Sharon RUAN Lab
Together, great things are possible.
Selected Publications
The epithelial Na+ channel (ENaC) in ovarian granulosa cells modulates Ca2+ mobilization and gonadotrophin signaling for estrogen homeostasis and female fertility
Cell Communication and Signaling volume 22, Article number: 398 (2024)
In this study, we report patch-clamp and Na+ imaging detection of ENaC expression and channel activity in both human and mouse ovarian granulosa cells, which are promoted by pituitary gonadotrophins, follicle stimulating hormone (FSH) or luteinizing hormone (LH). Cre-recombinase- and CRISPR-Cas9-based granulosa-specific knockout of ENaC α subunit (Scnn1a) in mice resulted in failed estrogen elevation at early estrus, reduced number of corpus luteum, abnormally extended estrus phase, reduced litter size and subfertility in adult female mice. Further analysis using technologies including RNA sequencing and Ca2+ imaging revealed that pharmacological inhibition, shRNA-based knockdown or the knockout of ENaC diminished spontaneous or stimulated Ca2+ oscillations, lowered the capacity of intracellular Ca2+ stores and impaired FSH/LH-stimulated transcriptome changes for estrogen production in mouse and/or human granulosa cells. Together, these results have revealed a previously undefined role of ENaC in modulating gonadotrophin signaling in granulosa cells for estrogen homeostasis and thus female fertility.
Magnesium implantation or supplementation ameliorates bone disorder in CFTR-mutant mice through an ATF4-dependent Wnt/β-catenin signaling
https://doi.org/10.1016/j.bioactmat.2021.06.034
Magnesium metal and its alloys are being developed as effective orthopedic implants; however, the mechanisms underlying the actions of magnesium on bones remain unclear. Cystic fibrosis, the most common genetic disease in Caucasians caused by the mutation of CFTR, has shown bone disorder as a key clinical manifestation, which currently lacks effective therapeutic options. Here we report that implantation of magnesium-containing implant stimulates bone formation and improves bone fracture healing in CFTR-mutant mice. Wnt/β-catenin signaling in the bone is enhanced by the magnesium implant, and inhibition of Wnt/β-catenin by iCRT14 blocks the magnesium implant to improve fracture healing in CFTR-mutant mice. We further demonstrate that magnesium ion enters osteocytes, increases intracellular cAMP level and activates ATF4, a key transcription factor known to regulate Wnt/β-catenin signaling. In vivo knockdown of ATF4 abolishes the magnesium implant-activated β-catenin in bones and reverses the improved-fracture healing in CFTR-mutant mice. In addition, oral supplementation of magnesium activates ATF4 and β-catenin as well as enhances bone volume and density in CFTR-mutant mice. Together, these results show that magnesium implantation or supplementation may serve as a potential anabolic therapy for cystic fibrosis-related bone disease. Activation of ATF4-dependent Wnt/β-catenin signaling in osteocytes is identified as a previously undefined mechanism underlying the beneficial effect of magnesium on bone formation.
MRP4 sustains Wnt/β-catenin signaling for pregnancy, endometriosis and endometrial cancer
Abnormal Wnt/β-catenin signaling in the endometrium can lead to both embryo implantation failure and severe pathogenic changes of the endometrium such as endometrial cancer and endometriosis. However, how Wnt/β-catenin signaling is regulated in the endometrium remains elusive. We demonstrated in this study that MRP4-knockdown, but not its transporter-function-inhibition, accelerates β-catenin degradation in human endometrial cells. MRP4 and β-catenin are co-localized and co-immunoprecipitated in mouse and human endometrium. MRP4-knockdown in mouse uterus reduces β-catenin levels, downregulates a series of Wnt/β-catenin target genes and impairs embryo implantation, which are all reversed by blocking β-catenin degradation. Analysis of human endometrial biopsy samples and available databases reveals significant and positive correlations of MRP4 with β-catenin and Wnt/β-catenin target genes in the receptive endometrium in IVF, ectopic endometriotic lesions and endometrial cancers. Knockdown of MRP4 also inhibits in vitro and in vivo endometrial tumorigenesis. Therefore, a previously undefined role of MRP4 in stabilizing β-catenin to sustain Wnt/β-catenin signaling in endometrial cells is revealed for both embryo implantation and endometrial disorders, suggesting MRP4 as a theranostic target for endometrial diseases associated with Wnt/β-catenin signaling abnormality.
EMBO Mol Med (2018) e8868
Labor, the end step of pregnancy, remains poorly understood, which accounts for the lack of effective method to prevent or predict preterm labor, a leading cause of neonatal death and disability. This study reveals a previously unsuspected role of the epithelial sodium channel (ENaC) in transducing mechanical signal into cytokine profile shift to pro-inflammatory in labor and suggests ENaC as a potential target for the prevention and treatment of preterm labor.
Activation of the epithelial Na+ channel triggers prostaglandin E2 release and production required for embryo implantation
Nature Medicine volume18, pages1112–1117 (2012)
This study has revealed a previously unsuspected role of the epithelial sodium channel (ENaC) in regulating prostaglandin production and release required for embryo implantation, defects in which may be a cause of miscarriage and low success rates in IVF. Given the mechano-sensitivity of ENaC, it also provides an explanation for the long-observed induction of decidualization by mechanical stimuli in animal models and improved implantation rate in women undergoing IVF after endometrial scratch. The ability of ENaC to regulate PGE2 production and release may have far-reaching implications beyond embryo implantation or reproduction, as ENaC is widely distributed throughout the body and PGE2 is a versatile regulator of many physiological functions and pathological processes.
CFTR interacts with ZO-1 to regulate tight junction assembly and epithelial differentiation through the ZONAB pathway
J Cell Sci 2014 127: 4396-4408
Mutations in CFTR lead to dysfunction of tubular organs, which is currently attributed to impairment of its conductive properties. This study shows that CFTR regulates tight junction assembly and epithelial cell differentiation through modulation of the ZO-1–ZONAB pathway and provides a new paradigm for the etiology of diseases associated with CFTR mutations, including cystic fibrosis.
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Glucose-Sensitive CFTR Suppresses Glucagon Secretion by Potentiating KATP Channels in Pancreatic Islet α Cells. (Endocrinology, Volume 158, Issue 10, 1 October 2017, Pages 3188–3199)
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Glucose-induced electrical activities and insulin secretion in pancreatic islet β-cells are modulated by CFTR. (Nature Communications volume 5, Article number: 4420 ,2014)
These two consecutive studies have revealed previously unidentified roles of CFTR in modulating the excitability of pancreatic alpha and beta islet cells, contributing to glucagon and insulin secretion respectively upon glucose stimulation, defects in which may lead to endocrine and metabolic disorders such as diabetes.
This is a collaborative study with Prof Ling QIN
Implant-derived magnesium induces local neuronal production of CGRP to improve bone-fracture healing in rats.
Nature Medicine volume22, pages1160–1169 (2016)
Orthopedic implants containing biodegradable magnesium have been used for fracture repair with considerable efficacy; however, the underlying mechanisms by which these implants improve fracture healing remain elusive. This study reveals a previously undefined role of magnesium in promoting CGRP-mediated osteogenic differentiation, which suggests the therapeutic potential of this ion in orthopedics.
