Orthop Relat Res2015;473:2316-26 PMCID:PMC4457765

[71] Shimomura K,Moriguchi Y,Yasui Y.Next generation mesenchymal stem cell (MSC)-based cartilage repair using scaffold-free tissue engineered constructs generated with synovial mesenchymal stem cells..Cartilage2015;6:13S-29S PMCID:PMC4481383

[72] Chang CH,Lin FH,Hsu YM.Tissue engineering-based cartilage repair with mesenchymal stem cells in a porcine model..J Orthop Res2011;29:1874-80

[73] Chen CC,Wang YH,Huang SH.Cartilage fragments from osteoarthritic knee promote chondrogenesis of mesenchymal stem cells without exogenous growth factor induction..J Orthop Res2012;30:393-400

[74] Chang CH,Liao CH,Hsu YM.Human acellular cartilage matrix powders as a biological scaffold for cartilage tissue engineering with synovium-derived mesenchymal stem cells..J Biomed Mater Res A2014;102:2248-57

[75] Chen CC,Wang YH,Chang CH.A comparison of distinct bone marrow-derived cells on cartilage tissue engineering..J Taiwan Inst Chem Eng2017;78:32-8

[76] Yang YK,Wang See C,Barabino GA.Changes in phenotype and differentiation potential of human mesenchymal stem cells aging in vitro..Stem Cell Res Ther2018;9:131 PMCID:PMC5948736

[77] Raynauld JP,Ward R,Haraoui B.Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled trial..Arthritis Rheum2003;48:370-7

[78] Ray TR.Using viscosupplementation to treat knee osteoarthritis..Phys Sportsmed2013;41:16-24

[79] Volz M,Frick H,Anders S.A randomized controlled trial demonstrating sustained benefit of Autologous Matrix-Induced Chondrogenesis over microfracture at five years..Int Orthop2017;41:797-804

[80] Shive MS,McCormack R,Mohtadi N.BST-CarGel® treatment maintains cartilage repair superiority over microfracture at 5 years in a multicenter randomized controlled trial..Cartilage2015;6:62-72 PMCID:PMC4462252

[81] Jiang J,Ateshian GA,Hung CT.Bioactive stratified polymer ceramic-hydrogel scaffold for integrative osteochondral repair..Ann Biomed Eng2010;38:2183-96

[82] Chiang H,Hsieh CH,Huang YY.Clinical feasibility of a novel biphasic osteochondral composite for matrix-associated autologous chondrocyte implantation..Osteoarthritis Cartilage2013;21:589-98

[83] Xue D,Zong C,Li H.Osteochondral repair using porous poly(lactide-co-glycolide)/nano-hydroxyapatite hybrid scaffolds with undifferentiated mesenchymal stem cells in a rat model..J Biomed Mater Res A2010;94:259-70

[84] McCarthy HS.A histological comparison of the repair tissue formed when using either Chondrogide® or periosteum during autologous chondrocyte implantation..Osteoarthritis Cartilage2013;21:2048-57

[85] Schneider U,Andereya S,Fensky F.A prospective multicenter study on the outcome of type I collagen hydrogel-based autologous chondrocyte implantation (CaReS) for the repair of articular cartilage defects in the knee..Am J Sports Med2011;39:2558-65

[86] Trattnig S,Krestan C,Millington S.Matrix-based autologous chondrocyte implantation for cartilage repair with Hyalograft®C: two-year follow-up by magnetic resonance imaging..Eur J Radiol2006;57:9-15

[87] Erggelet C,Mrosek EH,Lahm A.Autologous chondrocyte implantation versus ACI using 3D-bioresorbable graft for the treatment of large full-thickness cartilage lesions of the knee..Arch Orthop Trauma Surg2010;130:957-64