Skip to main content
Log in

Human Fetal Cartilage-Derived Progenitor Cells Exhibit Anti-Inflammatory Effect on IL-1β-Mediated Osteoarthritis Phenotypes In Vitro

  • Original Article
  • Published:
Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

Background:

In this study, we have investigated whether human fetal cartilage progenitor cells (hFCPCs) have anti-inflammatory activity and can alleviate osteoarthritis (OA) phenotypes in vitro.

Methods:

hFCPCs were stimulated with various cytokines and their combinations and expression of paracrine factors was examined to find an optimal priming factor. Human chondrocytes or SW982 synoviocytes were treated with interleukin-1β (IL-1β) to produce OA phenotype, and co-cultured with polyinosinic-polycytidylic acid (poly(I-C))-primed hFCPCs to address their anti-inflammatory effect by measuring the expression of OA-related genes. The effect of poly(I-C) on the surface marker expression and differentiation of hFCPCs into 3 mesodermal lineages was also examined.

Results:

Among the priming factors tested, poly(I-C) (1 µg/mL) most significantly induced the expression of paracrine factors such as indoleamine 2,3-dioxygenase, histocompatibility antigen, class I, G, tumor necrosis factor- stimulated gene-6, leukemia inhibitory factor, transforming growth factor-β1 and hepatocyte growth factor from hFCPCs. In the OA model in vitro, co-treatment of poly(I-C)-primed hFCPCs significantly alleviated IL-1β-induced expression of inflammatory factors such as IL-6, monocyte chemoattractant protein-1 and IL-1β, and matrix metalloproteinases in SW982, while it increased the expression of cartilage extracellular matrix such as aggrecan and collagen type II in human chondrocytes. We also found that treatment of poly(I-C) did not cause significant changes in the surface marker profile of hFCPCs, while showed some changes in the 3 lineages differentiation.

Conclusion:

These results suggest that poly(I-C)-primed hFCPCs have an ability to modulate inflammatory response and OA phenotypes in vitro and encourage further studies to apply them in animal models of OA in the future.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Ishii T, Eto K. Fetal stem cell transplantation: past, present and future. World J Stem Cells. 2014;6:404–20.

    PubMed  PubMed Central  Google Scholar 

  2. Marcus AJ, Woodbury D. Fetal stem cells from extra-embryonic tissues: do not discard. J Cell Mol Med. 2008;12:730–42.

    PubMed  PubMed Central  CAS  Google Scholar 

  3. Shin KS, Na KH, Lee HJ, Kim DG, Shin SJ, Kim JK, et al. Characterization of fetal tissue-derived mesenchymal stem cells. Int J Stem Cells. 2009;2:51–8.

    PubMed  PubMed Central  CAS  Google Scholar 

  4. Götherström C, Ringdén O, Tammik C, Zetterberg E, Westgren M, Le Blanc K. Immunologic properties of human fetal mesenchymal stem cells. Am J Obstet Gynecol. 2004;190:239–45.

    PubMed  CAS  Google Scholar 

  5. Chen PM, Yen ML, Liu KJ, Sytwu HK, Yen BL. Immunomodulatory properties of human adult and fetal multipotent mesenchymal stem cells. J Biomed Sci. 2011;18:49.

    PubMed  PubMed Central  Google Scholar 

  6. Coulson-Thomas VJ, Coulson-Thomas YM, Gesteira TF, Kao WW. Extrinsic and intrinsic mechanisms by which mesenchymal stem cells suppress the immune system. Ocul Surf. 2016;14:121–34.

    PubMed  PubMed Central  Google Scholar 

  7. Shi Y, Wang Y, Li Q, Liu K, Hou J, Shao C, et al. Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases. Nat Rev Nephrol. 2018;14:493–507.

    PubMed  CAS  Google Scholar 

  8. Najar M, Krayem M, Meuleman N, Bron D, Lagneaux L. Mesenchymal stromal cells and toll-like receptor priming: a critical review. Immune Netw. 2017;17:89–102.

    PubMed  PubMed Central  Google Scholar 

  9. Shirjang S, Mansoori B, Solali S, Hagh MF, Shamsasenjan K. Toll-like receptors as a key regulator of mesenchymal stem cell function: An up-to-date review. Cell Immunol. 2017;135:1–10.

    Google Scholar 

  10. Choi WH, Kim HR, Lee SJ, Jeong N, Park SR, Choi BH, et al. Fetal cartilage-derived cells have stem cell properties and are a highly potent cell source for cartilage regeneration. Cell Transplant. 2016;25:449–61.

    PubMed  Google Scholar 

  11. Kim HR, Kim J, Park SR, Min BH, Choi BH. Characterization of human fetal cartilage progenitor cells during long-term expansion in a xeno-free medium. Tissue Eng Regen Med. 2018;15:649–59.

    PubMed  PubMed Central  CAS  Google Scholar 

  12. Lee SJ, Kim J, Choi WH, Park SR, Choi BH, Min BH. Immunophenotype and immune-modulatory activities of human fetal cartilage-derived progenitor cells. Cell Transplant. 2019;28:932–42.

    PubMed  PubMed Central  Google Scholar 

  13. Robinson WH, Lepus CM, Wang Q, Raghu H, Mao R, Lindstrom TM, et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat Rev Rheumatol. 2016;12:580–92.

    PubMed  PubMed Central  CAS  Google Scholar 

  14. Scanzello CR. Role of low-grade inflammation in osteoarthritis. Curr Opin Rheumatol. 2017;29:79–85.

    PubMed  PubMed Central  CAS  Google Scholar 

  15. Hermann W, Lambova S, Muller-Ladner U. Current treatment options for osteoarthritis. Curr Rheumatol Rev. 2018;14:108–16.

    PubMed  CAS  Google Scholar 

  16. Zhang W, Ouyang H, Dass CR, Xu J. Current research on pharmacologic and regenerative therapies for osteoarthritis. Bone Res. 2016;4:15040.

    PubMed  PubMed Central  CAS  Google Scholar 

  17. Gore M, Tai KS, Sadosky A, Leslie D, Stacey BR. Clinical comorbidities, treatment patterns, and direct medical costs of patients with osteoarthritis in usual care: a retrospective claims database analysis. J Med Econ. 2011;14:497–507.

    PubMed  Google Scholar 

  18. Richards MM, Maxwell JS, Weng L, Angelos MG, Golzarian J. Intra-articular treatment of knee osteoarthritis: from anti-inflammatories to products of regenerative medicine. Phys Sportsmed. 2016;44:101–8.

    PubMed  PubMed Central  Google Scholar 

  19. Im GI. Perspective on intra-articular injection cell therapy for osteoarthritis treatment. Tissue Eng Regen Med. 2019;16:357–63.

    PubMed  PubMed Central  CAS  Google Scholar 

  20. Hwang JJ, Rim YA, Nam Y, Ju JH. Recent developments in clinical applications of mesenchymal stem cells in the treatment of rheumatoid arthritis and osteoarthritis. Front Immunol. 2021;12:631291.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Kwon DG, Kim MK, Jeon YS, Nam YC, Park JS, Ryu DJ. State of the art: the immunomodulatory role of MSCs for osteoarthritis. Int J Mol Sci. 2022;23:1618.

    PubMed  PubMed Central  CAS  Google Scholar 

  22. Iijima H, Isho T, Kuroki H, Takahashi M, Aoyama T. Effectiveness of mesenchymal stem cells for treating patients with knee osteoarthritis: a meta-analysis toward the establishment of effective regenerative rehabilitation. NPJ Regen Med. 2018;3:15.

    Google Scholar 

  23. Song Y, Zhang J, Xu H, Lin Z, Chang H, Liu W, et al. Mesenchymal stem cells in knee osteoarthritis treatment: a systematic review and meta-analysis. J Orthop Translat. 2020;24:121–30.

    Google Scholar 

  24. Park YB, Ha CW, Lee CH, Yoon YC, Park YG. Cartilage regeneration in osteoarthritic patients by a composite of allogeneic umbilical cord blood-derived mesenchymal stem cells and hyaluronate hydrogel: results from a clinical trial for safety and proof-of-concept with 7 years of extended follow-up. Stem Cells Transl Med. 2017;6:613–21.

    PubMed  CAS  Google Scholar 

  25. Lim HC, Park YB, Ha CW, Cole BJ, Lee BK, Jeong HJ, et al. Allogeneic umbilical cord blood-derived mssenchymal stem cell implantation verus microfracture for large, full-tickness cartilage defects in older patients. Orthop J Sports Med. 2021;9:2325967120973052.

    PubMed  PubMed Central  Google Scholar 

  26. Im GI. The concept of early osteoarthritis and its significance in regenerative medicine. Tissue Eng Regen Med. 2022;19:431–6.

    Article  PubMed  Google Scholar 

  27. Yan H, Wu M, Yuan Y, Wang ZZ, Jiang H, Chen T. Priming of Toll-like receptor 4 pathway in mesenchymal stem cells increases expression of B cell activating factor. Biochem Biophys Res Commun. 2014;448:212–7.

    PubMed  CAS  Google Scholar 

  28. Raicevic G, Najar M, Stamatopoulos B, De Bruyn C, Meuleman N, Bron D, et al. The source of human mesenchymal stromal cells influences their TLR profile as well as their functional properties. Cell Immunol. 2011;270:207–16.

    PubMed  CAS  Google Scholar 

  29. Waterman RS, Tomchuck SL, Henkle SL, Betancourt AM. A new mesenchymal stem cells (MSC) paradigm: polarization into a pro-inflammatory MSC1 or an immunosuppressive MSC2 phenotype. PLoS One. 2010;5:e10088.

    PubMed  PubMed Central  Google Scholar 

  30. Kota DJ, DiCarlo B, Hetz RA, Smith P, Cox CS Jr, Olson SD. Differential MSC activation leads to distinct mononuclear leukocyte binding mechanisms. Sci Rep. 2014;4:4565.

    Google Scholar 

  31. Ryu JH, Park M, Kim BK, Ryu KH, Woo SY. Tonsil-derived mesenchymal stromal cells produce CXCR2-binding chemokines and acquire follicular dendritic cell-like phenotypes under TLR3 stimulation. Cytokine. 2015;73:225–35.

    PubMed  CAS  Google Scholar 

  32. Zhang L, Liu D, Pu D, Wang Y, Li L, He Y, et al. The role of Toll-like receptor 3 and 4 in regulating the function of mesenchymal stem cells isolated from umbilical cord. Int J Mol Med. 2015;35:1003–10.

    PubMed  CAS  Google Scholar 

  33. Lombardo E, DelaRosa O, Mancheño-Corvo P, Menta R, Ramírez C, Büscher D. Toll-like receptor-mediated signaling in human adipose-derived stem cells: implications for immunogenicity and immunosuppressive potential. Tissue Eng Part A. 2009;15:1579–89.

    PubMed  CAS  Google Scholar 

  34. Raicevic G, Najar M, Pieters K, De Bruyn C, Meuleman N, Bron D, et al. Inflammation and Toll-like receptor ligation differentially affect the osteogenic potential of human mesenchymal stromal cells depending on their tissue origin. Tissue Eng Part A. 2012;18:1410–8.

    PubMed  CAS  Google Scholar 

  35. Romieu-Mourez R, François M, Boivin MN, Bouchentouf M, Spaner DE, Galipeau J. Cytokine modulation of TLR expression and activation in mesenchymal stromal cells leads to a proinflammatory phenotype. J Immunol. 2009;182:7963–73.

    PubMed  CAS  Google Scholar 

  36. Dumitru CA, Hemeda H, Jakob M, Lang S, Brandau S. Stimulation of mesenchymal stromal cells (MSCs) via TLR3 reveals a novel mechanism of autocrine priming. FASEB J. 2014;28:3856–66.

    PubMed  PubMed Central  CAS  Google Scholar 

  37. Manferdini C, Maumus M, Gabusi E, Piacentini A, Filardo G, Peyrafitte JA, et al. Adipose-derived mesenchymal stem cells exert antiinflammatory effects on chondrocytes and synoviocytes from osteoarthritis patients through prostaglandin E2. Arthritis Rheum. 2013;65:1271–81.

    PubMed  CAS  Google Scholar 

  38. Ichiseki T, Shimazaki M, Ueda Y, Ueda S, Tsuchiya M, Souma D, et al. Intraarticularly-injected mesenchymal stem cells stimulate anti-inflammatory molecules and inhibit pain related protein and chondrolytic enzymes in a monoiodoacetate-induced rat arthritis model. Int J Mol Sci. 2018;19:203.

    PubMed Central  Google Scholar 

  39. Corsello T, Amico G, Corrao S, Anzalone R, Timoneri F, Lo Iacono M, et al. Wharton’s Jelly mesenchymal stromal cells from human umbilical cord: a close-up on immunomodulatory molecules featured in situ and in vitro. Stem Cell Rev Rep. 2019;15:900–18.

    PubMed  CAS  Google Scholar 

  40. Zhang S, Chuah SJ, Lai RC, Hui JHP, Lim SK, Toh WS. MSC exosomes mediate cartilage repair by enhancing proliferation, attenuating apoptosis and modulating immune reactivity. Biomaterials. 2018;156:16–27.

    PubMed  CAS  Google Scholar 

  41. Kim M, Shin DI, Choi BH, Min BH. Exosomes from IL1β -primed mesenchymal stem cells inhibited IL-1β and TNF-α-mediated inflammatory responses in osteoarthritic SW982 cells. Tissue Eng Regen Med. 2021;18:525–36.

    PubMed  PubMed Central  CAS  Google Scholar 

  42. Kawakubo K, Ohnishi S, Fujita H, Kuwatani M, Onishi R, Masamune A, et al. Effect of fetal membrane-derived mesenchymal stem cell transplantation in rats with acute and chronic pancreatitis. Pancreas. 2016;45:707–13.

    PubMed  CAS  Google Scholar 

  43. Wu KJ, Yu SJ, Chiang CW, Lee YW, Yen BL, Tseng PC, et al. Neuroprotective action of human Wharton’s jelly-derived mesenchymal stromal cell transplants in a rodent model of stroke. Cell Transplant. 2018;27:1603–12.

    PubMed  PubMed Central  Google Scholar 

  44. Moodley Y, Atienza D, Manuelpillai U, Samuel CS, Tchongue J, Ilancheran S, et al. Human umbilical cord mesenchymal stem cells reduce fibrosis of bleomycin-induced lung injury. Am J Pathol. 2009;17:303–13.

    Google Scholar 

  45. PrabhuDas M, Bonney E, Caron K, Dey S, Erlebacher A, Fazleabas A, et al. Immune mechanisms at the maternal-fetal interface: perspectives and challenges. Nat Immunol. 2015;16:328–34.

    PubMed  PubMed Central  CAS  Google Scholar 

  46. Fettke F, Schumacher A, Canellada A, Toledo N, Bekeredjian-Ding I, Bondt A, et al. Maternal and fetal mechanisms of B cell regulation during pregnancy: human chorionic gonadotropin stimulates B cells to produce IL-10 while alpha-fetoprotein drives them into apoptosis. Front Immunol. 2016;7:495.

    PubMed  PubMed Central  Google Scholar 

  47. Rebmann V, König L, Nardi Fda S, Wagner B, Manvailer LF, Horn PA. The potential of HLA-G-bearing extracellular vesicles as a future element in HLA-G immune biology. Front Immunol. 2016;7:173.

    PubMed  PubMed Central  Google Scholar 

  48. Xu YY, Wang SC, Li DJ, Du MR. Co-signaling molecules in maternal-fetal immunity. Trends Mol Med. 2017;23:46–58.

    PubMed  CAS  Google Scholar 

  49. Ferreira LMR, Meissner TB, Tilburgs T, Strominger JL. HLA-G: at the interface of maternal-fetal tolerance. Trends Immunol. 2017;38:272–86.

    PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This research was supported by a grant of the Korea Health Technology R&D Project funded by the Ministry of Health & Welfare, Republic of Korea (HI17C2191) and the National Research Foundation Grant (NRF-2019M3E5D1A02070861).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Byung Hyune Choi.

Ethics declarations

Conflict of interest

The authors declare that there is no conflict of interest.

Ethical statement

The experiments were conducted with the approval of institutional review board (IRB) of Ajou University Medical Center (AJIRB-CRO-07-139) and (AJIRB-MED-SMP-10–266).

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kim, J., Tran, A.NT., Lee, J.Y. et al. Human Fetal Cartilage-Derived Progenitor Cells Exhibit Anti-Inflammatory Effect on IL-1β-Mediated Osteoarthritis Phenotypes In Vitro. Tissue Eng Regen Med 19, 1237–1250 (2022). https://doi.org/10.1007/s13770-022-00478-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13770-022-00478-w

Keywords

Navigation