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

• Published in: Experimental & molecular medicine Vol. 54; no. 3; pp. 273 - 284
• Main Authors: Vukotić, Milica, Kapor, Sunčica, Dragojević, Teodora, Đikić, Dragoslava, Mitrović Ajtić, Olivera, Diklić, Miloš, Subotički, Tijana, Živković, Emilija, Beleslin Čokić, Bojana, Vojvodić, Aleksandar, Santibáñez, Juan F., Gotić, Mirjana, Čokić, Vladan P.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2022; Springer Nature B.V; 생화학분자생물학회
• Subjects: 13/31; 631/532/2074; 631/67/1059/99; 82/29; 82/80; 96/100; 96/106; 96/21; 96/63; 96/95; Biomedical and Life Sciences; Biomedicine; Bone marrow; Bone Marrow - metabolism; Bone Marrow - pathology; Bone Marrow Cells - metabolism; Cell differentiation; Drug development; Extracellular matrix; Fibrosis; Gelatinase B; Humans; Inflammation; Janus kinase; Janus kinase 2; Kinases; Leukocytes (mononuclear); Medical Biochemistry; Mesenchymal stem cells; Mesenchymal Stem Cells - metabolism; Mesenchyme; Molecular Medicine; Neoplasms - metabolism; NF-κB protein; Patients; Phenotypes; Signal Transduction; Smad3 protein; Stat3 protein; Stem Cells; Stromal cells; Tumors; 생화학
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/s12276-022-00742-y

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. Bone marrow disorders: Combined treatment option for fibrosis The treatment of fibrosis in patients with rare bone marrow disorders could be improved with a combined therapy that targets inflammatory pathways. Myeloproliferative neoplasms (MPN) are a group of bone marrow disorders characterized by the over-production of blood cells, which can lead to fibrosis in the bone marrow. Vladan Čokić at the University of Belgrade, Serbia, and co-workers examined how stem cells known as mesenchymal stromal cells from the bone marrow contribute to MPN fibrosis. They found an increase in three pro-inflammatory signaling pathways in MPN patients, resulting in the stromal cells differentiating into cells with dysregulated extracellular matrices. The differentiated cells did not behave correctly nor degrade properly, triggering fibrosis. The team combined two drugs that target the inflammatory signaling pathways, and successfully inhibited the development of fibrosis in MPN cell cultures.