Biology subjects

Mia, M. M.

Publications and source records attributed to Mia, M. M..

2 recordsLinked to original sources

bioRxiv2025

YAP/TAZ activation in fibroblasts coordinates fibrotic remodeling, fibroinflammation, and epithelial dysfunction in pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease marked by progressive scarring with unknown causes and limited treatments. Myofibroblasts drive fibrosis by depositing excess matrix, however the mechanisms driving fibroblast-to-myofibroblast transformation and how myofibroblast-secreted factors disrupt the alveolar niche, undermining lung repair and regeneration remain poorly understood. Here we show that YAP and TAZ are activated in lung fibroblasts from pulmonary fibrosis patients and bleomycin-treated mice. Targeted deletion of Yap/Taz in fibroblasts significantly dampened the fibroinflammatory response, decreased myofibroblast activation, and ultimately resulted in attenuated fibrosis and enhanced regeneration of alveolar epithelial cells after bleomycin-induced injury. Conversely, fibroblast-specific overexpression of constitutively active YAP (YAP5SA) aggravated fibrosis by amplifying fibroinflammatory responses and simultaneously suppressing alveolar epithelial regeneration. Pharmacological inhibition of YAP/TAZ using verteporfin halted the development of bleomycin-induced fibrosis and even reversed established fibrosis in mice. Verteporfin effectively prevented fibroblast-to-myofibroblast transition and promoted collagen I degradation by lowering TIMP levels and enhancing activation of MMP1 and MMP9, demonstrating the significance of the YAP-TIMP-MMP1/9 axis in facilitating ECM breakdown. Furthermore, YAP activation in fibroblasts disrupted alveolar type II (AT2) cell homeostasis by inducing senescence through IGF1-IGF1R-mediated paracrine signaling. Blocking IGF1 signaling with a neutralizing antibody reduced the number of senescent AT2 cells, demonstrating the significance of the YAP-IGF1-IGF1R axis in maintaining alveolar epithelial cell homeostasis. Targeting YAP/TAZ may offer therapeutic strategies to mitigate pulmonary fibrosis by simultaneously mitigating pathological fibroblast activation, fibroinflammatory response, reducing AT2 cell senescence, and promoting alveolar epithelial regeneration.

cell biology↗

bioRxiv2023

YAP/TAZ are Crucial Regulator of Macrophage-mediated Pulmonary Inflammation and Fibrosis after Bleomycin-induced Injury

Pulmonary fibrosis (PF) is the most common form of end stage interstitial devastating lung disease characterized by the scarring of lung due to excessive production of extracellular matrix (ECM). Recent studies have revealed the impact of macrophages in inflammation-induced fibrosis and distinct subsets of macrophages differentially contributes to the development of PF. However, the regulatory mechanisms and proinflammatory/profibrotc behaviour of heterogeneous population of lung macrophages during fibrogenesis remain incompletely understood. Here, we demonstrate the macrophage-specific role of Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in the development of bleomycin-induced inflammation and PF in mice. Both YAP/TAZ are activated in lung macrophages of fibrotic patients and of mice after bleomycin-induced injury. Myeloid-specific genetic deletion of Yap/Taz resulted in reduced recruitment of monocyte-derived alveolar macrophages (Mo-AMs), leading to an impaired inflammatory response, reduced PF and improved regeneration of alveolar epithelial cells in bleomycin-injured lung. However, overexpression of Yap in macrophages augmented the Mo-AMs recruitment in lung leading to increased proinflammatory response, exacerbated fibrotic response and decreased regeneration of alveolar epithelial cells in bleomycin-injured lung. We demonstrate that YAP/TAZ regulate PF through the activation of macrophage recruitment driver C-C motif chemokine ligand 2 (CCL2) and blocking of CCL2 with neutralizing antibody prevented YAP-induced inflammatory and fibrotic response. We also demonstrate that YAP/TAZ regulate macrophage polarization as well as macrophage-fibroblasts crosstalk by regulating expression of Methyl-CpG-binding domain 2 (MBD2) during bleomycin-induced PF. Taken together, we show that YAP/TAZ are potent regulators of macrophage polarization, infiltration and macrophage-mediated proinflammatory/profibrotic response during PF.

molecular biology↗