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Inhibition of proinflammatory signaling impairs fibrosis of bone marrow mesenchymal stromal cells in myeloproliferative neoplasms

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2022
Inhibition_of_proinflammatory_signaling_impairs_fibrosis_pub_2022.pdf (12.21Mb)
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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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 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.

Source:
Experimental & Molecular Medicine, 2022, 54, 3, 273-284
Publisher:
  • Korean Society of Medical Biochemistry and Molecular Biology [Associate Organisation]
  • Springer Nature [Commercial Publisher]
Funding / projects:
  • Ministry of Education, Science and Technological Development, Republic of Serbia, Grant no. 200015 (University of Belgrade, Institute for Medical Research) (RS-200015)

DOI: 10.1038/s12276-022-00742-y

ISSN: 1226-3613

[ Google Scholar ]
URI
http://rimi.imi.bg.ac.rs/handle/123456789/1226
Collections
  • Radovi istraživača / Researchers' publications
Institution/Community
Institut za medicinska istraživanja
TY  - 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 . .

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