Human umbilical cord mesenchymal stem cells in the treatment of knee osteoarthritis: study protocol for a clinical trial

doi:10.3969/j.issn.2095-4344.0472

Abstract

Abstract:

BACKGROUND: Osteoarthritis (OA) is a kind of chronic bone and joint disease which seriously endangers human health. Cell therapy for OA has aroused widespread concern and gotten rapid development in recent years. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) have the advantages of easy amplification and differentiation, anti-inflammation and recruiting function such as MSCs from other sources. Furthermore, UC-MSCs are young cells that have large quantity, no ethical problems, high proliferative potential and pluripotent differentiation. UC-MSCs have been the most commonly used seed cells in clinical cell therapy.
OBJECTIVE: To evaluate the efficacy and safety of UC-MSCs in the treatment of human knee OA to provide theoretical and clinical basis for stem cell therapy of OA.
METHODS: The trail will be completed in Arthritis Clinic & Research Center, Beijing, China. Participants will be recruited according to established inclusion/exclusion criteria after obtaining the informed consent and the approval of the Ethics Committee (the first and second parts of the trial have been registered (https://register.clinicaltrials.gov/), with the identifier No. NCT03357770 and NCT03358654, and the third part will be carried out according to the conclusion of the first and second parts). The clinical trial will be divided into three parts: in the first part three groups will be recruited. Each group will contain three participants. The three groups of participants will be treated with high, medium and low dose of MSCs, respectively. Participants will be followed up to evaluate dose-limiting toxicity so as to determine the maximum tolerated dose. The second part will be a single-arm clinical trial. Nine participants will be recruited. The injection dose will be the maximum tolerated dose determined in the first part. Participants will be followed up to evaluate the safety and efficacy of the treatment. The third part will be a randomized controlled trial. Participants will be randomly divided into two groups (n=7 per group) and treated with MSCs and hyaluronic acid, respectively. During the trial, evaluators, participants and interveners will be unaware of grouping information and interventions. Participants will be followed up at designed time points after treatment to evaluate the safety and efficacy of the intervention. The trial will be terminated if there are unexplained local and systemic symptoms or death according to the NCI-CTCAE criteria.
EXPECTED RESULTS: With reference to the previous literature, the knee pain will be relieved, the score of knee joint function will increase, and the cartilage defect area will decrease on MRI at 1-2 years after the intervention. The trail is expected to spend 3 years and 6 months.

中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

Key words: Stem Cells, Osteoarthritis, Tissue Engineering

CLC Number:

R394.2

Yang Zi-yi, Lin Jian-hao, Xing Dan, Wang Bin, Hou Yun-fei . Human umbilical cord mesenchymal stem cells in the treatment of knee osteoarthritis: study protocol for a clinical trial[J]. Chinese Journal of Tissue Engineering Research, 2018, 22(9): 1407-1412.

Figures/Tables 1

References

[1] Bijlsma JW, Berenbaum F, Lafeber FP. Osteoarthritis: an update with relevance for clinical practice. Lancet. 2011; 377(9783): 2115-2126.

[2] Tang X, Wang S, Zhan S, et al. The Prevalence of Symptomatic Knee Osteoarthritis in China: Results From the China Health and Retirement Longitudinal Study. Arthritis Rheumatol. 2016; 68(3):648-653.

[3] Kang X, Fransen M, Zhang Y, et al. The high prevalence of knee osteoarthritis in a rural Chinese population: the Wuchuan osteoarthritis study. Arthritis Rheum. 2009;61(5): 641-647.

[4] Liu Q, Niu J, Huang J, et al. Knee osteoarthritis and all-cause mortality: the Wuchuan Osteoarthritis Study. Osteoarthritis Cartilage. 2015;23(7):1154-1157.

[5] Burke J, Hunter M, Kolhe R, et al. Therapeutic potential of mesenchymal stem cell based therapy for osteoarthritis. Clin Transl Med. 2016;5(1):27.

[6] Davatchi F, Abdollahi BS, Mohyeddin M, et al. Mesenchymal stem cell therapy for knee osteoarthritis. Preliminary report of four patients. Int J Rheum Dis. 2011;14(2):211-215.

[7] Bianco P, Cao X, Frenette PS, et al. The meaning, the sense and the significance: translating the science of mesenchymal stem cells into medicine. Nat Med. 2013;19(1):35-42.

[8] Ding DC, Chou HL, Chang YH, et al. Characterization of HLA-G and Related Immunosuppressive Effects in Human Umbilical Cord Stroma-Derived Stem Cells. Cell Transplant. 2016;25(2):217-228.

[9] Ding DC, Shyu WC, Chiang MF, et al. Enhancement of neuroplasticity through upregulation of beta1-integrin in human umbilical cord-derived stromal cell implanted stroke model. Neurobiol Dis. 2007;27(3):339-353.

[10] Wang D, Chen K, Du WT, et al. CD14+ monocytes promote the immunosuppressive effect of human umbilical cord matrix stem cells. Exp Cell Res. 2010;316(15):2414-2423.

[11] Fong CY, Chak LL, Biswas A, et al. Human Wharton's jelly stem cells have unique transcriptome profiles compared to human embryonic stem cells and other mesenchymal stem cells. Stem Cell Rev. 2011;7(1): 1-16.

[12] Fong CY, Subramanian A, Gauthaman K, et al. Human umbilical cord Wharton's jelly stem cells undergo enhanced chondrogenic differentiation when grown on nanofibrous scaffolds and in a sequential two-stage culture medium environment. Stem Cell Rev. 2012;8(1):195-209.

[13] La Rocca G, Lo IM, Corsello T, et al. Human Wharton's jelly mesenchymal stem cells maintain the expression of key immunomodulatory molecules when subjected to osteogenic, adipogenic and chondrogenic differentiation in vitro: new perspectives for cellular therapy. Curr Stem Cell Res Ther. 2013;8(1):100-113.

[14] Diekman BO, Wu CL, Louer CR, et al. Intra-articular delivery of purified mesenchymal stem cells from C57BL/6 or MRL/MpJ superhealer mice prevents posttraumatic arthritis. Cell Transplant. 2013;22(8):1395-1408.

[15] ter HM, Schelbergen R, Blattes R, et al. Antiinflammatory and chondroprotective effects of intraarticular injection of adipose-derived stem cells in experimental osteoarthritis. Arthritis Rheum. 2012;64(11):3604-3613.

[16] Horie M, Choi H, Lee RH, et al. Intra-articular injection of human mesenchymal stem cells (MSCs) promote rat meniscal regeneration by being activated to express Indian hedgehog that enhances expression of type II collagen. Osteoarthritis Cartilage. 2012;20(10):1197-1207.

[17] Sato M, Uchida K, Nakajima H,et al. Direct transplantation of mesenchymal stem cells into the knee joints of Hartley strain guinea pigs with spontaneous osteoarthritis. Arthritis Res Ther. 2012; 14(1): R31.

[18] Al FH, Nor HBM, Chen HC, et al. The potential of intra-articular injection of chondrogenic-induced bone marrow stem cells to retard the progression of osteoarthritis in a sheep model. Exp Gerontol. 2012;47(6):458-464.

[19] Guercio A, Di MP, Casella S, et al. Production of canine mesenchymal stem cells from adipose tissue and their application in dogs with chronic osteoarthritis of the humeroradial joints. Cell Biol Int. 2012;36(2):189-194.

[20] Frisbie DD, Kisiday JD, Kawcak CE, et al. Evaluation of adipose-derived stromal vascular fraction or bone marrow-derived mesenchymal stem cells for treatment of osteoarthritis. J Orthop Res. 2009;27(12):1675-1680.

[21] Ha CW, Park YB, Chung JY, et al. 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(9):1044-1051.

[22] Uth K, Trifonov D. Stem cell application for osteoarthritis in the knee joint: A minireview. World J Stem Cells. 2014;6(5): 629-636.

[23] [Jo CH, Lee YG, Shin WH, et al. Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem Cells. 2014; 32(5): 1254-1266.

[24] Vega A, Martín-Ferrero MA, Del Canto F, et al. Treatment of Knee Osteoarthritis With Allogeneic Bone Marrow Mesenchymal Stem Cells: A Randomized Controlled Trial. Transplantation. 2015; 99(8):1681-1690.