| Autor: |
Milica Vukotić, Sunčica Kapor, Teodora Dragojević, Dragoslava Đikić, Olivera Mitrović Ajtić, Miloš Diklić, Tijana Subotički, Emilija Živković, Bojana Beleslin Čokić, Aleksandar Vojvodić, Juan F. Santibáñez, Mirjana Gotić, Vladan P. Čokić |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Experimental & Molecular Medicine |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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