Runx1-Stat3 signaling regulates the epithelial stem cells in continuously growing incisors

Abstract

Rodent incisors grow permanently and the homeostasis of enamel production is maintained by a continuous supply of epithelial progenitors from putative stem cells in the cervical loop. We herein report that Runx1 regulates the Lgr5-expressing epithelial stem cells and their subsequent continuous differentiation into ameloblasts. Mice deficient in epithelial Runx1 demonstrate remarkable shortening of the incisors with underdevelopment of the cervical loop and enamel defects. In this mutant cervical loop, the proliferation of the dental epithelium was significantly disturbed and the expression of Lgr5 and enamel matrix proteins was remarkably downregulated. Interestingly, the expression of Socs3, an inhibitor of Stat3 signaling, was upregulated and Stat3 phosphorylation was suppressed specifically in the mutant cervical loop. The expression of Lgr5 and the enamel matrix protein in the wild-type incisor germs is disturbed by pharmaceutical Stat3 inhibition in vitro., of. Conversely, pharmaceutical activation of Stat3 rescues the defective phenotypes of the Runx1 mutant with upregulated Lgr5 and enamel matrix protein genes. The present results provide the first evidence of the role of Runx1 regulates the Lgr5-expressing epithelial stem cells and differentiation of ameloblast progenitors in the developing incisors. Our study also demonstrates that Stat3 modulates the Runx1-Lgr5 axis in the cervical loop.

Observation of the Epithelial Cell Behavior in the Nasal Septum During Primary Palate Closure in Mice

“…From our previous results, the epithelial-specific elimination of Runx1 is known to be exhibited at the anterior cleft palate ( Sarper et al, 2018a , b ). It is also known that fewer TUNEL-positive cells were detected on the unfused epithelium in Runx1 mutants ( Sarper et al, 2018b ).…”

“…The present and previous findings suggest that the induction of extrusion is critical for the fusion of facial processes and that it can be inhibited by Runx1 depletion ( Martínez-Alvarez et al, 2000 ; Takigawa and Shiota, 2004 , 2007 ; Charoenchaikorn et al, 2009 ; Hu et al, 2015 ). Importantly, our previous report showed that the excision of Runx1 in epithelial tissues takes place at the beginning of explant culture ( Sarper et al, 2018a , b , 2019 ).…”

“…In Runx1 mutant mice, the anterior cleft palate is associated with reduced apoptosis and retained periderm, at the boundary between the primary and secondary palate junction. In these mutants, the expression of Tgfb3, a critical regulator of apoptosis, was significantly disturbed and TGFB3 protein rescued the formation of the anterior cleft ( Sarper et al, 2018a , b , 2019 ). The molecular mechanism through which apoptosis is initiated remains unclear; however, the reduced induction of extrusion is associated with a reduction in the expression of Tgfb3 .…”

STAT3‑PTTG11 abrogation inhibits proliferation and induces apoptosis in malignant glioma cells

“…Effects of S3I-201 and IL-6 on viability and apoptosis of U251 cells. It has been reported that S3I-201 and IL-6 are an inhibitor and an agonist of STAT3, respectively (22,23). To investigate the effects of IL-6 and S3I-201 on glioma cells, the CCK-8 assay was used at 0, 6, 12, 24, 48 and 72 h after treatment with different doses of S3I-201 (0, 50, 100 or 200 µM) or IL-6 (0, 20, 40 or 80 ng/ml) to measure U251 cell viability and proliferation, respectively.…”

“…Cell Counting Kit-8 (CCK-8) was purchased from Dalian Meilun Biotechnology Co., Ltd. An inhibitor (S3I-201) and agonist (IL-6) of STAT3 were purchased from Sigma-Aldrich; Merck KGaA. Based on previous reports, a dose of 200 µm S3I-201 was used in the present study (21)(22)(23) Cell transfection. U251 cells in the logarithmic growth phase were selected for transfection.…”