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

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.

miR‐146a−/− mice model reveals that NF‐κB inhibition reverts inflammation‐driven myelofibrosis‐like phenotype

“…With a similar approach than we 52 and other groups 53 previously used to mimic the BM microenvironment in the context of MPN with driver mutations, we established the co‐culture of BM‐derived mesenchymal stromal cells (HS‐27A) with or without JAK2 ‐mutated human cells. In consonance with reticulin fibrosis results observed in the miR‐146a KO mice model, besides demonstrating the lack of efficacy of ruxolitinib in monotherapy on collagen expression, 52 our results corroborate the benefits of inhibiting NF‐κB signaling on the reversion of fibrosis, underlining their involvement in MPN fibrosis.…”

Mesenchymal Stromal Cells in Myeloid Malignancies: Immunotherapeutic Opportunities

“…Moreover, the inflammatory JAK2/STAT3 signaling pathway significantly contributed to TGF-β-induced fibrosis of BM-MSC. In this sense, combined inhibition of JAK1/2 and SMAD3 synergistically mitigates BM-MSCs fibrosis [187]. Remarkably, human MPN and mice harboring HSCs with JAK2 V617F display decreased BM innervation, including sympathetic nerve fibers and Schwann cells, and reduced nestin + MSCs.…”

Mesenchymal stromal cells in myeloid malignancies: Immunotherapeutic opportunities

“…Moreover, the inflammatory JAK2/STAT3 signaling pathway significantly contributed to TGF-β-induced fibrosis of BM-MSC. In this sense, combined inhibition of JAK1/2 and SMAD3 synergistically mitigates BM-MSCs fibrosis [ 187 ].…”