141
Views
2
CrossRef citations to date
0
Altmetric
Review

Epigenetic Modifications in the Pathogenesis of Systemic Sclerosis

ORCID Icon, &
Pages 3155-3166 | Published online: 19 Mar 2022

References

  • Orvain C, Assassi S, Avouac J, et al. Systemic sclerosis pathogenesis: contribution of recent advances in genetics. Curr Opin Rheumatol. 2020;32(6):505–514. doi:10.1097/BOR.0000000000000735
  • Ferri C, Arcangeletti M-C, Caselli E, et al. Insights into the knowledge of complex diseases: environmental infectious/toxic agents as potential etiopathogenetic factors of systemic sclerosis. J Autoimmun. 2021;124:102727. doi:10.1016/j.jaut.2021.102727
  • Hughes M, Pauling JD, Armstrong-James L, et al. Gender-related differences in systemic sclerosis. Autoimmun Rev. 2020;19(4):102494. doi:10.1016/j.autrev.2020.102494
  • Zuber JP, Spertini F. Immunological basis of systemic sclerosis. Rheumatology (Oxford). 2006;45 Suppl 3:iii23–25. doi:10.1093/rheumatology/kel285
  • Pattanaik D, Brown M, Postlethwaite BC, et al. Pathogenesis of systemic sclerosis. Front Immunol. 2015;6:272. doi:10.3389/fimmu.2015.00272
  • van den Hoogen F, Khanna D, Fransen J, et al. 2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis. 2013;72(11):1747–1755. doi:10.1136/annrheumdis-2013-204424
  • Arnett FC, Cho M, Chatterjee S, et al. Familial occurrence frequencies and relative risks for systemic sclerosis (scleroderma) in three United States cohorts. Arthritis Rheum. 2001;44(6):1359–1362. doi:10.1002/1529-0131(200106)44:6<1359::AID-ART228>3.0.CO;2-S
  • Barnes J, Mayes MD. Epidemiology of systemic sclerosis: incidence, prevalence, survival, risk factors, malignancy, and environmental triggers. Curr Opin Rheumatol. 2012;24(2):165–170. doi:10.1097/BOR.0b013e32834ff2e8
  • Feghali-Bostwick C, Medsger TJ, Wright TM. Analysis of systemic sclerosis in twins reveals low concordance for disease and high concordance for the presence of antinuclear antibodies. Arthritis Rheum. 2003;48(7):1956–1963. doi:10.1002/art.11173
  • Luo Y, Wang Y, Shu Y, et al. Epigenetic mechanisms: an emerging role in pathogenesis and its therapeutic potential in systemic sclerosis. Int J Biochem Cell Biol. 2015;67:92–100. doi:10.1016/j.biocel.2015.05.023
  • Wu H, Chen Y, Zhu H, et al. The pathogenic role of dysregulated epigenetic modifications in autoimmune diseases. Front Immunol. 2019;10:2305. doi:10.3389/fimmu.2019.02305
  • Schubeler D. Function and information content of DNA methylation. Nature. 2015;517(7534):321–326. doi:10.1038/nature14192
  • Bernstein BE, Meissner A, Lander ES. The mammalian epigenome. Cell. 2007;128(4):669–681. doi:10.1016/j.cell.2007.01.033
  • Jurkowska RZ, Jeltsch A. Mechanisms and biological roles of DNA methyltransferases and DNA methylation: from past achievements to future challenges. Adv Exp Med Biol. 2016;945:1–17.
  • Rothbart SB, Strahl BD. Interpreting the language of histone and DNA modifications. Biochim Biophys Acta. 2014;1839(8):627–643. doi:10.1016/j.bbagrm.2014.03.001
  • Kouzarides T. Chromatin modifications and their function. Cell. 2007;128(4):693–705. doi:10.1016/j.cell.2007.02.005
  • Wapenaar H, Dekker FJ. Histone acetyltransferases: challenges in targeting bi-substrate enzymes. Clin Epigenetics. 2016;8:59. doi:10.1186/s13148-016-0225-2
  • Song Y, Wu F, Wu J. Targeting histone methylation for cancer therapy: enzymes, inhibitors, biological activity and perspectives. J Hematol Oncol. 2016;9(1):49. doi:10.1186/s13045-016-0279-9
  • Zhao C-N, Mao Y-M, Liu L-N, et al. Emerging role of lncRNAs in systemic lupus erythematosus. Biomed Pharmacother. 2018;106:584–592. doi:10.1016/j.biopha.2018.06.175
  • Winter J, Jung S, Keller S, et al. Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol. 2009;11(3):228–234. doi:10.1038/ncb0309-228
  • Zhang T, Hu J, Wang X, et al. MicroRNA-378 promotes hepatic inflammation and fibrosis via modulation of the NF-kappaB-TNFalpha pathway. J Hepatol. 2019;70(1):87–96. doi:10.1016/j.jhep.2018.08.026
  • Robinson EK, Covarrubias S, Carpenter S. The how and why of lncRNA function: an innate immune perspective. Biochim Biophys Acta Gene Regul Mech. 2020;1863(4):194419. doi:10.1016/j.bbagrm.2019.194419
  • Zhao M, Zhou Y, Zhu B, et al. IFI44L promoter methylation as a blood biomarker for systemic lupus erythematosus. Ann Rheum Dis. 2016;75(11):1998–2006. doi:10.1136/annrheumdis-2015-208410
  • Christmann RB, Hayes E, Pendergrass S, et al. Interferon and alternative activation of monocyte/macrophages in systemic sclerosis-associated pulmonary arterial hypertension. Arthritis Rheum. 2011;63(6):1718–1728. doi:10.1002/art.30318
  • Bos CL, van Baarsen LGM, Timmer TCG, et al. Molecular subtypes of systemic sclerosis in association with anti-centromere antibodies and digital ulcers. Genes Immun. 2009;10(3):210–218. doi:10.1038/gene.2008.98
  • Tan FK, Zhou X, Mayes MD, et al. Signatures of differentially regulated interferon gene expression and vasculotrophism in the peripheral blood cells of systemic sclerosis patients. Rheumatology (Oxford). 2006;45(6):694–702. doi:10.1093/rheumatology/kei244
  • Ramos PS, Zimmerman KD, Haddad S, et al. Integrative analysis of DNA methylation in discordant twins unveils distinct architectures of systemic sclerosis subsets. Clin Epigenetics. 2019;11(1):58. doi:10.1186/s13148-019-0652-y
  • Chen S, Pu W, Guo S, et al. Genome-wide DNA methylation profiles reveal common epigenetic patterns of interferon-related genes in multiple autoimmune diseases. Front Genet. 2019;10:223. doi:10.3389/fgene.2019.00223
  • Chen K, Liu J, Cao X. Regulation of type I interferon signaling in immunity and inflammation: a comprehensive review. J Autoimmun. 2017;83:1–11. doi:10.1016/j.jaut.2017.03.008
  • Bujor AM, El Adili F, Parvez A, et al. Fli1 downregulation in scleroderma myeloid cells has profibrotic and proinflammatory effects. Front Immunol. 2020;11:800. doi:10.3389/fimmu.2020.00800
  • Kim D, Peck A, Santer D, et al. Induction of interferon-alpha by scleroderma sera containing autoantibodies to topoisomerase I: association of higher interferon-alpha activity with lung fibrosis. Arthritis Rheum. 2008;58(7):2163–2173. doi:10.1002/art.23486
  • Assassi S, Mayes MD, Arnett FC, et al. Systemic sclerosis and lupus: points in an interferon-mediated continuum. Arthritis Rheum. 2010;62(2):589–598. doi:10.1002/art.27224
  • Wang YY, Wang Q, Sun XH, et al. DNA hypermethylation of the forkhead box protein 3 (FOXP3) promoter in CD4+ T cells of patients with systemic sclerosis. Br J Dermatol. 2014;171(1):39–47. doi:10.1111/bjd.12913
  • Matatiele P, Tikly M, Tarr G, et al. DNA methylation similarities in genes of black South Africans with systemic lupus erythematosus and systemic sclerosis. J Biomed Sci. 2015;22(1):34. doi:10.1186/s12929-015-0142-2
  • Lian X, Xiao R, Hu X, et al. DNA demethylation of CD40l in CD4+ T cells from women with systemic sclerosis: a possible explanation for female susceptibility. Arthritis Rheum. 2012;64(7):2338–2345. doi:10.1002/art.34376
  • Zhu H, Zhu C, Mi W, et al. Integration of genome-wide DNA methylation and transcription uncovered aberrant methylation-regulated genes and pathways in the peripheral blood mononuclear cells of systemic sclerosis. Int J Rheumatol. 2018;2018:7342472. doi:10.1155/2018/7342472
  • Altorok N, Tsou P-S, Coit P, et al. Genome-wide DNA methylation analysis in dermal fibroblasts from patients with diffuse and limited systemic sclerosis reveals common and subset-specific DNA methylation aberrancies. Ann Rheum Dis. 2015;74(8):1612–1620. doi:10.1136/annrheumdis-2014-205303
  • Hattori M, Yokoyama Y, Hattori T, et al. Global DNA hypomethylation and hypoxia-induced expression of the ten eleven translocation (TET) family, TET1, in scleroderma fibroblasts. Exp Dermatol. 2015;24(11):841–846. doi:10.1111/exd.12767
  • Zhang Y, Pötter S, Chen C-W, et al. Poly(ADP-ribose) polymerase-1 regulates fibroblast activation in systemic sclerosis. Ann Rheum Dis. 2018;77(5):744–751. doi:10.1136/annrheumdis-2017-212265
  • Baker FD, da Silveira W, Hazard ES, et al. Differential DNA methylation landscape in skin fibroblasts from African Americans with systemic sclerosis. Genes (Basel). 2021;12(2):129.
  • Wang Y, Fan PS, Kahaleh B. Association between enhanced type I collagen expression and epigenetic repression of the FLI1 gene in scleroderma fibroblasts. Arthritis Rheum. 2006;54(7):2271–2279. doi:10.1002/art.21948
  • Noda S, Asano Y, Nishimura S, et al. Simultaneous downregulation of KLF5 and Fli1 is a key feature underlying systemic sclerosis. Nat Commun. 2014;5(1):5797. doi:10.1038/ncomms6797
  • Henderson J, Brown M, Horsburgh S, et al. Methyl cap binding protein 2: a key epigenetic protein in systemic sclerosis. Rheumatology (Oxford). 2019;58(3):527–535. doi:10.1093/rheumatology/key327
  • He Y, Tsou P-S, Khanna D, et al. Methyl-CpG-binding protein 2 mediates antifibrotic effects in scleroderma fibroblasts. Ann Rheum Dis. 2018;77(8):1208–1218. doi:10.1136/annrheumdis-2018-213022
  • Marden G, Wan Q, Wilks J, et al. The role of the oncostatin M/OSM receptor beta axis in activating dermal microvascular endothelial cells in systemic sclerosis. Arthritis Res Ther. 2020;22(1):179. doi:10.1186/s13075-020-02266-0
  • Takagi K, Kawamoto M, Higuchi T, et al. Single nucleotide polymorphisms of the HIF1A gene are associated with susceptibility to pulmonary arterial hypertension in systemic sclerosis and contribute to SSc-PAH disease severity. Int J Rheum Dis. 2020;23(5):674–680. doi:10.1111/1756-185X.13822
  • Nakamura K, Taniguchi T, Hirabayashi M, et al. Altered properties of endothelial cells and mesenchymal stem cells underlying the development of scleroderma-like vasculopathy in KLF5 +/−;Fli-1 +/− Mice. Arthritis Rheumatol. 2020;72(12):2136–2146. doi:10.1002/art.41423
  • Zhang Y, Zhu H, Layritz F, et al. Recombinant adenosine deaminase ameliorates inflammation, vascular disease, and fibrosis in preclinical models of systemic sclerosis. Arthritis Rheumatol. 2020;72(8):1385–1395. doi:10.1002/art.41259
  • Wang Y, Kahaleh B. Epigenetic repression of bone morphogenetic protein receptor II expression in scleroderma. J Cell Mol Med. 2013;17(10):1291–1299. doi:10.1111/jcmm.12105
  • Fish JE, Marsden PA. Endothelial nitric oxide synthase: insight into cell-specific gene regulation in the vascular endothelium. Cell Mol Life Sci. 2006;63(2):144–162. doi:10.1007/s00018-005-5421-8
  • Ramahi A, Altorok N, Kahaleh B. Epigenetics and systemic sclerosis: an answer to disease onset and evolution? Eur J Rheumatol. 2020;7(Suppl 3):S147–S156. doi:10.5152/eurjrheum.2020.19112
  • Zhu HL, Du Q, Chen WL, et al. [Altered serum cytokine expression profile in systemic sclerosis and its regulatory mechanisms]. Beijing Da Xue Xue Bao Yi Xue Ban. 2019;51(4):716–722. Chinese. doi:10.19723/j.issn.1671-167X.2019.04.021
  • Wang Y, Yang Y, Luo Y, et al. Aberrant histone modification in peripheral blood B cells from patients with systemic sclerosis. Clin Immunol. 2013;149(1):46–54. doi:10.1016/j.clim.2013.06.006
  • Ciechomska M, O’Reilly S, Przyborski S, et al. Histone demethylation and toll-like receptor 8-Dependent cross-talk in monocytes promotes transdifferentiation of fibroblasts in systemic sclerosis Via Fra-2. Arthritis Rheumatol. 2016;68(6):1493–1504. doi:10.1002/art.39602
  • van der Kroef M, Castellucci M, Mokry M, et al. Histone modifications underlie monocyte dysregulation in patients with systemic sclerosis, underlining the treatment potential of epigenetic targeting. Ann Rheum Dis. 2019;78(4):529–538. doi:10.1136/annrheumdis-2018-214295
  • Tsou PS, Varga J, O’Reilly S. Advances in epigenetics in systemic sclerosis: molecular mechanisms and therapeutic potential. Nat Rev Rheumatol. 2021;17(10):596–607. doi:10.1038/s41584-021-00683-2
  • Kramer M, Dees C, Huang J, et al. Inhibition of H3K27 histone trimethylation activates fibroblasts and induces fibrosis. Ann Rheum Dis. 2013;72(4):614–620. doi:10.1136/annrheumdis-2012-201615
  • Tsou PS, Campbell P, Amin MA, et al. Inhibition of EZH2 prevents fibrosis and restores normal angiogenesis in scleroderma. Proc Natl Acad Sci U S A. 2019;116(9):3695–3702. doi:10.1073/pnas.1813006116
  • Wasson CW, Abignano G, Hermes H, et al. Long non-coding RNA HOTAIR drives EZH2-dependent myofibroblast activation in systemic sclerosis through miRNA 34a-dependent activation of NOTCH. Ann Rheum Dis. 2020;79(4):507–517. doi:10.1136/annrheumdis-2019-216542
  • Tsou P-S, Wren JD, Amin MA, et al. Histone deacetylase 5 is overexpressed in scleroderma endothelial cells and impairs angiogenesis via repression of proangiogenic factors. Arthritis Rheumatol. 2016;68(12):2975–2985. doi:10.1002/art.39828
  • Huber LC, Distler JHW, Moritz F, et al. Trichostatin A prevents the accumulation of extracellular matrix in a mouse model of bleomycin-induced skin fibrosis. Arthritis Rheum. 2007;56(8):2755–2764. doi:10.1002/art.22759
  • Maleszewska M, Vanchin B, Harmsen MC, et al. The decrease in histone methyltransferase EZH2 in response to fluid shear stress alters endothelial gene expression and promotes quiescence. Angiogenesis. 2016;19(1):9–24. doi:10.1007/s10456-015-9485-2
  • Chouri E, Servaas NH, Bekker CPJ, et al. Serum microRNA screening and functional studies reveal miR-483-5p as a potential driver of fibrosis in systemic sclerosis. J Autoimmun. 2018;89:162–170. doi:10.1016/j.jaut.2017.12.015
  • Koba S, Jinnin M, Inoue K, et al. Expression analysis of multiple microRNAs in each patient with scleroderma. Exp Dermatol. 2013;22(7):489–491. doi:10.1111/exd.12173
  • Ciechomska M, Zarecki P, Merdas M, et al. The role of microRNA-5196 in the pathogenesis of systemic sclerosis. Eur J Clin Invest. 2017;47(8):555–564. doi:10.1111/eci.12776
  • Rossato M, Affandi AJ, Thordardottir S, et al. Association of MicroRNA-618 expression with altered frequency and activation of plasmacytoid dendritic cells in patients with systemic sclerosis. Arthritis Rheumatol. 2017;69(9):1891–1902. doi:10.1002/art.40163
  • Christmann RB, Wooten A, Sampaio-Barros P, et al. miR-155 in the progression of lung fibrosis in systemic sclerosis. Arthritis Res Ther. 2016;18(1):155. doi:10.1186/s13075-016-1054-6
  • Jiang Z, Tao J-H, Zuo T, et al. The correlation between miR-200c and the severity of interstitial lung disease associated with different connective tissue diseases. Scand J Rheumatol. 2017;46(2):122–129. doi:10.3109/03009742.2016.1167950
  • Wuttge DM, Carlsen AL, Teku G, et al. Specific autoantibody profiles and disease subgroups correlate with circulating micro-RNA in systemic sclerosis. Rheumatology (Oxford). 2015;54(11):2100–2107. doi:10.1093/rheumatology/kev234
  • Liakouli V, Cipriani P, Di Benedetto P, et al. Epidermal growth factor like-domain 7 and miR-126 are abnormally expressed in diffuse systemic sclerosis fibroblasts. Sci Rep. 2019;9(1):4589. doi:10.1038/s41598-019-39485-8
  • Stypinska B, Wajda A, Walczuk E, et al. The serum cell-free microRNA expression profile in MCTD, SLE, SSc, and RA patients. J Clin Med. 2020;9(1):161. doi:10.3390/jcm9010161
  • Jafarinejad-Farsangi S, Gharibdoost F, Farazmand A, et al. MicroRNA-21 and microRNA-29a modulate the expression of collagen in dermal fibroblasts of patients with systemic sclerosis. Autoimmunity. 2019;52(3):108–116. doi:10.1080/08916934.2019.1621856
  • Zhu H, Luo H, Li Y, et al. MicroRNA-21 in scleroderma fibrosis and its function in TGF-beta-regulated fibrosis-related genes expression. J Clin Immunol. 2013;33(6):1100–1109. doi:10.1007/s10875-013-9896-z
  • O’Reilly S. miRNA-29a in systemic sclerosis: a valid target. Autoimmunity. 2015;48(8):511–512. doi:10.3109/08916934.2015.1077232
  • Maurer B, Stanczyk J, Jüngel A, et al. MicroRNA-29, a key regulator of collagen expression in systemic sclerosis. Arthritis Rheum. 2010;62(6):1733–1743. doi:10.1002/art.27443
  • Jafarinejad-Farsangi S, Farazmand A, Mahmoudi M, et al. MicroRNA-29a induces apoptosis via increasing the Bax: bcl-2 ratio in dermal fibroblasts of patients with systemic sclerosis. Autoimmunity. 2015;48(6):369–378. doi:10.3109/08916934.2015.1030616
  • Jafarinejad-Farsangi S, Farazmand A, Gharibdoost F, et al. Inhibition of MicroRNA-21 induces apoptosis in dermal fibroblasts of patients with systemic sclerosis. Int J Dermatol. 2016;55(11):1259–1267. doi:10.1111/ijd.13308
  • Mullenbrock S, Liu F, Szak S, et al. Systems analysis of transcriptomic and proteomic profiles identifies novel regulation of fibrotic programs by miRNAs in pulmonary fibrosis fibroblasts. Genes (Basel). 2018;9(12):588. doi:10.3390/genes9120588
  • Henderson J, Distler J, O’Reilly S. The role of epigenetic modifications in systemic sclerosis: a druggable target. Trends Mol Med. 2019;25(5):395–411. doi:10.1016/j.molmed.2019.02.001
  • Long H, Wang X, Chen Y, et al. Dysregulation of microRNAs in autoimmune diseases: pathogenesis, biomarkers and potential therapeutic targets. Cancer Lett. 2018;428:90–103. doi:10.1016/j.canlet.2018.04.016
  • Wermuth PJ, Piera-Velazquez S, Rosenbloom J, et al. Existing and novel biomarkers for precision medicine in systemic sclerosis. Nat Rev Rheumatol. 2018;14(7):421–432. doi:10.1038/s41584-018-0021-9
  • Bagnato G, Roberts WN, Roman J, et al. A systematic review of overlapping microRNA patterns in systemic sclerosis and idiopathic pulmonary fibrosis. Eur Respir Rev. 2017;26(144):160125. doi:10.1183/16000617.0125-2016
  • Zuo X, Zhang L, Luo H, et al. Systematic approach to understanding the pathogenesis of systemic sclerosis. Clin Genet. 2017;92(4):365–371. doi:10.1111/cge.12946
  • Artlett CM, Sassi-Gaha S, Hope JL, et al. Mir-155 is overexpressed in systemic sclerosis fibroblasts and is required for NLRP3 inflammasome-mediated collagen synthesis during fibrosis. Arthritis Res Ther. 2017;19(1):144. doi:10.1186/s13075-017-1331-z
  • Zhang L, Wu H, Zhao M, et al. Meta-analysis of differentially expressed microRNAs in systemic sclerosis. Int J Rheum Dis. 2020;23(10):1297–1304. doi:10.1111/1756-185X.13924
  • He Y, Liu H, Wang S, Chen Y. In silico detection and characterization of microRNAs and their target genes in microRNA microarray datasets from patients with systemic sclerosis-interstitial lung disease. DNA Cell Biol. 2019;38(9):933–944. doi:10.1089/dna.2019.4780
  • Hoffmann-Vold AM, Weigt SS, Palchevskiy V, et al. Augmented concentrations of CX3CL1 are associated with interstitial lung disease in systemic sclerosis. PLoS One. 2018;13(11):e0206545. doi:10.1371/journal.pone.0206545
  • Rajasekaran S, Vaz M, Reddy SP. Fra-1/AP-1 transcription factor negatively regulates pulmonary fibrosis in vivo. PLoS One. 2012;7(7):e41611. doi:10.1371/journal.pone.0041611
  • Mariotti B, Servaas NH, Rossato M, et al. The long non-coding RNA NRIR drives IFN-response in monocytes: implication for systemic sclerosis. Front Immunol. 2019;10:100. doi:10.3389/fimmu.2019.00100
  • Abd-Elmawla MA, Hassan M, Elsabagh YA, et al. Deregulation of long noncoding RNAs ANCR, TINCR, HOTTIP and SPRY4-IT1 in plasma of systemic sclerosis patients: SPRY4-IT1 as a novel biomarker of scleroderma and its subtypes. Cytokine. 2020;133:155124. doi:10.1016/j.cyto.2020.155124
  • Takata M, Pachera E, Frank-Bertoncelj M, et al. OTUD6B-AS1 might be a novel regulator of apoptosis in systemic sclerosis. Front Immunol. 2019;10:1100. doi:10.3389/fimmu.2019.01100
  • Pachera E, Assassi S, Salazar GA, et al. Long noncoding RNA H19X is a key mediator of TGF-beta-driven fibrosis. J Clin Invest. 2020;130(9):4888–4905. doi:10.1172/JCI135439
  • Muntyanu A, Le M, Ridha Z, et al. Novel role of long non-coding RNAs in autoimmune cutaneous disease. J Cell Commun Signal. 2021. doi:10.1007/s12079-021-00639-x
  • Wang Z, Jinnin M, Nakamura K, et al. Long non-coding RNA TSIX is upregulated in scleroderma dermal fibroblasts and controls collagen mRNA stabilization. Exp Dermatol. 2016;25(2):131–136. doi:10.1111/exd.12900
  • Wasson CW, Ross RL, Wells R, et al. Long non-coding RNA HOTAIR induces GLI2 expression through Notch signalling in systemic sclerosis dermal fibroblasts. Arthritis Res Ther. 2020;22(1):286. doi:10.1186/s13075-020-02376-9
  • Dolcino M, Tinazzi E, Puccetti A, et al. In systemic sclerosis, a unique long non coding RNA regulates genes and pathways involved in the three main features of the disease (vasculopathy, fibrosis and autoimmunity) and in carcinogenesis. J Clin Med. 2019;8(3):320. doi:10.3390/jcm8030320
  • Servaas NH, Mariotti B, van der Kroef M, et al. Characterization of long non-coding RNAs in systemic sclerosis monocytes: a potential role for PSMB8-AS1 in altered cytokine secretion. Int J Mol Sci. 2021;22(9):4365. doi:10.3390/ijms22094365
  • Wermuth PJ, Piera-Velazquez S, Jimenez SA. Exosomes isolated from serum of systemic sclerosis patients display alterations in their content of profibrotic and antifibrotic microRNA and induce a profibrotic phenotype in cultured normal dermal fibroblasts. Clin Exp Rheumatol. 2017;35 Suppl 106(4):21–30.
  • Fang S, Xu C, Zhang Y, et al. Umbilical cord-derived mesenchymal stem cell-derived exosomal MicroRNAs suppress myofibroblast differentiation by inhibiting the transforming growth factor-beta/SMAD2 pathway during wound healing. Stem Cells Transl Med. 2016;5(10):1425–1439. doi:10.5966/sctm.2015-0367