RGD peptide hydrogel downregulates mechanosignal YAP to inhibit postoperative scarring.

Abstract

Objective: Glaucoma filtration failure may result from an overabundance of human Tenon's capsule fibroblasts (HTFs) forming a filtration tract scar. Conversely, the Yes-associated protein (YAP), a transcriptional activator of the Hippo signaling pathway, is a crucial matrix stiffness regulator of matrix production and fibroblast activation. With superior biocompatibility and biodegradability, RGD peptide hydrogels imitate the structure of real tissues' extracellular matrix (ECM). The purpose of this research was to determine whether down-regulating YAP expression via RGD peptide hydrogels may prevent HTFs activation and ECM protein secretion. Transforming growth factor-β2 (TGF-β2) was used to induce the activation of HTFs in a cellular model of scarring following glaucoma filtration surgery. Utilizing SD rats, a murine model of subconjunctival injury was established. The shape of collagen fibers was observed through Masson staining, and the expression of YAP and α-smooth muscle actin (α-SMA) was identified through immunohistochemistry. RGD peptide hydrogel was discovered to have anti-scarring properties in a mouse eye injury model, as well as the ability to lessen HTFs activation, YAP expression, cytosolic nucleus accumulation, and the expression of connective tissue growth factor (CTGF) and ECM proteins. The best concentration was found to be 1.0 weight percent among them. This concentration not only makes it easier to inject a drug subconjunctivally in vivo and maintain the filtration vesicle space in the conjunctiva, but it also inhibits the activation of fibroblasts into myofibroblasts and down-regulates the expression of the Hippo-YAP signaling pathway in Tenon's capsule fibroblasts.

Statement of significance: 1. The homogenous reticular three-dimensional nanostructure that made up the interior structure of the 1.0 weight percent gel had good drug delivery characteristics for long-lasting controlled drug release. 2. RGD peptide hydrogel had a certain matrix hardness, which could mimic the normal connective tissue hardness under the conjunctiva. 3. RGD peptide hydrogels could prevented the development of rat conjunctival fibrosis. 4. RGD peptide hydrogel could inhibit the expression of YAP and its target gene CTGF, as well as α-SMA, ECM proteins in HTFs. 5. RGD peptide hydrogel has good biocompatibility, biodegradability, and stable mechanical properties, and can also be used as a promising carrier for the controlled release of drugs.