Mesenchymal Deficiency of Notch1 Attenuates Bleomycin-Induced Pulmonary Fibrosis

Abstract

Notch signaling pathway is involved in the regulation of cell fate, differentiation, proliferation, and apoptosis in development and disease. Previous studies suggest the importance of Notch1 in myofibroblast differentiation in lung alveogenesis and fibrosis. However, direct in vivo evidence of Notch1-mediated myofibroblast differentiation is lacking. In this study, we examined the effects of conditional mesenchymal-specific deletion of Notch1 on pulmonary fibrosis. Crossing of mice bearing the floxed Notch1 gene with α2(I) collagen enhancer-Cre-ER(T)-bearing mice successfully generated progeny with a conditional knockout (CKO) of Notch1 in collagen I-expressing (mesenchymal) cells on treatment with tamoxifen (Notch1 CKO). Because Notch signaling is known to be activated in the bleomycin model of pulmonary fibrosis, control and Notch1 CKO mice were analyzed for their responses to bleomycin treatment. The results showed significant attenuation of pulmonary fibrosis in CKO relative to control mice, as examined by collagen deposition, myofibroblast differentiation, and histopathology. However, there were no significant differences in inflammatory or immune cell influx between bleomycin-treated CKO and control mouse lungs. Analysis of isolated lung fibroblasts confirmed absence of Notch1 expression in cells from CKO mice, which contained fewer myofibroblasts and significantly diminished collagen I expression relative to those from control mice. These findings revealed an essential role for Notch1-mediated myofibroblast differentiation in the pathogenesis of pulmonary fibrosis.

Endothelial sirtuin 1 inactivation enhances capillary rarefaction and fibrosis following kidney injury through Notch activation

“…On the other hand, deletion of Notch1 in collagen-producing cells suppresses myofibroblast differentiation and fibrosis in the lung [30]. This implicates, together with our findings, that DLL4-Notch1 cascade regulates myofibroblast differentiation and fibrosis during tissue injury.…”

Cancer driver mutations in endometriosis: Variations on the major theme of fibrogenesis

“…and TGF-β1 are shown to be responsible for the induction of Hes1, an important gene for HSC activation. 350 In contrast, conditional ablation of NOTCH1 attenuates pulmonary fibrosis through reduced myofibroblast activation and expression of α-SMA and collagen I, 351 and inhibition of Notch signaling attenuates Schistosomiasis-induced hepatic fibrosis via suppression of macrophage M2 polarization. 347 In endometriosis, Musashi-1, a positive regulator of NOTCH1 through suppression of NOTCH1 inhibitor NUMB, has been shown to be elevated.…”

Notch in fibrosis and as a target of anti-fibrotic therapy

“…Impairment of Notch signaling due to impaired fucosylation in FXKO mice inhibits myofibroblast differentiation and bleomycin induced fibrosis [18]. Additionally mesenchymal-specific conditional Notch1 deficient mice exhibited significant reduction of pulmonary fibrosis in the same bleomycin model [81]. …”