PIEZO1 promotes odontoblast-mediated reactionary dentinogenesis via Ca2+-SEMA3A axis
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ABSTRACT:
PROVIDER: PRJNA1096361 | ENA |
REPOSITORIES: ENA
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Project description:The odontoblasts are specialized cells responsible for dentin synthesis and nociceptive signal detection in response to external stimuli. Recent studies have shown that the mechanosensitive ion channel PIEZO1 is involved in bone formation and remodeling through the influx of calcium ions, and it is abundantly expressed in odontoblasts. However, the specific role of PIEZO1 in reactionary dentinogenesis by odontoblasts and the underlying mechanisms still remain elusive. In this study, we found intense PIEZO1 expression in the plasma membrane and cytoplasm of odontoblasts in human and mouse mandibular molars, and human odontoblast-like cells (hOBLCs). In hOBLCs, PIEZO1 positively regulated DSPP, DMP1, and COL1A1 expression through the Ca2+/PI3K-Akt/SEMA3A signaling pathway. Additionally, exogenous SEMA3A supplementation effectively reversed reduced mineralization capacity in PIEZO1-knockdown hOBLCs. In vivo, Piezo1 expression peaked at day 7 and returned to baseline at day 21 in a wild-type (WT) mice dentin injury model, with Sema3a presenting a similar expression pattern. To investigate the specific role of PIEZO1 in reactionary dentinogenesis, mice with a conditional knockout of PIEZO1 in odontoblasts were generated, and no significant differences of teeth phenotypes were observed between the control and conditional knockout (cKO) mice. Nevertheless, cKO mice exhibited reduced reactionary dentin formation, and decreased Sema3a and Dsp positive staining after dentin injury, indicating impaired dental pulp repair mediated by odontoblasts. In summary, these findings suggest that PIEZO1 enhances mineralization capacity of hOBLCs in vitro via the Ca2+/Akt/SEMA3A signaling pathway and contributes to dental pulp repair through enhancing reactionary dentinogenesis in vivo.
2025-06-30 | GSE263258 | GEO
Project description:Ventricular arrhythmogenesis is a key cause of sudden cardiac death following myocardial infarction (MI). Accumulating data show that ischemia, sympathetic activation, and inflammation contribute to arrhythmogenesis. However, the role and mechanisms of abnormal mechanical stress in ventricular arrhythmia following MI remain undefined. We aimed to examine the impact of increased mechanical stress and identify the role of the key sensor Piezo1 in ventricular arrhythmogenesis in MI. Concomitant with increased ventricular pressure, Piezo1, as a newly recognized mechano-sensitive cation channel, was the most up-regulated mechanosensor in the myocardium of patients with advanced heart failure. Piezo1 was mainly located at the intercalated discs and T-tubules of cardiomyocytes, which are responsible for intracellular calcium homeostasis and intercellular communication. Cardiomyocyte-conditional Piezo1 knockout mice (Piezo1Cko) exhibited preserved cardiac function after MI. Piezo1Cko mice also displayed a dramatically decreased mortality in response to the programmed electrical stimulation after MI with a markedly reduced incidence of ventricular tachycardia. In contrast, activation of Piezo1 in mouse myocardium increased the electrical instability as indicated by prolonged QT interval and sagging ST segment. Mechanistically, Piezo1 impaired intracellular calcium cycling dynamics by mediating the intracellular Ca2+overload and increasing the activation of Ca2+-modulated signaling, CaMKII, and calpain, which led to the enhancement of phosphorylation of RyR2 and further increment of Ca2+leaking, finally provoking cardiac arrhythmias. Furthermore, in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), Piezo1 activation remarkably triggered cellular arrhythmogenic remodeling by significantly shortening the duration of the action potential, inducing early afterdepolarization, and enhancing triggered activity.This study uncovered a proarrhythmic role of Piezo1 during cardiac remodeling, which is achieved by regulating Ca2+handling, implying a promising therapeutic target in sudden cardiac death and heart failure.
2025-04-30 | GSE230042 | GEO
Project description:Negative pressure-induced fibroblast activation for wound healing through the Piezo1-Ca2+-NFAT3 signaling pathway
2025-07-12 | PXD066120 |
Project description:Necrotizing enterocolitis (NEC) is a devastating inflammatory bowel necrosis of very preterm infants with limited therapeutic approaches. Mounting evidence supports the role of Piezo1, a widely distributed mechanosensor on intestinal epithelial cells (IECs), in intestinal inflammation, but its underlying mechanism in the development of NEC has not been explored. Here we demonstrated that Piezo1 protein expression was higher in very preterm infants compared to full-term infants, and positively associated with serum inflammation levels in NEC patients. C57BL/6J mice in which Piezo1 was selectively deleted IECs (villin specific knockout; CKO) and floxed control mice were subjected to induce NEC, and Piezo1 regulated intestinal barrier function, restricted cytokines secretion, and diminished the inflammatory response in NEC mouse models.
2025-02-17 | GSE283887 | GEO
Project description:Piezo1 promotes the progression of necrotizing enterocolitis via activating Ca2(+)/CaMKII-dependent pathway
| PRJNA1195969 | ENA
Project description:PIEZO1 is a mechanically-activated ion channel that contributes to flow sensing in vascular endothelium. Moreover, deletion of endothelial PIEZO1 was recently found to suppress activation of Notch1 target genes in hepatic microvascular endothelium. Here, because of the liver’s dominant role in lipid regulation, we set out to test the novel hypothesis that endothelial PIEZO1 regulates hepatic lipid homeostasis. We performed bulk RNA sequencing on PIEZO1-deleted mice exposed to chow and high fat diets. Our transcriptomics analysis reveal unexpected relevance to lipid and glucose homeostasis.
2024-06-29 | E-MTAB-9996 | biostudies-arrayexpress
Project description:Most cancer cells are exposed to extracellular environments, such as extracellular matrix, which commonly becomes stiffer along with transformation. It is conceivable that tumorous extracellular environments would be changing to affect tumor cell behavior. It has been reported that Hippo pathway responds to the extracellular environments and induces the nuclear localization of transcription activator, yes-associated protein (YAP), resulting in stimulating cell proliferation. Its pathway also regulates gene expression, but the precise molecule to meditate cell proliferating effect of Hippo pathway in oral squamous cell carcinoma (OSCC) is not well understood. Here, we examined the effects of YAP-mediated Hippo pathway in OSCC tumorigenesis. Loss-of-function experiments using siRNA or an inhibitor, and immunohistochemical analyses of tissue specimens obtained from OSCC specimens demonstrated that YAP-mediated Hippo pathway was involved in OSCC cell proliferation. We identified Piezo-type mechanosensitive ion channel component 1 (PIEZO1), a Ca2+ channel, as a downstream molecule of Hippo pathway and showed that elevated PIEZO1 expression was required for PIEZO1 agonist-dependent Ca2+ entry and cell proliferation in OSCC cells. Furthermore, the experiments using three-dimensional culture and suspension culture revealed that PIEZO1, of which expression was regulated by YAP-mediated Hippo pathway, was involved in OSCC cellular growth. Immunohistochemically, YAP overexpression with nucleus and/or cytoplasm was detected with both PIEZO1 and Ki-67 expression at high frequencies in tumor lesion, but not in non-tumor region, of OSCC specimens. These results suggest that the YAP-mediated Hippo/PIEZO1 axis, which might be activated by the tumorous extracellular environments, promotes OSCC tumor cell growth.
2020-05-08 | GSE150044 | GEO
Project description:Dentin is a major mineralized component of teeth generated by odontoblasts. Several types of histone methylation have been reported to play important roles in odontoblast differentiation and dentinogenesis. However, the role of methylation on histone 3 at lysine 36 (H3K36) remains enigmatic. Here we find a high expression of SETD2, a methyltransferase catalyzing the trimethylation of H3K36 (H3K36me3), in the odontoblast layer. In vitro knockdown experiments and in vivo observations of two conditional knockout mouse models reveal SETD2 is essential for odontoblast differentiation and dentinogenesis. Integrated analyses of RNA sequencing and Spike-in Cleavage Under Targets and Tagmentation sequencing data show SETD2 is crucial for both H3K36me3 occupancy on the loci of Col11a2 and Sema3e and their transcription. Further experiments verify COL11A2 and SEMA3E act upstream of AKT1 signaling, promoting odontoblastic differentiation. In vitro and in vivo activation of AKT1 using SC79 (an AKT activator) partially rescues the impaired odontoblast differentiation caused by Setd2 knockdown or deficiency. Therefore, our findings indicate that H3K36me3 mediated by SETD2 is essential for dentinogenesis through regulating the expression of Col11a2 and Sema3e and AKT1 signaling.
2025-02-03 | GSE288311 | GEO
Project description:Dentin is a major mineralized component of teeth generated by odontoblasts. Several types of histone methylation have been reported to play important roles in odontoblast differentiation and dentinogenesis. However, the role of methylation on histone 3 at lysine 36 (H3K36) remains enigmatic. Here we find a high expression of SETD2, a methyltransferase catalyzing the trimethylation of H3K36 (H3K36me3), in the odontoblast layer. In vitro knockdown experiments and in vivo observations of two conditional knockout mouse models reveal SETD2 is essential for odontoblast differentiation and dentinogenesis. Integrated analyses of RNA sequencing and Spike-in Cleavage Under Targets and Tagmentation sequencing data show SETD2 is crucial for both H3K36me3 occupancy on the loci of Col11a2 and Sema3e and their transcription. Further experiments verify COL11A2 and SEMA3E act upstream of AKT1 signaling, promoting odontoblastic differentiation. In vitro and in vivo activation of AKT1 using SC79 (an AKT activator) partially rescues the impaired odontoblast differentiation caused by Setd2 knockdown or deficiency. Therefore, our findings indicate that H3K36me3 mediated by SETD2 is essential for dentinogenesis through regulating the expression of Col11a2 and Sema3e and AKT1 signaling.
2025-02-03 | GSE288310 | GEO
Project description:The odontogenic differentiation of human dental pulp stem cells (HDPSCs) is associated with reparative dentinogenesis. Transcription factor GATA binding protein 4 (GATA4) is proved to be essential for osteoblast differentiation and bone remodeling. This study clarified the function of GATA4 in HDPSCs odontoblast differentiation.
2025-06-30 | GSE234905 | GEO