Significance of Stat3 Signaling in Epithelial Cell Differentiation of Fetal Mouse Lungs

Abstract

To study the significance of signal transducer and activator of transcription (Stat) 3 in lung epithelial development of fetal mice, we examined fetal mouse lungs, focusing on the expression of Clara cell secretory protein (CCSP), Forkhead box protein J1 (Foxj1), calcitonin gene-related peptide (CGRP), phosphorylated Stat3 (Tyr705), and hairy/enhancer of split (Hes) 1, and observed cultured fetal lungs upon treatment with IL-6, a Stat3 activator, or cucurbitacin I, a Stat3 inhibitor. Moreover, the interaction of Stat3 signaling and Hes1 was studied using Hes1 gene-deficient mice. Phosphorylated Stat3 was detected in fetal lungs and, immunohistochemically, phosphorylated Stat3 was found to be co-localized in developing Clara cells, but not in ciliated cells. In the organ culture studies, upon treatment with IL-6, quantitative RT-PCR revealed that CCSP mRNA increased with increasing Stat3 phosphorylation, while cucurbitacin I decreased Hes1, CCSP, Foxj1 and CGRP mRNAs with decreasing Stat3 phosphorylation. In the lungs of Hes1 gene-deficient mice, Stat3 phosphorylation was not markedly different from wild-type mice, the expression of CCSP and CGRP was enhanced, and the treatment of IL-6 or cucurbitacin I induced similar effects on mouse lung epithelial differentiation regardless of Hes1 expression status. Stat3 signaling acts in fetal mouse lung development, and seems to regulate Clara cell differentiation positively. Hes1 could regulate Clara cell differentiation in a manner independent from Stat3 signaling.

An RNAi Screen Reveals an Essential Role for HIPK4 in Human Skin Epithelial Differentiation from iPSCs

“…PTEN signaling is involved in epithelial migration, proliferation, and morphogenesis ( Castilho et al., 2013 , Georgescu et al., 2014 ). Although IL-6 signaling (and its downstream target STAT3 ) was recently shown to be involved in lung epithelial development, its role in skin epithelial development is yet to be clarified ( Kameyama et al., 2017 ). Of note, IL-6 can increase the phosphorylation of K18 in epithelial cells ( Wang et al., 2007 ).…”

FGF9 and FGF10 activate distinct signaling pathways to direct lung epithelial specification and branching

“…7, E and F). STAT3 is produced in the developing lung (22,53) and can be activated by FGFRs (54). In the presence of the STAT3 inhibitor, Stattic (55), control explants showed modestly increased branching, but cotreatment with Stattic and FGF10 did not increase branching compared to treatment with FGF10 alone (fig.…”

SARS-CoV-2 particles promote airway epithelial differentiation and ciliation

“…However, here-to our knowledge for the first time-FOXJ1 expression is studied in the first hours upon contact with SARS-CoV-2 iVP, suggesting that the early cellular response is a transient increase of FOXJ1 expression. FOXJ1 induction is required for the generation of ciliated cells from basal stem cells and club cells, through the activation of the STAT3 transcription factor (Tadokoro et al, 2014;Tanabe and Rubin, 2016;Kameyama et al, 2017). Robinot et al (2021) showed that respiratory epithelial cells synthesize both interleukin 6 (IL 6) and interferon-γ soon after SARS-CoV-2 inoculation as an antiviral defense.…”