miR-210 promotes IPF fibroblast proliferation in response to hypoxia

Abstract

Idiopathic pulmonary fibrosis (IPF) is characterized by the relentless spread of fibroblasts from scarred alveoli into adjacent alveolar units, resulting in progressive hypoxia and death by asphyxiation. Although hypoxia is a prominent clinical feature of IPF, the role of hypoxia as a driver of the progressive fibrotic nature of the disease has not been explored. Here, we demonstrate that hypoxia robustly stimulates the proliferation of IPF fibroblasts. We found that miR-210 expression markedly increases in IPF fibroblasts in response to hypoxia and that knockdown of miR-210 decreases hypoxia-induced IPF fibroblast proliferation. Silencing hypoxia-inducible factor (HIF)-2α inhibits the hypoxia-mediated increase in miR-210 expression and blocks IPF fibroblast proliferation, indicating that HIF-2α is upstream of miR-210. We demonstrate that the miR-210 downstream target MNT is repressed in hypoxic IPF fibroblasts and that knockdown of miR-210 increases MNT expression. Overexpression of MNT inhibits hypoxia-induced IPF fibroblast proliferation. Together, these data indicate that hypoxia potently stimulates miR-210 expression via HIF-2α, and high miR-210 expression drives fibroblast proliferation by repressing the c-myc inhibitor, MNT. In situ analysis of IPF lung tissue demonstrates miR-210 expression in a similar distribution with HIF-2α and the hypoxic marker carbonic anhydrase-IX in cells within the IPF fibrotic reticulum. Our results raise the possibility that a pathological feed-forward loop exists in the IPF lung, in which hypoxia promotes IPF fibroblast proliferation via stimulation of miR-210 expression, which in turn worsens hypoxia.

Tumor-Promoting Effects of Myeloid-Derived Suppressor Cells Are Potentiated by Hypoxia-Induced Expression of miR-210

“…It participates in the hypoxic response of endothelial cells (26) and fibroblasts (27). More importantly, in human Tregs, miR-210 negatively regulated FOXP3 expression (28).…”

The code of non-coding RNAs in lung fibrosis

“…They showed that knockdown of miR-210 diminishes hypoxia induced proliferation of IPF fibroblasts. They also showed that HIF-2α, but not HIF-1α, regulates miR-210 expression by directly binding to the hypoxic response element (HRE) in the miR-210 promoter [82]. Mechanistically, miR-210 promoted IPF fibroblast proliferation by targeting MNT, a c-myc suppressor that can inhibit cell cycle entry and proliferation [82,83].…”

“…They also showed that HIF-2α, but not HIF-1α, regulates miR-210 expression by directly binding to the hypoxic response element (HRE) in the miR-210 promoter [82]. Mechanistically, miR-210 promoted IPF fibroblast proliferation by targeting MNT, a c-myc suppressor that can inhibit cell cycle entry and proliferation [82,83]. Moreover, they found that miR-210 expression is located to cells that are also positive with hypoxic marker carbonic anhydrase-IX and HIF-2α within the IPF fibrotic reticulum, indicating an interactive relationship among miR-210, hypoxia and IPF pathogenesis [82].…”

“…Mechanistically, miR-210 promoted IPF fibroblast proliferation by targeting MNT, a c-myc suppressor that can inhibit cell cycle entry and proliferation [82,83]. Moreover, they found that miR-210 expression is located to cells that are also positive with hypoxic marker carbonic anhydrase-IX and HIF-2α within the IPF fibrotic reticulum, indicating an interactive relationship among miR-210, hypoxia and IPF pathogenesis [82]. Taken together, these findings suggest that miR-210 is one of the hypoxamirs that mediates the profibrotic roles of hypoxia by promoting profibrotic phenotype of IPF fibroblasts in the lungs.…”

Increased hemoglobin-oxygen affinity ameliorates bleomycin-induced hypoxemia and pulmonary fibrosis

“…; Bodempudi et al. ). Dyspnea or hypoxemia induced physical activity limitation is a prominent driver of QOL impairment among IPF patients (Swigris et al.…”