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PFN1 and integrin-β1/mTOR axis involvement in cornea differentiation of fibroblast limbal stem cells.

ABSTRACT: Ex vivo limbal stem cell transplantation is the main therapeutic approach to address a complete and functional re-epithelialization in corneal blindness, the second most common eye disorder. Although important key points were defined, the molecular mechanisms involved in the epithelial phenotype determination are unclear. Our previous studies have demonstrated the pluripotency and immune-modulatory of fibroblast limbal stem cells (f-LSCs), isolated from the corneal limbus. We defined a proteomic profile especially enriched in wound healing and cytoskeleton-remodelling proteins, including Profilin-1 (PFN1). In this study we postulate that pfn-1 knock down promotes epithelial lineage by inhibiting the integrin-β1(CD29)/mTOR pathway and subsequent NANOG down-expression. We showed that it is possible modulate pfn1 expression levels by treating f-LSCs with Resveratrol (RSV), a natural compound: pfn1 decline is accompanied with up-regulation of the specific differentiation epithelial genes pax6 (paired-box 6), sox17 (sex determining region Y-box 17) and ΔNp63-α (p63 splice variant), consistent with drop-down of the principle stem gene levels. These results contribute to understand the molecular biology of corneal epithelium development and suggest that pfn1 is a potential molecular target for the treatment of corneal blindness based on epithelial cell dysfunction.

SUBMITTER: Tomasello L

PROVIDER: S-EPMC6815913 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAbdominal aortic aneurysms have a high mortality rate. While surgery is the preferred treatment method, the biological repair of abdominal aortic aneurysms is being increasingly studied. We performed cellular and animal experiments to investigate the simultaneous function and mechanism of fibroblast growth factor 18 and integrin β1 in the biological repair of abdominal aortic aneurysms.MethodsEndothelial and smooth muscle cells of rat arteries were used for the cellular experiments. Intracellular integrin β1 expression was regulated through lentiviral transfection. Interventions with fibroblast growth factor 18 were determined according to the experimental protocol. Several methods were used to detect the expression of elastic fiber component proteins, cell proliferation, and migratory activity of endothelial and smooth muscle cells after different treatments. For animal experiments, abdominal aortic aneurysms were induced in rats by wrapping the abdominal aortae in sterile cotton balls soaked with CaCl2 solution. Fibroblast growth factor 18 was administered through tail vein injections. The local expression of integrin β1 was regulated through lentiviral injections into the adventitia of the abdominal aortic aneurysms. The abdominal aortae were harvested for pathological examinations and tensile mechanical tests.ResultsThe expression of integrin β1 in endothelial and smooth muscle cells could be regulated effectively through lentiviral transfection. Animal and cellular experiments showed that fibroblast growth factor 18 + integrin β1 could improve the expression of elastic fiber component proteins and enhance the migratory and proliferative activities of smooth muscle and endothelial cells. Moreover, animal experiments showed that fibroblast growth factor 18 + integrin β1 could enhance the aortic integrity to withstand stretch of aortic aneurysm tissue.ConclusionFibroblast growth factor 18 + integrin β1 improved the biological repair of abdominal aortic aneurysms in rats by increasing the expression of elastic proteins, improving the migratory and proliferative abilities of endothelial and smooth muscle cells, and improving aortic remodeling.

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PFN1 and integrin-β1/mTOR axis involvement in cornea differentiation of fibroblast limbal stem cells.

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