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

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 Cokic 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. 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 alpha SMA-positive myofibroblasts. These cells display a dysregulated extracellular matrix with increased FN1 production and secretion of profibrotic MMP9 compared to healthy donor cells. Fibrogenic TGF beta and inflammatory JAK2/STAT3 and NF kappa B 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 NF kappa B 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 alpha SMA and FN1 expression in BM-MSCs. These results support the combined inhibition of TGF beta and inflammatory signaling to extenuate fibrosis in MPN.

Automated summary

Combining treatment options that target inflammatory pathways can improve fibrosis in patients with rare bone marrow disorders. Research has shown that an increase in inflammatory signaling pathways in patients with myeloproliferative neoplasms (MPN) leads to the differentiation of stem cells in the bone marrow into cells with dysregulated extracellular matrices, causing fibrosis. By combining two drugs that target these pathways, the development of fibrosis in MPN cell cultures can be inhibited.