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Mesenchymal stromal cells facilitate resolution of pulmonary fibrosis by miR-29c and miR-129 intercellular transfer

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초록

To date, pulmonary fibrosis remains an unmet medical need. In this study, we evaluated the potency of mesenchymal stromal cell (MSC) secretome components to prevent pulmonary fibrosis development and facilitate fibrosis resolution. Surprisingly, the intratracheal application of extracellular vesicles (MSC-EVs) or the vesicle-depleted secretome fraction (MSC-SF) was not able to prevent lung fibrosis when applied immediately after the injury caused by bleomycin instillation in mice. However, MSC-EV administration induced the resolution of established pulmonary fibrosis, whereas the vesicle-depleted fraction did not. The application of MSC-EVs caused a decrease in the numbers of myofibroblasts and FAPa+ progenitors without affecting their apoptosis. Such a decrease likely occurred due to their dedifferentiation caused by microRNA (miR) transfer by MSC-EVs. Using a murine model of bleomycin-induced pulmonary fibrosis, we confirmed the contribution of specific miRs (miR-29c and miR-129) to the antifibrotic effect of MSC-EVs. Our study provides novel insights into possible antifibrotic therapy based on the use of the vesicle-enriched fraction of the MSC secretome.

Abstract

To date, pulmonary fibrosis remains an unmet medical need. In this study, we evaluated the potency of mesenchymal stromal cell (MSC) secretome components to prevent pulmonary fibrosis development and facilitate fibrosis resolution. Surprisingly, the intratracheal application of extracellular vesicles (MSC-EVs) or the vesicle-depleted secretome fraction (MSC-SF) was not able to prevent lung fibrosis when applied immediately after the injury caused by bleomycin instillation in mice. However, MSC-EV administration induced the resolution of established pulmonary fibrosis, whereas the vesicle-depleted fraction did not. The application of MSC-EVs caused a decrease in the numbers of myofibroblasts and FAPa+ progenitors without affecting their apoptosis. Such a decrease likely occurred due to their dedifferentiation caused by microRNA (miR) transfer by MSC-EVs. Using a murine model of bleomycin-induced pulmonary fibrosis, we confirmed the contribution of specific miRs (miR-29c and miR-129) to the antifibrotic effect of MSC-EVs. Our study provides novel insights into possible antifibrotic therapy based on the use of the vesicle-enriched fraction of the MSC secretome.

참고문헌 (59)

  1. Herrera, J., "Registration of the extracellular matrix components constituting the fibroblastic focus in idiopathic pulmonary fibrosis", JCI Insight, 4, pp.e125185~ (2019)
  2. Abreu, S. C., "Mesenchymal stromal cell-derived extracellular vesicles in lung diseases: current status and perspectives", Front. Cell Dev. Biol, 15, pp.600711~ (2021)
  3. Fan, X. L., "Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy", Cell. Mol. Life Sci, 77, pp.2771~2794 (2020)
  4. Gatti, S., "Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia-reperfusion-induced acute and chronic kidney injury", Nephrol. Dial. Transpl, 26, pp.1474~1483 (2011)
  5. Tan, C. Y., "Mesenchymal stem cell-derived exosomes promote hepatic regeneration in drug-induced liver injury models", Stem Cell Res. Ther, 5, pp.76~ (2014)
  6. Rockel, J. S., "Anti-fibrotic mechanisms of exogenously-expanded mesenchymal stromal cells for fibrotic diseases", Semin. Cell Dev. Biol, 101, pp.87~103 (2020)
  7. Vizoso, F., "Mesenchymal stem cell secretome : toward cell-free therapeutic strategies in regenerative medicine", Int. J. Mol. Sci, 18, pp.1852~ (2017)
  8. Basalova, N., "Secretome of mesenchymal stromal cells prevents myofibroblasts differentiation by transferring fibrosis-associated microRNAs within extracellular vesicles", Cells, 9, pp.1272~ (2020)
  9. Lobb, R. J., "Optimized exosome isolation protocol for cell culture supernatant and human plasma", J. Extracell. Vesicles, 4, pp.27031~ (2015)
  10. Otsuru, S., "Extracellular vesicles released from mesenchymal stromal cells stimulate bone growth in osteogenesis imperfecta", Cytotherapy, 20, pp.62~73 (2018)
  11. Phatak, P., "Biotinylated micro-RNA pull down assay for identifying miRNA targets", Bio Protoc, 7, pp.e2253~ (2017)
  12. Liu, T., "Fibrosis, vol. 1627", pp.27~42 (2017), Springer
  13. Lässer, C., "Human saliva, plasma and breast milk exosomes contain RNA : uptake by macrophages", J. Transl. Med, 9, pp.9~ (2011)
  14. Grange, C., "Biodistribution of mesenchymal stem cell-derived extracellular vesicles in a model of acute kidney injury monitored by optical imaging", Int. J. Mol. Med, 33, pp.1055~1063 (2014)
  15. Fang, Y., "miR-29c is downregulated in renal interstitial fibrosis in humans and rats and restored by HIF-α activation", Am. J. Physiol. Ren. Physiol, 304, pp.F1274~F1282 (2013)
  16. Hübner, R. H., "Standardized quantification of pulmonary fibrosis in histological samples", Biotechniques, 44, pp.507~517 (2008)
  17. Moeller, A., "The bleomycin animal model: a useful tool to investigate treatment options for idiopathic pulmonary fibrosis?", Int. J. Biochem. Cell Biol, 40, pp.362~382 (2008)
  18. Théry, C., "Minimal information for studies of extracellular vesicles 2018(MISEV2018) : a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines", J. Extracell. Vesicles, 7, pp.1535750~ (2018)
  19. Fang, S., "Umbilical cord-derived mesenchymal stem cell-derived exosomal microRNAs suppress myofibroblast differentiation by inhibiting the transforming growth factor-β", SMAD2 pathway during wound healing, 2016, pp.5, 1425~1439
  20. Grange, C., "Stem cell-derived extracellular vesicles inhibit and revert fibrosis progression in a mouse model of diabetic nephropathy", Sci. Rep, 9, pp.4468~ (2019)
  21. Guo, L., "Extracellular vesicles derived from mesenchymal stem cells prevent skin fibrosis in the cGVHD mouse model by suppressing the activation of macrophages and B cells immune response", Int. Immunopharmacol, 84, pp.106541~ (2020)
  22. Mansouri, N., "Mesenchymal stromal cell exosomes prevent and revert experimental pulmonary fibrosis through modulation of monocyte phenotypes", JCI Insight, 4, pp.e128060~ (2019)
  23. Ramírez-Hernández, A. A., "The role of extracellular vesicles in idiopathic pulmonary fibrosis progression : an approach on their therapeutics potential", Cells, 11, pp.630~ (2022)
  24. Gibbons, M. A., "Ly6C hi monocytes direct alternatively activated profibrotic macrophage regulation of lung fibrosis", Am. J. Resp. Crit. Care, 184, pp.569~581 (2011)
  25. Ogawa, T., "Macrophages in lung fibrosis", Int. Immunol, 33, pp.665~671 (2021)
  26. Kloth, C., "Flow cytometric analysis of the leukocyte landscape during bleomycin-induced lung injury and fibrosis in the rat", Am. J. Physiol. Lung Cell. Mol. Physiol, 317, pp.L109~L126 (2019)
  27. Ashley, S. L., "Periostin regulates fibrocyte function to promote myofibroblast differentiation and lung fibrosis", Mucosal Immunol, 10, pp.341~351 (2017)
  28. Avery, D., "Extracellular matrix directs phenotypic heterogeneity of activated fibroblasts", Matrix Biol, 67, pp.90~106 (2018)
  29. Chung, K. -M., "Fibroblast activation protein(FAP)is essential for the migration of bone marrow mesenchymal stem cells through RhoA activation", PLoS ONE, 9, pp.e88772~ (2014)
  30. Scanlan, M. J., "Molecular cloning of fibroblast activation protein alpha, a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers", Proc. Natl Acad. Sci. USA, 91, pp.5657~5661 (1994)
  31. Acharya, P. S., "Fibroblast activation protein : a serine protease expressed at the remodeling interface in idiopathic pulmonary fibrosis", Hum. Pathol, 37, pp.352~360 (2006)
  32. Kimura, T., "Loss of cells expressing fibroblast activation protein has variable effects in models of TGF-β and chronic bleomycin-induced fibrosis", Am. J. Physiol. Lung Cell. Mol. Physiol, 317, pp.L271~L282 (2019)
  33. Yang, P., "Comprehensive analysis of fibroblast activation protein(FAP)expression in interstitial lung diseases(ILDs)", Am. J. Respir. Crit. Care Med, 207, pp.160~172 (2022)
  34. Fan, M. -H., "Fibroblast activation protein(FAP)accelerates collagen degradation and clearance from lungs in mice", J. Biol. Chem, 291, pp.8070~8089 (2016)
  35. Li, Q., "Exosomal microRNA-21 promotes keloid fibroblast proliferation and collagen production by inhibiting Smad7", J. Burn Care Res, 42, pp.1266~1274 (2021)
  36. Mayourian, J., "Exosomal microRNA-21-5p mediates mesenchymal stem cell paracrine effects on human cardiac tissue contractility", Circ. Res, 122, pp.933~944 (2018)
  37. Li, C. X., "MicroRNA-21 preserves the fibrotic mechanical memory of mesenchymal stem cells", Nat. Mater, 16, pp.379~389 (2017)
  38. Cui, H., "miR-34a inhibits lung fibrosis by inducing lung fibroblast senescence", Am. J. Resp. Cell Mol, 56, pp.168~178 (2016)
  39. Glasser, S. W., "Mechanisms of lung fibrosis resolution", Am. J. Pathol, 186, pp.1066~1077 (2016)
  40. Thannickal, V. J., "Evolving concepts of apoptosis in idiopathic pulmonary fibrosis", Proc. Am. Thorac. Soc, 3, pp.350~356 (2006)
  41. Xie, T., "MicroRNA-29c prevents pulmonary fibrosis by regulating epithelial cell renewal and apoptosis", Am. J. Resp. Cell Mol, 57, pp.721~732 (2017)
  42. Gustafsson Sheppard, N., "The folate-coupled enzyme MTHFD2 is a nuclear protein and promotes cell proliferation", Sci. Rep, 5, pp.15029~ (2015)
  43. Maggini, J., "Mouse bone marrow-derived mesenchymal stromal cells turn activated macrophages into a regulatory-like profile", PLoS ONE, 5, pp.e9252~ (2010)
  44. Wang, X., "Mesenchymal stem cell-derived exosomes have altered microRNA profiles and induce osteogenic differentiation depending on the stage of differentiation", PLoS ONE, 13, pp.e0193059~ (2018)
  45. Cheng, R., "MicroRNA-98 inhibits TGF-β1-induced differentiation and collagen production of cardiac fibroblasts by targeting TGFBR1", Hum. Cell, 30, pp.192~200 (2017)
  46. Gong, M., "Mesenchymal stem cells release exosomes that transfer miRNAs to endothelial cells and promote angiogenesis", Oncotarget, 8, pp.45200~45212 (2017)
  47. Xiao, L., "MicroRNA-129-5p modulates epithelial-to-mesenchymal transition by targeting SIP1 and SOX4 during peritoneal dialysis", Lab. Invest, 95, pp.817~832 (2015)
  48. El Agha, E., "Two-way conversion between lipogenic and myogenic fibroblastic phenotypes marks the progression and resolution of lung fibrosis", Cell Stem Cell, 20, pp.261~273 (2017)
  49. Guo, J., "Lipopolysaccharide activated TLR4", NF-κB signaling pathway of fibroblasts from uterine fibroids, 2015, pp.8, 10014~10025
  50. Yu, J. -W., "MicroRNA-29b inhibits peritoneal fibrosis in a mouse model of peritoneal dialysis", Lab. Invest, 94, pp.978~990 (2014)
  51. Chen, Y., "Osteopontin promotes collagen I synthesis in hepatic stellate cells by miRNA-129-5p inhibition", Exp. Cell Res, 362, pp.343~348 (2018)
  52. Kanisicak, O., "Genetic lineage tracing defines myofibroblast origin and function in the injured heart", Nat. Commun, 7, pp.12260~ (2016)
  53. Lazarides, E., "Actin, alpha-actinin, and tropomyosin interaction in the structural organization of actin filaments in nonmuscle cells", J. Cell Biol, 68, pp.202~219 (1976)
  54. Wachsstock, D. H., "Affinity of alpha-actinin for actin determines the structure and mechanical properties of actin filament gels", Biophys. J, 65, pp.205~214 (1993)
  55. Fortier, S. M., "Myofibroblast dedifferentiation proceeds via distinct transcriptomic and phenotypic transitions", JCI Insight, 6, pp.e144799~ (2021)
  56. Dugina, V., "Focal adhesion features during myofibroblastic differentiation are controlled by intracellular and extracellular factors", J. Cell Sci, 114, pp.3285~3296 (2001)
  57. Goffin, J. M., "Focal adhesion size controls tension-dependent recruitment of α-smooth muscle actin to stress fibers", J. Cell Biol, 172, pp.259~268 (2006)
  58. Hinz, B., "α-Smooth muscle actin is crucial for focal adhesion maturation in myofibroblasts", Mol. Biol. Cell, 14, pp.2508~2519 (2003)
  59. Lemos, D. R., "Tissue-resident mesenchymal stromal cells: Implications for tissue-specific antifibrotic therapies", Sci. Transl. Med, 10, pp.eaan5174~ (2018)

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