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Inhibition of proinflammatory signaling impairs fibrosis of bone marrow mesenchymal stromal cells in myeloproliferative neoplasms
dc.creator | Vukotić, Milica | |
dc.creator | Kapor, Sunčica | |
dc.creator | Dragojević, Teodora | |
dc.creator | Đikić, Dragoslava | |
dc.creator | Mitrović-Ajtić, Olivera | |
dc.creator | Diklić, Miloš | |
dc.creator | Subotički, Tijana | |
dc.creator | Živković, Emilija | |
dc.creator | Beleslin-Čokić, Bojana | |
dc.creator | Vojvodić, Aleksandar | |
dc.creator | Santibanez, Juan F. | |
dc.creator | Gotić, Mirjana | |
dc.creator | Čokić, Vladan | |
dc.date.accessioned | 2022-03-14T13:18:46Z | |
dc.date.available | 2022-03-14T13:18:46Z | |
dc.date.issued | 2022 | |
dc.identifier.issn | 1226-3613 | |
dc.identifier.uri | http://rimi.imi.bg.ac.rs/handle/123456789/1226 | |
dc.description.abstract | Although bone marrow-derived mesenchymal stromal cells (BM-MSCs) have been identified as a major cellular source of fibrosis, the exact molecular mechanism and signaling pathways involved have not been identified thus far. Here, we show that BM-MSCs contribute to fibrosis in myeloproliferative neoplasms (MPNs) by differentiating into αSMA-positive myofibroblasts. These cells display a dysregulated extracellular matrix with increased FN1 production and secretion of profibrotic MMP9 compared to healthy donor cells. Fibrogenic TGFβ and inflammatory JAK2/STAT3 and NFκB signaling pathway activity is increased in BM-MSCs of MPN patients. Moreover, coculture with mononuclear cells from MPN patients was sufficient to induce fibrosis in healthy BM-MSCs. Inhibition of JAK1/2, SMAD3 or NFκB significantly reduced the fibrotic phenotype of MPN BM-MSCs and was able to prevent the development of fibrosis induced by coculture of healthy BM-MSCs and MPN mononuclear cells with overly active JAK/STAT signaling, underlining their involvement in fibrosis. Combined treatment with JAK1/2 and SMAD3 inhibitors showed synergistic and the most favorable effects on αSMA and FN1 expression in BM-MSCs. These results support the combined inhibition of TGFβ and inflammatory signaling to extenuate fibrosis in MPN. | |
dc.publisher | Korean Society of Medical Biochemistry and Molecular Biology [Associate Organisation] | |
dc.publisher | Springer Nature [Commercial Publisher] | |
dc.relation | info:eu-repo/grantAgreement/MESTD/inst-2020/200015/RS// | |
dc.rights | openAccess | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | |
dc.source | Experimental & Molecular Medicine | |
dc.title | Inhibition of proinflammatory signaling impairs fibrosis of bone marrow mesenchymal stromal cells in myeloproliferative neoplasms | |
dc.type | article | |
dc.rights.license | BY | |
dc.citation.epage | 284 | |
dc.citation.issue | 3 | |
dc.citation.rank | aM21~ | |
dc.citation.spage | 273 | |
dc.citation.volume | 54 | |
dc.identifier.doi | 10.1038/s12276-022-00742-y | |
dc.identifier.fulltext | http://rimi.imi.bg.ac.rs/bitstream/id/2710/Inhibition_of_proinflammatory_signaling_impairs_fibrosis_pub_2022.pdf | |
dc.type.version | publishedVersion |