Hippo signaling impairs alveolar epithelial regeneration in pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) consists of fibrotic alveolar remodeling and progressive loss of pulmonary function. Genetic and experimental evidence indicate that chronic alveolar injury and failure to properly repair the respiratory epithelium are intrinsic to IPF pathogenesis. Loss of alveolar type 2 (AT2) stem cells or mutations that either impair their self-renewal and/or impair their differentiation into AT1 cells can serve as a trigger of pulmonary fibrosis. Recent reports indicate increased YAP activity in respiratory epithelial cells in IPF lungs. Individual IPF epithelial cells with aberrant YAP activation in bronchiolized regions frequently co-express AT1, AT2, conducting airway selective markers and even mesenchymal or EMT markers, demonstrating 'indeterminate' states of differentiation and suggesting that aberrant YAP signaling might promote pulmonary fibrosis. Yet, Yap and Taz have recently also been shown to be important for AT1 cell maintenance and alveolar epithelial regeneration after Streptococcus pneumoniae induced injury. To investigate how epithelial Yap/Taz might promote pulmonary fibrosis or drive alveolar epithelial regeneration, we inactivated the Hippo pathway in AT2 stem cells resulting in increased nuclear Yap/Taz and found that this promotes their alveolar regenerative capacity and reduces pulmonary fibrosis following bleomycin injury by pushing them along the AT1 cell lineage. Vice versa, inactivation of both Yap1 and Wwtr1 (encoding Taz) or Wwtr1 alone in AT2 cells stem cells impaired alveolar epithelial regeneration and resulted in increased pulmonary fibrosis upon bleomycin injury. Interestingly, inactivation of only Yap1 in AT2 stem cells promoted alveolar epithelial regeneration and reduced pulmonary fibrosis. Together, these data suggest that epithelial Yap promotes, and epithelial Taz reduces pulmonary fibrosis suggesting that targeting Yap but not Taz mediated transcription might help promote AT1 cell regeneration and treat pulmonary fibrosis.

Screening of factors inducing alveolar type 1 epithelial cells using human pluripotent stem cells

“…Indeed, Alpelisib and AZD6482 did not reach hit criteria but increased HiBiT values (1.87- and 1.65-fold change vs DMSO, respectively), which helped identify the involvement of PI3K/AKT signaling in AT1 cell differentiation. Wnt signaling inhibitor and YAP/TAZ signaling activator were expected to be hits in the compound screening since we previously reported that XAV939, a suppressor of the canonical Wnt signaling via inhibition of tankyrase, promoted iAT1 cell differentiation from iAT2 cells in FD-AOs, and YAP/TAZ signaling is essential in AT1 cell differentiation ( DiGiovanni et al., 2023 ; Gokey et al., 2021 ; Kanagaki et al., 2021 ; LaCanna et al., 2019 ; Liu et al., 2016 ; Nguyen et al., 2021 ; Warren et al., 2023 ). In the present study, we removed CHIR99021, which activates the canonical Wnt signaling via inhibition of GSK3β, from the medium before screening.…”

“…Signals that regulate the differentiation of AT2-to-AT1 cells have been explored. Among them, the activation of yes-associated protein and the transcriptional coactivator with PDZ-binding motif (YAP/TAZ) signaling is essential for AT1 cell differentiation ( DiGiovanni et al., 2023 ; Gokey et al., 2021 ; LaCanna et al., 2019 ; Liu et al., 2016 ; Nguyen et al., 2021 ; Penkala et al., 2021 ; Warren et al., 2023 ). Other signals such as Notch, transforming growth factor β (TGF-β), Wnt, and p53 are also involved in AT2-to-AT1 cell differentiation ( Finn et al., 2019 ; Frank et al., 2016 ; Kaiser et al., 2023 ; Kanagaki et al., 2021 ; Zhao et al., 2013 ).…”

Influence of intersignaling crosstalk on the intracellular localization of YAP/TAZ in lung cells

“…The Hippo signaling pathway is an important participant in lung cellular homeostasis and is described in detail in both healthy and pathological states [ 11 – 13 ]. The transcriptional coactivators of the Hippo pathway are YAP and its homolog TAZ; they regulate target gene expression and, as a consequence, proliferation, differentiation, and cell viabilty.…”

Idiopathic pulmonary fibrosis: Addressing the current and future therapeutic advances along with the role of Sotatercept in the management of pulmonary hypertension

“…The process is thought to be an accumulation of extracellular matrix (ECM) over the long term. Permanent inhibition of oxygen transfer occurs due to this accumulation, which causes shortness of breath 1–5 …”

“…Permanent inhibition of oxygen transfer occurs due to this accumulation, which causes shortness of breath. [1][2][3][4][5] The precise causes of histopathological changes in IPF remain unknown. IPF is associated with various risk factors like smoking, infections, pollutants, genetics, and drugs.…”