Research progress in treatment of knee osteoarthritis by paracrine effect of stem cells_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

CHEN Wenbo , CAI Jiangyu , SUN Yaying , CHEN Jun ,  CHEN Shiyi

Department of Sports Medicine and Arthroscopy, Huashan Hospital, Fudan University, Shanghai, 200040, P.R.China;

Corresponding author：

CHEN Shiyi, Email: cshiyi@163.com

Keywords：

Osteoarthritis; stem cells therapy; paracrine effect; exosome; microvesicle; extracellular matrix

DOI：

10.7507/1002-1892.201903074

Video：

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Objective To review the advances in utilizing paracrine effect of stem cells in knee osteoarthritis (OA) treatment.Methods The researches in applying stem cells derived conditioned medium, extracellular matrix, exosomes, and microvesicles in knee OA treatment and cartilage repair were reviewed and analyzed.Results The satisfying outcomes of using different products of stem cells paracrine effect in knee OA condition as well as cartilage defect is revealed in studies in vitro and in vivo. The mechanism including suppressing the intraarticular inflammation, the apoptosis of chondrocytes, and the degradation of cartilage matrix, while enhancing the synthesis of cartilage matrix, the differentiation of in-situ stem cells into chondrocytes and the migration to the affected area. The effectiveness can be further improved supplemented with the tissue engineering methods or gene modification.Conclusion Compared with the traditional stem cell therapy, applying the products from paracrine effect of stem cells in knee OA treatment is more economical and safer, presenting great potential in clinical practice.

Citation： CHEN Wenbo, CAI Jiangyu, SUN Yaying, CHEN Jun, CHEN Shiyi. Research progress in treatment of knee osteoarthritis by paracrine effect of stem cells. Chinese Journal of Reparative and Reconstructive Surgery, 2019, 33(11): 1446-1451. doi: 10.7507/1002-1892.201903074 Copy

1.	Toh WS, Lai RC, Hui JHP, et al. MSC exosome as a cell-free MSC therapy for cartilage regeneration: Implications for osteoarthritis treatment. Semin Cell Dev Biol, 2017, 67: 56-64.
2.	Neogi T, Zhang Y. Epidemiology of osteoarthritis. Rheum Dis Clin North Am, 2013, 39(1): 1-19.
3.	Bijlsma JW, Berenbaum F, Lafeber FP. Osteoarthritis: an update with relevance for clinical practice. Lancet, 2011, 377(9783): 2115-2126.
4.	Mi B, Wang J, Liu Y, et al. Icariin activates autophagy via down-regulation of the NF-κB signaling-mediated apoptosis in chondrocytes. Front Pharmacol, 2018, 9: 605.
5.	Wang Y, Yu D, Liu Z, et al. Exosomes from embryonic mesenchymal stem cells alleviate osteoarthritis through balancing synthesis and degradation of cartilage extracellular matrix. Stem Cell Res Ther, 2017, 8(1): 189.
6.	Zhang W, Nuki G, Moskowitz RW, et al. OARSI recommendations for the management of hip and knee osteoarthritis: part III: Changes in evidence following systematic cumulative update of research published through January 2009. Osteoarthritis Cartilage, 2010, 18(4): 476-499.
7.	McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage, 2014, 22(3): 363-388.
8.	Rhon D. Re: Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part Ⅱ: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 2008; 16: 137-62. Osteoarthritis Cartilage, 2008, 16(12): 1585, 1589.
9.	Jiang YZ, Zhang SF, Qi YY, et al. Cell transplantation for articular cartilage defects: principles of past, present, and future practice. Cell Transplant, 2011, 20(5): 593-607.
10.	Murphy JM, Fink DJ, Hunziker EB, et al. Stem cell therapy in a caprine model of osteoarthritis. Arthritis Rheum, 2003, 48(12): 3464-3474.
11.	Centeno CJ, Busse D, Kisiday J, et al. Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells. Pain Physician, 2008, 11(3): 343-353.
12.	Jo CH, Chai JW, Jeong EC, et al. 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, 2017, 45(12): 2774-2783.
13.	Zhang S, Jiang YZ, Zhang W, et al. Neonatal desensitization supports long-term survival and functional integration of human embryonic stem cell-derived mesenchymal stem cells in rat joint cartilage without immunosuppression. Stem Cells Dev, 2013, 22(1): 90-101.
14.	Nori S, Okada Y, Nishimura S, et al. Long-term safety issues of iPSC-based cell therapy in a spinal cord injury model: oncogenic transformation with epithelial-mesenchymal transition. Stem Cell Reports, 2015, 4(3): 360-373.
15.	Zhang S, Chu WC, Lai RC, et al. Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration. Osteoarthritis Cartilage, 2016, 24(12): 2135-2140.
16.	Jin LH, Choi BH, Kim YJ, et al. Implantation of bone marrow-derived buffy coat can supplement bone marrow stimulation for articular cartilage repair. Osteoarthritis Cartilage, 2011, 19(12): 1440-1448.
17.	Wu L, Leijten JC, Georgi N, et al. Trophic effects of mesenchymal stem cells increase chondrocyte proliferation and matrix formation. Tissue Eng Part A, 2011, 17(9-10): 1425-1436.
18.	Fu Q, Ohnishi S, Sakamoto N. Conditioned medium from human amnion-derived mesenchymal stem cells regulates activation of primary hepatic stellate cells. Stem Cells Int, 2018, 2018: 4898152.
19.	Gnecchi M, He H, Noiseux N, et al. Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J, 2006, 20(6): 661-669.
20.	van Buul GM, Villafuertes E, Bos PK, et al. Mesenchymal stem cells secrete factors that inhibit inflammatory processes in short-term osteoarthritic synovium and cartilage explant culture. Osteoarthritis Cartilage, 2012, 20(10): 1186-1196.
21.	Platas J, Guillén MI, del Caz MD, et al. Conditioned media from adipose-tissue-derived mesenchymal stem cells downregulate degradative mediators induced by interleukin-1β in osteoarthritic chondrocytes. Mediators Inflamm, 2013, 2013: 357014.
22.	Platas J, Guillén MI, Pérez Del Caz MD, et al. Paracrine effects of human adipose-derived mesenchymal stem cells in inflammatory stress-induced senescence features of osteoarthritic chondrocytes. Aging (Albany NY), 2016, 8(8): 1703-1717.
23.	Hassan Famian M, Montazer Saheb S, Montaseri A. Conditioned medium of Wharton's jelly derived stem cells can enhance the cartilage specific genes expression by chondrocytes in monolayer and mass culture systems. Adv Pharm Bull, 2017, 7(1): 123-130.
24.	Radin EL, Rose RM. Role of subchondral bone in the initiation and progression of cartilage damage. Clin Orthop Relat Res, 1986, (213): 34-40.
25.	Chang W, Kim R, Park SI, et al. Enhanced healing of rat calvarial bone defects with hypoxic conditioned medium from mesenchymal stem cells through increased endogenous stem cell migration via regulation of ICAM-1 targeted-microRNA-221. Mol Cells, 2015, 38(7): 643-650.
26.	Griffith LG, Swartz MA. Capturing complex 3D tissue physiology in vitro. Nat Rev Mol Cell Biol, 2006, 7(3): 211-224.
27.	Pei M, He F. Extracellular matrix deposited by synovium-derived stem cells delays replicative senescent chondrocyte dedifferentiation and enhances redifferentiation. J Cell Physiol, 2012, 227(5): 2163-2174.
28.	Pei M, Zhang Y, Li J, et al. Antioxidation of decellularized stem cell matrix promotes human synovium-derived stem cell-based chondrogenesis. Stem Cells Dev, 2013, 22(6): 889-900.
29.	Zhang Y, Li J, Davis ME, et al. Delineation of in vitro chondrogenesis of human synovial stem cells following preconditioning using decellularized matrix. Acta Biomater, 2015, 20: 39-50.
30.	Yang Y, Lin H, Shen H, et al. Mesenchymal stem cell-derived extracellular matrix enhances chondrogenic phenotype of and cartilage formation by encapsulated chondrocytes in vitro and in vivo. Acta Biomater, 2018, 69: 71-82.
31.	Meirelles Lda S, Fontes AM, Covas DT, et al. Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev, 2009, 20(5-6): 419-427.
32.	Li JJ, Hosseini-Beheshti E, Grau GE, et al. Stem cell-derived extracellular vesicles for treating joint injury and osteoarthritis. Nanomaterials (Basel), 2019, 9(2): pii: E261.
33.	Zhang S, Chuah SJ, Lai RC, et al. MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity. Biomaterials, 2018, 156: 16-27.
34.	Zhu Y, Wang Y, Zhao B, et al. Comparison of exosomes secreted by induced pluripotent stem cell-derived mesenchymal stem cells and synovial membrane-derived mesenchymal stem cells for the treatment of osteoarthritis. Stem Cell Res Ther, 2017, 8(1): 64.
35.	Tao SC, Yuan T, Zhang YL, et al. Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model. Theranostics, 2017, 7(1): 180-195.
36.	Mao G, Zhang Z, Hu S, et al. Exosomes derived from miR-92a-3p-overexpressing human mesenchymal stem cells enhance chondrogenesis and suppress cartilage degradation via targeting WNT5A. Stem Cell Res Ther, 2018, 9(1): 247.
37.	Liu Y, Lin L, Zou R, et al. MSC-derived exosomes promote proliferation and inhibit apoptosis of chondrocytes via lncRNA-KLF3-AS1/miR-206/GIT1 axis in osteoarthritis. Cell Cycle, 2018, 17(21-22): 2411-2422.
38.	Liu X, Yang Y, Li Y, et al. Integration of stem cell-derived exosomes with in situ hydrogel glue as a promising tissue patch for articular cartilage regeneration. Nanoscale, 2017, 9(13): 4430-4438.
39.	Lawson C, Vicencio JM, Yellon DM, et al. Microvesicles and exosomes: new players in metabolic and cardiovascular disease. J Endocrinol, 2016, 228(2): R57-R71.
40.	Cosenza S, Ruiz M, Toupet K, et al. Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis. Sci Rep, 2017, 7(1): 16214.
41.	Xiang C, Yang K, Liang Z, et al. Sphingosine-1-phosphate mediates the therapeutic effects of bone marrow mesenchymal stem cell-derived microvesicles on articular cartilage defect. Transl Res, 2018, 193: 42-53.
42.	Tofiño-Vian M, Guillén MI, Pérez Del Caz MD, et al. Microvesicles from human adipose tissue-derived mesenchymal stem cells as a new protective strategy in osteoarthritic chondrocytes. Cell Physiol Biochem, 2018, 47(1): 11-25.

1. Toh WS, Lai RC, Hui JHP, et al. MSC exosome as a cell-free MSC therapy for cartilage regeneration: Implications for osteoarthritis treatment. Semin Cell Dev Biol, 2017, 67: 56-64.
2. Neogi T, Zhang Y. Epidemiology of osteoarthritis. Rheum Dis Clin North Am, 2013, 39(1): 1-19.
3. Bijlsma JW, Berenbaum F, Lafeber FP. Osteoarthritis: an update with relevance for clinical practice. Lancet, 2011, 377(9783): 2115-2126.
4. Mi B, Wang J, Liu Y, et al. Icariin activates autophagy via down-regulation of the NF-κB signaling-mediated apoptosis in chondrocytes. Front Pharmacol, 2018, 9: 605.
5. Wang Y, Yu D, Liu Z, et al. Exosomes from embryonic mesenchymal stem cells alleviate osteoarthritis through balancing synthesis and degradation of cartilage extracellular matrix. Stem Cell Res Ther, 2017, 8(1): 189.
6. Zhang W, Nuki G, Moskowitz RW, et al. OARSI recommendations for the management of hip and knee osteoarthritis: part III: Changes in evidence following systematic cumulative update of research published through January 2009. Osteoarthritis Cartilage, 2010, 18(4): 476-499.
7. McAlindon TE, Bannuru RR, Sullivan MC, et al. OARSI guidelines for the non-surgical management of knee osteoarthritis. Osteoarthritis Cartilage, 2014, 22(3): 363-388.
8. Rhon D. Re: Zhang W, Moskowitz RW, Nuki G, et al. OARSI recommendations for the management of hip and knee osteoarthritis, Part Ⅱ: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 2008; 16: 137-62. Osteoarthritis Cartilage, 2008, 16(12): 1585, 1589.
9. Jiang YZ, Zhang SF, Qi YY, et al. Cell transplantation for articular cartilage defects: principles of past, present, and future practice. Cell Transplant, 2011, 20(5): 593-607.
10. Murphy JM, Fink DJ, Hunziker EB, et al. Stem cell therapy in a caprine model of osteoarthritis. Arthritis Rheum, 2003, 48(12): 3464-3474.
11. Centeno CJ, Busse D, Kisiday J, et al. Increased knee cartilage volume in degenerative joint disease using percutaneously implanted, autologous mesenchymal stem cells. Pain Physician, 2008, 11(3): 343-353.
12. Jo CH, Chai JW, Jeong EC, et al. 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, 2017, 45(12): 2774-2783.
13. Zhang S, Jiang YZ, Zhang W, et al. Neonatal desensitization supports long-term survival and functional integration of human embryonic stem cell-derived mesenchymal stem cells in rat joint cartilage without immunosuppression. Stem Cells Dev, 2013, 22(1): 90-101.
14. Nori S, Okada Y, Nishimura S, et al. Long-term safety issues of iPSC-based cell therapy in a spinal cord injury model: oncogenic transformation with epithelial-mesenchymal transition. Stem Cell Reports, 2015, 4(3): 360-373.
15. Zhang S, Chu WC, Lai RC, et al. Exosomes derived from human embryonic mesenchymal stem cells promote osteochondral regeneration. Osteoarthritis Cartilage, 2016, 24(12): 2135-2140.
16. Jin LH, Choi BH, Kim YJ, et al. Implantation of bone marrow-derived buffy coat can supplement bone marrow stimulation for articular cartilage repair. Osteoarthritis Cartilage, 2011, 19(12): 1440-1448.
17. Wu L, Leijten JC, Georgi N, et al. Trophic effects of mesenchymal stem cells increase chondrocyte proliferation and matrix formation. Tissue Eng Part A, 2011, 17(9-10): 1425-1436.
18. Fu Q, Ohnishi S, Sakamoto N. Conditioned medium from human amnion-derived mesenchymal stem cells regulates activation of primary hepatic stellate cells. Stem Cells Int, 2018, 2018: 4898152.
19. Gnecchi M, He H, Noiseux N, et al. Evidence supporting paracrine hypothesis for Akt-modified mesenchymal stem cell-mediated cardiac protection and functional improvement. FASEB J, 2006, 20(6): 661-669.
20. van Buul GM, Villafuertes E, Bos PK, et al. Mesenchymal stem cells secrete factors that inhibit inflammatory processes in short-term osteoarthritic synovium and cartilage explant culture. Osteoarthritis Cartilage, 2012, 20(10): 1186-1196.
21. Platas J, Guillén MI, del Caz MD, et al. Conditioned media from adipose-tissue-derived mesenchymal stem cells downregulate degradative mediators induced by interleukin-1β in osteoarthritic chondrocytes. Mediators Inflamm, 2013, 2013: 357014.
22. Platas J, Guillén MI, Pérez Del Caz MD, et al. Paracrine effects of human adipose-derived mesenchymal stem cells in inflammatory stress-induced senescence features of osteoarthritic chondrocytes. Aging (Albany NY), 2016, 8(8): 1703-1717.
23. Hassan Famian M, Montazer Saheb S, Montaseri A. Conditioned medium of Wharton's jelly derived stem cells can enhance the cartilage specific genes expression by chondrocytes in monolayer and mass culture systems. Adv Pharm Bull, 2017, 7(1): 123-130.
24. Radin EL, Rose RM. Role of subchondral bone in the initiation and progression of cartilage damage. Clin Orthop Relat Res, 1986, (213): 34-40.
25. Chang W, Kim R, Park SI, et al. Enhanced healing of rat calvarial bone defects with hypoxic conditioned medium from mesenchymal stem cells through increased endogenous stem cell migration via regulation of ICAM-1 targeted-microRNA-221. Mol Cells, 2015, 38(7): 643-650.
26. Griffith LG, Swartz MA. Capturing complex 3D tissue physiology in vitro. Nat Rev Mol Cell Biol, 2006, 7(3): 211-224.
27. Pei M, He F. Extracellular matrix deposited by synovium-derived stem cells delays replicative senescent chondrocyte dedifferentiation and enhances redifferentiation. J Cell Physiol, 2012, 227(5): 2163-2174.
28. Pei M, Zhang Y, Li J, et al. Antioxidation of decellularized stem cell matrix promotes human synovium-derived stem cell-based chondrogenesis. Stem Cells Dev, 2013, 22(6): 889-900.
29. Zhang Y, Li J, Davis ME, et al. Delineation of in vitro chondrogenesis of human synovial stem cells following preconditioning using decellularized matrix. Acta Biomater, 2015, 20: 39-50.
30. Yang Y, Lin H, Shen H, et al. Mesenchymal stem cell-derived extracellular matrix enhances chondrogenic phenotype of and cartilage formation by encapsulated chondrocytes in vitro and in vivo. Acta Biomater, 2018, 69: 71-82.
31. Meirelles Lda S, Fontes AM, Covas DT, et al. Mechanisms involved in the therapeutic properties of mesenchymal stem cells. Cytokine Growth Factor Rev, 2009, 20(5-6): 419-427.
32. Li JJ, Hosseini-Beheshti E, Grau GE, et al. Stem cell-derived extracellular vesicles for treating joint injury and osteoarthritis. Nanomaterials (Basel), 2019, 9(2): pii: E261.
33. Zhang S, Chuah SJ, Lai RC, et al. MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity. Biomaterials, 2018, 156: 16-27.
34. Zhu Y, Wang Y, Zhao B, et al. Comparison of exosomes secreted by induced pluripotent stem cell-derived mesenchymal stem cells and synovial membrane-derived mesenchymal stem cells for the treatment of osteoarthritis. Stem Cell Res Ther, 2017, 8(1): 64.
35. Tao SC, Yuan T, Zhang YL, et al. Exosomes derived from miR-140-5p-overexpressing human synovial mesenchymal stem cells enhance cartilage tissue regeneration and prevent osteoarthritis of the knee in a rat model. Theranostics, 2017, 7(1): 180-195.
36. Mao G, Zhang Z, Hu S, et al. Exosomes derived from miR-92a-3p-overexpressing human mesenchymal stem cells enhance chondrogenesis and suppress cartilage degradation via targeting WNT5A. Stem Cell Res Ther, 2018, 9(1): 247.
37. Liu Y, Lin L, Zou R, et al. MSC-derived exosomes promote proliferation and inhibit apoptosis of chondrocytes via lncRNA-KLF3-AS1/miR-206/GIT1 axis in osteoarthritis. Cell Cycle, 2018, 17(21-22): 2411-2422.
38. Liu X, Yang Y, Li Y, et al. Integration of stem cell-derived exosomes with in situ hydrogel glue as a promising tissue patch for articular cartilage regeneration. Nanoscale, 2017, 9(13): 4430-4438.
39. Lawson C, Vicencio JM, Yellon DM, et al. Microvesicles and exosomes: new players in metabolic and cardiovascular disease. J Endocrinol, 2016, 228(2): R57-R71.
40. Cosenza S, Ruiz M, Toupet K, et al. Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis. Sci Rep, 2017, 7(1): 16214.
41. Xiang C, Yang K, Liang Z, et al. Sphingosine-1-phosphate mediates the therapeutic effects of bone marrow mesenchymal stem cell-derived microvesicles on articular cartilage defect. Transl Res, 2018, 193: 42-53.
42. Tofiño-Vian M, Guillén MI, Pérez Del Caz MD, et al. Microvesicles from human adipose tissue-derived mesenchymal stem cells as a new protective strategy in osteoarthritic chondrocytes. Cell Physiol Biochem, 2018, 47(1): 11-25.

Chinese Journal of Reparative and Reconstructive Surgery

Research progress in treatment of knee osteoarthritis by paracrine effect of stem cells

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