Gli signaling pathways play critical

Gli signaling pathways play critical roles in embryonic and postnatal lung development [22]. Many reports suggest that wound healing and fibrotic diseases involve activation of pathways used during development [23]. In the adult lung, Gli signaling activity measured by Gli1 expression is restricted to peribronchial and perivascular areas in bronchovascular bundles but is absent in Mesoridazine [24,25]. In bleomycin-induced lung fibrosis, however, activated fibroblasts in scars have Gli signaling activity, suggesting that the Gli signaling pathway is activated in scar-forming fibroblasts in alveoli after injury [24]. This is consistent with the present study, which suggests Gli proteins are upstream regulators of activated fibroblasts in fibrotic phase. How Gli signalings is activated in activated fibroblasts is still unknown. Inhibiting canonical hedgehog pathways does not attenuate bleomycin-induced lung fibrosis [17,24], suggesting that Gli pathway activation in fibrotic lesions is mainly caused by a non-canonical pathway. A previous study showed that Gli signaling inhibition by GANT61 reduces collagen deposition in lung fibrosis [17]. In the present study, we revealed that GANT61 treatment also alters the pattern of scar formation. Pulmonary fibrosis is associated with spatially dynamic remodeling of alveoli, which results in loss of surface area of alveoli as well as reduction of total lung volume [3]. How alveoli undergo such remodeling after injury is an important question to understand the pathology of pulmonary fibrosis. Our data suggest that attenuating fibroblast activation in injured alveolar airspaces suppresses massive scar formation and preserves alveolar surface area. This raises a point that preserving alveolar airspaces, rather than just reducing ECM deposition, could be another strategy for treating pulmonary fibrosis. It is worth investigating if the effect on respiratory function by pirfenidone treatment is mediated by the preservation of alveolar airspaces through Gli signaling inhibition [11].
Author contributions
Acknowledgments We thank Shun-ichi Fujita, Shin Aoki, Ai Yamashita, and other colleagues in the lab for their assistance with the experiments presented in this study. This research was supported by AMED, CREST, Japan and JSPS KAKENHI Grant-in-Aid for Scientific Research on Innovative Areas 17H06392. T.T. was supported by a Japan Society for the Promotion of Science fellowship (DC1). T.T. and S.S. were supported by The University of Tokyo Life Innovation Leading Graduate School, Graduate Program for Leaders in Life Innovation.
Introduction The mature multinucleated skeletal myofiber is formed by the fusion of mononucleated myoblasts during development. Skeletal myogenesis can be described as a two-step process: a proliferation phase, when myoblast cells divide; and a differentiation phase, when post-mitotic myoblasts fuse to form fully contractile multinucleated myofibers. An intricate network of signaling pathways, including Wnt, Notch, bone morphogenetic proteins (BMP) and Sonic Hedgehog (Shh), regulates this complex two-step process. Shh has been implicated in both the proliferative and the differentiation steps of myogenesis [[1], [2], [3], [4], [5]]. Indeed, the graft of Shh-secreting cells into the presumptive first branchial arch region, at 5 somite stage, was able to increase the territory of MyoD expression [6]. When activated, the Shh signaling pathway triggers a chain of events in target cells, leading to the activation of specific genes by the glioma-associated oncogene homolog (Gli) family of zinc finger transcription factors [7,8]. Upon secretion, Shh binds to the transmembrane receptor proteins, Patched-1 and Patched-2, in target cells [9]. Patched-1 inhibit downstream signaling of the transmembrane protein Smoothened (Smo) via an indirect mechanism not yet described. Patched-1 inhibition of Smo results in the nuclear localization of Gli proteins, which are the terminal effectors of the Shh signaling. In vertebrates, there are three Gli transcription factors (Gli-1, Gli-2 and Gli-3). Gli-1 is the only full-length transcriptional activator whereas Gli-2 and Gli-3 act as either positive or negative regulators. In the absence of Shh, Suppressor of Fused (SUFU) negatively regulates the pathway by directly binding to Gli proteins and anchoring them in the cytoplasm preventing the activation of Gli target genes.