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Transplantation of Gelatin Microspheres Loaded with Wharton's Jelly Derived Mesenchymal Stem Cells Facilitates Cartilage Repair in Mice

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Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

Background:

Knee osteoarthritis (KOA) is a prevalent chronic joint disease caused by various factors. Mesenchymal stem cells (MSCs) therapy is an increasingly promising therapeutic option for osteoarthritis. However, the chronic inflammation of knee joint can severely impede the therapeutic effects of transplanted cells. Gelatin microspheres (GMs) are degradable biomaterial that have various porosities for cell adhesion and cell–cell interaction. Excellent elasticity and deformability of GMs make it an excellent injectable vehicle for cell delivery.

Methods:

We created Wharton’s jelly derived mesenchymal stem cells (WJMSCs)-GMs complexes and assessed the effects of GMs on cell activity, proliferation and chondrogenesis. Then, WJMSCs loaded in GMs were transplanted in the joint of osteoarthritis mice. After four weeks, joint tissue was collected for histological analysis. Overexpressing-luciferase WJMSCs were performed to explore cell retention in mice.

Results:

In vitro experiments demonstrated that WJMSCs loaded with GMs maintained cell viability and proliferative potential. Moreover, GMs enhanced the chondrogenesis differentiation of WJMSCs while alleviated cell hypertrophy. In KOA mice model, transplantation of WJMSCs-GMs complexes promoted cartilage regeneration and cartilage matrix formation, contributing to the treatment of KOA. Compared with other groups, in WJMSCs+GMs group, there were fewer cartilage defects and with a more integrated tibia structure. Tracking results of stable-overexpressing luciferase WJMSCs demonstrated that GMs significantly extended the retention time of WJMSCs in knee joint cavity.

Conclusion:

Our results indicated that GMs facilitate WJMSCs mediated knee osteoarthritis healing in mice by promoting cartilage regeneration and prolonging cell retention. It might potentially provide an optimal strategy for the biomaterial-stem cell based therapy for knee osteoarthritis.

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References

  1. Leilei D, Pengpeng Y, Haagsma JA, Ye J, Yuan W, Yuliang E, et al. The burden of injury in China, 1990–2017: findings from the Global Burden of Disease Study 2017. Lancet Public Health. 2019;4:e449–61.

    PubMed  PubMed Central  Google Scholar 

  2. Safiri S, Kolahi AA, Smith E, Hill C, Bettampadi D, Mansournia MA, et al. Global, regional and national burden of osteoarthritis 1990–2017: a systematic analysis of the Global Burden of Disease Study 2017. Ann Rheum Dis. 2020;79:819–28.

    PubMed  Google Scholar 

  3. Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet. 2019;393:1745–59.

    CAS  PubMed  Google Scholar 

  4. Hunter DJ, Schofield D, Callander E. The individual and socioeconomic impact of osteoarthritis. Nat Rev Rheumatol. 2014;10:437–41.

    PubMed  Google Scholar 

  5. Kurtz SM, Ong KL, Lau E, Bozic KJ. Impact of the economic downturn on total joint replacement demand in the United States: updated projections to 2021. J Bone Joint Surg Am. 2014;96:624–30.

    PubMed  Google Scholar 

  6. Makarczyk MJ, Gao Q, He Y, Li Z, Gold MS, Hochberg MC, et al. Current models for development of disease-modifying osteoarthritis drugs. Tissue Eng Part C Methods. 2021;27:124–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Michael JW, Schlüter-Brust KU, Eysel P. The epidemiology, etiology, diagnosis, and treatment of osteoarthritis of the knee. Dtsch Arztebl Int. 2010;107:152–62.

    PubMed  PubMed Central  Google Scholar 

  8. Bennell KL, Hunter DJ, Paterson KL. Platelet-rich plasma for the management of hip and knee osteoarthritis. Curr Rheumatol Rep. 2017;19:24.

    PubMed  Google Scholar 

  9. Skou ST, Roos EM, Laursen MB, Rathleff MS, Arendt-Nielsen L, Simonsen O, et al. A randomized, controlled trial of total knee replacement. N Engl J Med. 2015;373:1597–606.

    CAS  PubMed  Google Scholar 

  10. Li X, Bai J, Ji X, Li R, Xuan Y, Wang Y. Comprehensive characterization of four different populations of human mesenchymal stem cells as regards their immune properties, proliferation and differentiation. Int J Mol Med. 2014;34:695–704.

    PubMed  PubMed Central  Google Scholar 

  11. Liang X, Ding Y, Zhang Y, Tse HF, Lian Q. Paracrine mechanisms of mesenchymal stem cell-based therapy: current status and perspectives. Cell Transpl. 2014;23:1045–59.

    Google Scholar 

  12. Friedenstein AJ, Piatetzky-Shapiro II, Petrakova KV. Osteogenesis in transplants of bone marrow cells. J Embryol Exp Morphol. 1966;16:381–90.

    CAS  PubMed  Google Scholar 

  13. Mitrano TI, Grob MS, Carrión F, Nova-Lamperti E, Luz PA, Fierro FS, et al. Culture and characterization of mesenchymal stem cells from human gingival tissue. J Periodontol. 2010;81:917–25.

    PubMed  Google Scholar 

  14. 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.

    CAS  PubMed  Google Scholar 

  15. Xiang XN, Zhu SY, He HC, Yu X, Xu Y, He CQ. Mesenchymal stromal cell-based therapy for cartilage regeneration in knee osteoarthritis. Stem Cell Res Ther. 2022;13:14.

    PubMed  PubMed Central  Google Scholar 

  16. Van Buul GM, Villafuertes E, Bos PK, Waarsing JH, Kops N, Narcisi R, et al. Mesenchymal stem cells secrete factors that inhibit inflammatory processes in short-term osteoarthritic synovium and cartilage explant culture. Osteoarthritis Cartilage. 2012;20:1186–96.

    PubMed  Google Scholar 

  17. Murphy JM, Fink DJ, Hunziker EB, Barry FP. Stem cell therapy in a caprine model of osteoarthritis. Arthritis Rheum. 2003;48:3464–74.

    PubMed  Google Scholar 

  18. Centeno CJ, Busse D, Kisiday J, Keohan C, Freeman M, Karli D. Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells. Pain Physician. 2008;11:343–53.

    PubMed  Google Scholar 

  19. Huang J, Liu Q, Xia J, Chen X, Xiong J, Yang L, et al. Modification of mesenchymal stem cells for cartilage-targeted therapy. J Transl Med. 2022;20:515.

    PubMed  PubMed Central  Google Scholar 

  20. Baker BM, Chen CS. Deconstructing the third dimension: how 3D culture microenvironments alter cellular cues. J Cell Sci. 2012;125:3015–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Kim H, Bae C, Kook YM, Koh WG, Lee K, Park MH. Mesenchymal stem cell 3D encapsulation technologies for biomimetic microenvironment in tissue regeneration. Stem Cell Res Ther. 2019;10:51.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Zonderland J, Moroni L. Steering cell behavior through mechanobiology in 3D: a regenerative medicine perspective. Biomaterials. 2021;268:120572.

    CAS  PubMed  Google Scholar 

  23. Thorp H, Kim K, Kondo M, Maak T, Grainger DW, Okano T. Trends in articular cartilage tissue engineering: 3D mesenchymal stem cell sheets as candidates for engineered hyaline-like cartilage. Cells. 2021;10:643.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Saraswat R, Ratnayake I, Perez EC, Schutz WM, Zhu Z, Ahrenkiel SP, et al. Micropatterned biphasic nanocomposite platform for maintaining chondrocyte morphology. ACS Appl Mater Interfaces. 2020;12:14814–24.

    CAS  PubMed  Google Scholar 

  25. Glowacki J, Trepman E, Folkman J. Cell shape and phenotypic expression in chondrocytes. Proc Soc Exp Biol Med. 1983;172:93–8.

    CAS  PubMed  Google Scholar 

  26. Xu J, Wang W, Ludeman M, Cheng K, Hayami T, Lotz JC, et al. Chondrogenic differentiation of human mesenchymal stem cells in three-dimensional alginate gels. Tissue Eng Part A. 2008;14:667–80.

    CAS  PubMed  Google Scholar 

  27. Li YY, Choy TH, Ho FC, Chan PB. Scaffold composition affects cytoskeleton organization, cell-matrix interaction and the cellular fate of human mesenchymal stem cells upon chondrogenic differentiation. Biomaterials. 2015;52:208–20.

    CAS  PubMed  Google Scholar 

  28. Li Y, Liu W, Liu F, Zeng Y, Zuo S, Feng S, et al. Primed 3D injectable microniches enabling low-dosage cell therapy for critical limb ischemia. Proc Natl Acad Sci U S A. 2014;111:13511–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Van Der Sluijs JA, Geesink RG, Van Der Linden AJ, Bulstra SK, Kuyer R, Drukker J. The reliability of the Mankin score for osteoarthritis. J Orthop Res. 1992;10:58–61.

    PubMed  Google Scholar 

  30. Rutgers M, Van Pelt MJ, Dhert WJ, Creemers LB, Saris DB. Evaluation of histological scoring systems for tissue-engineered, repaired and osteoarthritic cartilage. Osteoarthritis Cartilage. 2010;18:12–23.

    CAS  PubMed  Google Scholar 

  31. Pinamont WJ, Yoshioka NK, Young GM, Karuppagounder V, Carlson EL, Ahmad A, et al. Standardized histomorphometric evaluation of osteoarthritis in a surgical mouse model. J Vis Exp. 2020;159:e60991.

    Google Scholar 

  32. Jiao Y, Chen X, Niu Y, Huang S, Wang J, Luo M, et al. Wharton’s jelly mesenchymal stem cells embedded in PF-127 hydrogel plus sodium ascorbyl phosphate combination promote diabetic wound healing in type 2 diabetic rat. Stem Cell Res Ther. 2021;12:559.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Doege KJ, Garrison K, Coulter SN, Yamada Y. The structure of the rat aggrecan gene and preliminary characterization of its promoter. J Biol Chem. 1994;269:29232–40.

    CAS  PubMed  Google Scholar 

  34. Turinetto V, Vitale E, Giachino C. Senescence in human mesenchymal stem cells: functional changes and implications in stem cell-based therapy. Int J Mol Sci. 2016;17:1164.

    PubMed  PubMed Central  Google Scholar 

  35. Swanson WB, Omi M, Zhang Z, Nam HK, Jung Y, Wang G, et al. Macropore design of tissue engineering scaffolds regulates mesenchymal stem cell differentiation fate. Biomaterials. 2021;272:120769.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Gupte MJ, Swanson WB, Hu J, Jin X, Ma H, Zhang Z, et al. Pore size directs bone marrow stromal cell fate and tissue regeneration in nanofibrous macroporous scaffolds by mediating vascularization. Acta Biomater. 2018;82:1–11.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Corradetti B, Taraballi F, Minardi S, Van Eps J, Cabrera F, Francis LW, et al. Chondroitin sulfate immobilized on a biomimetic scaffold modulates inflammation while driving chondrogenesis. Stem Cells Transl Med. 2016;5:670–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Chang YH, Wu KC, Wang CC, Ding DC. Enhanced chondrogenesis of human umbilical cord mesenchymal stem cells in a gelatin honeycomb scaffold. J Biomed Mater Res A. 2020;108:2069–79.

    CAS  PubMed  Google Scholar 

  39. Ke W, Ma L, Wang B, Song Y, Luo R, Li G, et al. N-cadherin mimetic hydrogel enhances MSC chondrogenesis through cell metabolism. Acta Biomater. 2022;150:83–95.

    CAS  PubMed  Google Scholar 

  40. Yang L, Tsang KY, Tang HC, Chan D, Cheah KS. Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation. Proc Natl Acad Sci U S A. 2014;111:12097–102.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Jahangir S, Eglin D, Pötter N, Khozaei Ravari M, Stoddart MJ, Samadikuchaksaraei A, et al. Inhibition of hypertrophy and improving chondrocyte differentiation by MMP-13 inhibitor small molecule encapsulated in alginate-chondroitin sulfate-platelet lysate hydrogel. Stem Cell Res Ther. 2020;11:436.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Rajagopal K, Ramesh S, Madhuri V. Early addition of parathyroid hormone-related peptide regulates the hypertrophic differentiation of mesenchymal stem cells. Cartilage. 2021;13:143S–52S.

    CAS  PubMed  Google Scholar 

  43. Tang Z, Lu Y, Zhang S, Wang J, Wang Q, Xiao Y, et al. Chondrocyte secretome enriched microparticles encapsulated with the chondrocyte membrane to facilitate the chondrogenesis of BMSCs and reduce hypertrophy. J Mater Chem B. 2021;9:9989–10002.

    PubMed  Google Scholar 

  44. Xie M, Zhang Y, Xiong Z, Hines S, Shang J, Clark KL, et al. Generation of hyaline-like cartilage tissue from human mesenchymal stromal cells within the self-generated extracellular matrix. Acta Biomater. 2022;149:150–66.

    CAS  PubMed  Google Scholar 

  45. Barry F. MSC therapy for osteoarthritis: an unfinished story. J Orthop Res. 2019;37:1229–35.

    PubMed  Google Scholar 

  46. Liu W, Li Y, Zeng Y, Zhang X, Wang J, Xie L, et al. Microcryogels as injectable 3-D cellular microniches for site-directed and augmented cell delivery. Acta Biomater. 2014;10:1864–75.

    CAS  PubMed  Google Scholar 

  47. Jiao Y, Chen X, Nong B, Luo M, Niu Y, Huang S, et al. Transplantation of Wharton’s jelly mesenchymal stem cells encapsulated with Hydroactive® Gel promotes diabetic wound antifibrotic healing in type 2 diabetic rats. J Mater Chem B. 2022;10:8330–46.

    CAS  PubMed  Google Scholar 

  48. Zhang X, Liu S, Wang Z, Luo C, Dai Z, Sun J, et al. Implanted 3D gelatin microcryogel enables low-dose cell therapy for osteoarthritis by preserving the viability and function of umbilical cord MSCs. Chem Eng J. 2021;416:129140.

    CAS  Google Scholar 

  49. 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.

    PubMed  Google Scholar 

  50. 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.

    PubMed  Google Scholar 

  51. Bondeson J, Blom AB, Wainwright S, Hughes C, Caterson B, Van Den Berg WB. The role of synovial macrophages and macrophage-produced mediators in driving inflammatory and destructive responses in osteoarthritis. Arthritis Rheum. 2010;62:647–57.

    CAS  PubMed  Google Scholar 

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Acknowledgements

This study was funded by the National Natural Science Foundation of China (31971365 and 82271688) and the Guangdong Basic and Applied Basic Research Foundation (2020B1515120090)

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Correspondence to Yiren Jiao or Junjiu Huang.

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The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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The animal studies were performed after receiving approval the Institutional Animal Care and Use Committee (IACUC) in Sun Yat-sen University, P.R. China. (IACUC approval No. SYSU-IACUC-2021-B1256).

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Chen, X., Huang, S., Niu, Y. et al. Transplantation of Gelatin Microspheres Loaded with Wharton's Jelly Derived Mesenchymal Stem Cells Facilitates Cartilage Repair in Mice. Tissue Eng Regen Med 21, 171–183 (2024). https://doi.org/10.1007/s13770-023-00574-5

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