The common YAP activation mediates corneal epithelial regeneration and repair with different-sized wounds.
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ABSTRACT:
SUBMITTER: Li Y
PROVIDER: S-EPMC7997881 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Corneal blindness is the fifth leading cause of blindness worldwide, and therapeutic options are still often limited to corneal transplantation. The corneal epithelium has a strong barrier function, and regeneration is highly dependent on limbal stem cell proliferation and basement membrane remodeling. As a result of the lack of corneal donor tissues, regenerative medicine for corneal diseases affecting the epithelium is an area with quite advanced basic and clinical research. Surgery still plays a prominent role in the treatment of epithelial diseases; indeed, innovative surgical techniques have been developed to transplant corneal and non-corneal stem cells onto diseased corneas for epithelial regeneration applications. The main goal of applying regenerative medicine to clinical practice is to restore function by providing viable cells based on the use of a novel therapeutic approach to generate biological substitutes and improve tissue functions. Interest in corneal epithelium rehabilitation medicine is rapidly growing, given the exposure of the corneal outer layers to external insults. Here, we performed a review of basic, clinical and surgical research reports on regenerative medicine for corneal epithelial disorders, classifying therapeutic approaches according to their macro- or microscopic target, i.e., into cellular or subcellular therapies, respectively.
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Project description:Chronic cutaneous wounds remain a persistent unmet medical need that decrease expectancy and quality of life. Here, we report that topical application of PY-60, a small molecule activator of the transcriptional coactivator YAP, promotes regenerative repair of cutaneous wounds in pig and human models. Pharmacological YAP activation enacts a reversible pro-proliferative transcriptional program in keratinocytes and dermal cells that results in accelerated re-epithelization and regranulation of the wound bed. These results demonstrate that transient topical administration of a YAP activating agent may represent a generalizable therapeutic approach to treating chronic wounds.
2023-06-11 | GSE234332 | GEO
Project description:Corneal wound healing is essential for the maintenance of corneal integrity and transparency and involves a series of physiological processes that depend on the proliferation of epithelial cells. However, the molecular mechanisms that control corneal epithelial cell proliferation are poorly understood. Here, we show that Sestrin2, a stress-inducible protein, is downregulated in the corneal epithelium during wound healing and that the proliferation of epithelial basal cells is enhanced in Sestrin2-deficient mice. We also show that YAP, a major downstream effector of the Hippo signaling pathway, regulates cell proliferation during corneal epithelial wound repair and that Sestrin2 suppresses its activity. Moreover, increased levels of reactive oxygen species in the Sestrin2-deficient corneal epithelium promote the nuclear localization and dephosphorylation of YAP, activating it to enhance the proliferation of corneal epithelial cells. These results reveal that Sestrin2 is a negative regulator of YAP, which regulates the proliferative capacity of basal epithelial cells, and may serve as a potential therapeutic target for corneal epithelial damage.
| S-EPMC7338388 | biostudies-literature
Project description:BackgroundAge-related changes affecting the ocular surface cause vision loss in the elderly. Cisd2 deficiency drives premature aging in mice as well as resulting in various ocular surface abnormalities. Here we investigate the role of CISD2 in corneal health and disease.MethodsWe studied the molecular mechanism underlying the ocular phenotypes brought about by Cisd2 deficiency using both Cisd2 knockout (KO) mice and a human corneal epithelial cell (HCEC) cell line carrying a CRISPR-mediated CISD2KO background. We also develop a potential therapeutic strategy that targets the Ca2+ signaling pathway, which has been found to be dysregulated in the corneal epithelium of subjects with ocular surface disease in order to extend the mechanistic findings into a translational application.FindingsFirstly, in patients with corneal epithelial disease, CISD2 is down-regulated in their corneal epithelial cells. Secondly, using mouse cornea, Cisd2 deficiency causes a cycle of chronic injury and persistent repair resulting in exhaustion of the limbal progenitor cells. Thirdly, in human corneal epithelial cells, CISD2 deficiency disrupts intracellular Ca2+ homeostasis, impairing mitochondrial function, thereby retarding corneal repair. Fourthly, cyclosporine A and EDTA facilitate corneal epithelial wound healing in Cisd2 knockout mice. Finally, cyclosporine A treatment restores corneal epithelial erosion in patients with dry eye disease, which affects the ocular surface.InterpretationThese findings reveal that Cisd2 plays an essential role in the cornea and that Ca2+ signaling pathways are potential targets for developing therapeutics of corneal epithelial diseases.FundingThis study was supported by the Ministry of Science and Technology (MOST) and Chang Gung Medical Research Foundation, Taiwan.
| S-EPMC8577409 | biostudies-literature
Project description:Inflammation promotes regeneration of injured tissues through poorly understood mechanisms, some of which involve interleukin (IL)-6 family members, the expression of which is elevated in many diseases including inflammatory bowel diseases and colorectal cancer. Here we show in mice and human cells that gp130, a co-receptor for IL-6 cytokines, triggers activation of YAP and Notch, transcriptional regulators that control tissue growth and regeneration, independently of the gp130 effector STAT3. Through YAP and Notch, intestinal gp130 signalling stimulates epithelial cell proliferation, causes aberrant differentiation and confers resistance to mucosal erosion. gp130 associates with the related tyrosine kinases Src and Yes, which are activated on receptor engagement to phosphorylate YAP and induce its stabilization and nuclear translocation. This signalling module is strongly activated upon mucosal injury to promote healing and maintain barrier function.
| S-EPMC4447318 | biostudies-literature
Project description:Background and aimsPeroxisome proliferator-activated receptor α (PPARα, NR1C1) is a ligand-activated nuclear receptor involved in the regulation of lipid catabolism and energy homeostasis. PPARα activation induces hepatomegaly and plays an important role in liver regeneration, but the underlying mechanisms remain unclear.Approach and resultsIn this study, the effect of PPARα activation on liver enlargement and regeneration was investigated in several strains of genetically modified mice. PPARα activation by the specific agonist WY-14643 significantly induced hepatomegaly and accelerated liver regeneration after 70% partial hepatectomy (PHx) in wild-type mice and Pparafl/fl mice, while these effects were abolished in hepatocyte-specific Ppara-deficient (PparaΔHep ) mice. Moreover, PPARα activation promoted hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. Mechanistically, PPARα activation regulated expression of yes-associated protein (YAP) and its downstream targets (connective tissue growth factor, cysteine-rich angiogenic inducer 61, and ankyrin repeat domain 1) as well as proliferation-related proteins (cyclins A1, D1, and E1). Binding of YAP with the PPARα E domain was critical for the interaction between YAP and PPARα. PPARα activation further induced nuclear translocation of YAP. Disruption of the YAP-transcriptional enhancer factor domain family member (TEAD) association significantly suppressed PPARα-induced hepatomegaly and hepatocyte enlargement and proliferation. In addition, PPARα failed to induce hepatomegaly in adeno-associated virus-Yap short hairpin RNA-treated mice and liver-specific Yap-deficient mice. Blockade of YAP signaling abolished PPARα-induced hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area.ConclusionsThis study revealed a function of PPARα in regulating liver size and liver regeneration through activation of the YAP-TEAD signaling pathway. These findings have implications for understanding the physiological functions of PPARα and suggest its potential for manipulation of liver size and liver regeneration.
| S-EPMC10259205 | biostudies-literature
Project description:DNase I has been reported to improve diabetic wound healing through the clearance of neutrophils extracellular traps (NETs) caused by neutrophil aggregation. However, the function of DNase I on diabetic corneal wound healing remains unclear. Here, we investigated the effect and mechanism of topical DNase I application on diabetic mouse corneal epithelial and nerve regeneration. Corneal epithelial defects, inflammatory response, regeneration-related signalling pathways, oxidative stress, corneal innervation and sensation were examined and compared between the diabetic and normal mice. The results confirmed firstly the increased NETs production during the delayed corneal epithelial wound healing of diabetic mice, which was significantly improved through either DNase I or Cl-amidine administration. Mechanistically, DNase I improved inflammation resolution, reactivated epithelial regeneration-related signalling pathways and attenuated the accumulation of reactive oxygen species (ROS). Moreover, DNase I application also promoted corneal nerve regeneration and restored the impaired corneal sensitivity in diabetic mice. Therefore, these results indicate that topical DNase I application promotes corneal epithelial wound healing and mechanical sensation restoration in diabetic mice, representing the potential therapeutic approach for diabetic keratopathy.
| S-EPMC7176839 | biostudies-literature
Project description:Biological materials derived from extracellular matrix (ECM) proteins have garnered interest as their composition is very similar to that of native tissue. Herein, we report the use of human cornea derived decellularized ECM (dECM) microparticles dispersed in human fibrin sealant as an accessible therapeutic alternative for corneal anterior stromal reconstruction. dECM microparticles had good particle size distribution (≤10 µm) and retained the majority of corneal ECM components found in native tissue. Fibrin-dECM hydrogels exhibited compressive modulus of 70.83 ± 9.17 kPa matching that of native tissue, maximum burst pressure of 34.3 ± 3.7 kPa, and demonstrated a short crosslinking time of ~17 min. The fibrin-dECM hydrogels were found to be biodegradable, cytocompatible, non-mutagenic, non-sensitive, non-irritant, and supported the growth and maintained the phenotype of encapsulated human corneal stem cells (hCSCs) in vitro. In a rabbit model of anterior lamellar keratectomy, fibrin-dECM bio-adhesives promoted corneal re-epithelialization within 14 days, induced stromal tissue repair, and displayed integration with corneal tissues in vivo. Overall, our results suggest that the incorporation of cornea tissue-derived ECM microparticles in fibrin hydrogels is non-toxic, safe, and shows tremendous promise as a minimally invasive therapeutic approach for the treatment of superficial corneal epithelial wounds and anterior stromal injuries.
| S-EPMC8066719 | biostudies-literature
Project description:PurposeThis study investigates the repairing process of rat cornea after surgery of lamellar keratoplasty (LKP) and evaluates the effects of gelatin methacrylate (GelMA) hydrogel.MethodsIn the LKP group, the lamellar stroma matrixes of Sprague-Dawley rats were transplanted to enhanced green fluorescent protein rats, whereas those in the GelMA group were also embedded with a GelMA hydrogel during the corneal transplantation. Grafted eyes were harvested on days seven, 30, and 90. Hematoxylin and eosin staining, immunofluorescence staining, scanning electron microscopy, optical coherence tomography, and a slit-lamp microscope were used to study the process of corneal restoration and regeneration.ResultsA total of 42 rats were analyzed, including 18 rats in each of the experimental group and six rats in the control group. After three months, the infiltration degree of inflammatory cells differed between the LKP group and the GelMA group (P < 0.001). Moreover, in multiple comparisons in corneal thickness, significant difference was observed between the LKP group and the GelMA group. There was also divergence in the results between the LKP group and the control group (P < 0.001, P < 0.001). At the same time, the expression of α-smooth muscle actin (α-SMA) and transforming growth factor (TGF)-β1 varied distinctly between the LKP group and the GelMA group (P < 0.05, P < 0.001).ConclusionsSignificant differences were demonstrated between the LKP group and the GelMA group in inflammatory cell infiltration, corneal thickness, as well as the expression of α-SMA and TGF-β1. Those differences indicate the ability of GelMA hydrogel to support alleviation in corneal stroma fibrosis and show the influences of fibrosis in the dysfunction of corneal refractive power.Translational relevanceOur research provides new ideas for the future development of LKP and tissue-engineered corneas.
| S-EPMC8711000 | biostudies-literature
Project description:A distinct boundary exists between the progenitor cells in the basal limbal epithelium and the more differentiated corneal epithelial basal cells. We have shown that reciprocal expression patterns of EphA2 and Ephrin-A1 are likely to contribute to normal limbal-corneal epithelial compartmentalization as well as play a role in response to injury. How this signaling axis is regulated remains unclear. We have demonstrated that microRNAs (miRNAs) play critical roles in corneal epithelial wound healing and several miRNAs (e.g. miR-210) have been predicted to target ephrins. Previous expression profiling experiments demonstrated that miR-210 is prominently expressed in corneal epithelial cells. RNA-seq data acquired from miR-210-depleted HCECs showed up-regulation of genes involved in cellular migration. In addition, miR-210 is decreased after corneal injury while EphA2 is increased. Moreover, antago-210-treated HCECs markedly enhanced wound closure in a scratch wound assay. Antago-210 treatment resulted in increased EphA2 protein levels as well as pS897-EphA2, the pro-migratory form of EphA2. As expected, Ephrin-A1 levels were reduced, while levels of a well-known target of miR-210, Ephrin-A3, were increased by antago-210 treatment. The increase in migration with antago-210 could be inhibited by Ephrin-A1 overexpression, Ephrin-A1-Fc treatment or siRNA depletion of EphA2. However, depletion of Ephrin-A3 did not have effects on the antago-210-induced increase in migration. In addition, Ephrin-A1 overexpression and siEphA2 dampened EGFR signaling, which is increased by antago-210. Our data clearly demonstrate a link between miR-210 and EphA2/Ephrin-A1 signaling that regulates, in part, corneal epithelial migration. This interaction might potentially control the limbal-corneal epithelial boundary.
| S-EPMC8647904 | biostudies-literature