Inhibition of proinflammatory signaling impairs fibrosis of bone marrow mesenchymal stromal cells in myeloproliferative neoplasms
Authors
Vukotić, Milica
Kapor, Sunčica

Dragojević, Teodora

Đikić, Dragoslava
Mitrović-Ajtić, Olivera

Diklić, Miloš

Subotički, Tijana

Živković, Emilija

Beleslin-Čokić, Bojana
Vojvodić, Aleksandar
Santibanez, Juan

Gotić, Mirjana
Čokić, Vladan

Article (Published version)
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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 sig...naling, 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.
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Experimental & Molecular Medicine, 2022, 54, 3, 273-284Publisher:
- Korean Society of Medical Biochemistry and Molecular Biology [Associate Organisation]
- Springer Nature [Commercial Publisher]
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Institut za medicinska istraživanjaTY - JOUR AU - Vukotić, Milica AU - Kapor, Sunčica AU - Dragojević, Teodora AU - Đikić, Dragoslava AU - Mitrović-Ajtić, Olivera AU - Diklić, Miloš AU - Subotički, Tijana AU - Živković, Emilija AU - Beleslin-Čokić, Bojana AU - Vojvodić, Aleksandar AU - Santibanez, Juan AU - Gotić, Mirjana AU - Čokić, Vladan PY - 2022 UR - http://rimi.imi.bg.ac.rs/handle/123456789/1226 AB - 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. PB - Korean Society of Medical Biochemistry and Molecular Biology [Associate Organisation] PB - Springer Nature [Commercial Publisher] T2 - Experimental & Molecular Medicine T1 - Inhibition of proinflammatory signaling impairs fibrosis of bone marrow mesenchymal stromal cells in myeloproliferative neoplasms EP - 284 IS - 3 SP - 273 VL - 54 DO - 10.1038/s12276-022-00742-y ER -
@article{ author = "Vukotić, Milica and Kapor, Sunčica and Dragojević, Teodora and Đikić, Dragoslava and Mitrović-Ajtić, Olivera and Diklić, Miloš and Subotički, Tijana and Živković, Emilija and Beleslin-Čokić, Bojana and Vojvodić, Aleksandar and Santibanez, Juan and Gotić, Mirjana and Čokić, Vladan", year = "2022", 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.", publisher = "Korean Society of Medical Biochemistry and Molecular Biology [Associate Organisation], Springer Nature [Commercial Publisher]", journal = "Experimental & Molecular Medicine", title = "Inhibition of proinflammatory signaling impairs fibrosis of bone marrow mesenchymal stromal cells in myeloproliferative neoplasms", pages = "284-273", number = "3", volume = "54", doi = "10.1038/s12276-022-00742-y" }
Vukotić, M., Kapor, S., Dragojević, T., Đikić, D., Mitrović-Ajtić, O., Diklić, M., Subotički, T., Živković, E., Beleslin-Čokić, B., Vojvodić, A., Santibanez, J., Gotić, M.,& Čokić, V.. (2022). Inhibition of proinflammatory signaling impairs fibrosis of bone marrow mesenchymal stromal cells in myeloproliferative neoplasms. in Experimental & Molecular Medicine Korean Society of Medical Biochemistry and Molecular Biology [Associate Organisation]., 54(3), 273-284. https://doi.org/10.1038/s12276-022-00742-y
Vukotić M, Kapor S, Dragojević T, Đikić D, Mitrović-Ajtić O, Diklić M, Subotički T, Živković E, Beleslin-Čokić B, Vojvodić A, Santibanez J, Gotić M, Čokić V. Inhibition of proinflammatory signaling impairs fibrosis of bone marrow mesenchymal stromal cells in myeloproliferative neoplasms. in Experimental & Molecular Medicine. 2022;54(3):273-284. doi:10.1038/s12276-022-00742-y .
Vukotić, Milica, Kapor, Sunčica, Dragojević, Teodora, Đikić, Dragoslava, Mitrović-Ajtić, Olivera, Diklić, Miloš, Subotički, Tijana, Živković, Emilija, Beleslin-Čokić, Bojana, Vojvodić, Aleksandar, Santibanez, Juan, Gotić, Mirjana, Čokić, Vladan, "Inhibition of proinflammatory signaling impairs fibrosis of bone marrow mesenchymal stromal cells in myeloproliferative neoplasms" in Experimental & Molecular Medicine, 54, no. 3 (2022):273-284, https://doi.org/10.1038/s12276-022-00742-y . .