S100A4 Silencing Facilitates Corneal Wound Healing After Alkali Burns by Promoting Autophagy via Blocking the PI3K/Akt/mTOR Signaling Pathway

Abstract

Purpose This study investigated the role of S100 calcium binding protein A4 (S100A4) in corneal wound healing and the underlying mechanism of the S100A4-mediated PI3K/Akt/mammalian target of rapamycin (mTOR) pathway. Methods The rabbit corneal alkali burn model was established in vivo. S100A4 expression, wound healing, inflammation, and autophagy in rabbit cornea after alkali burn were detected. The NaOH-treated rabbit corneal stromal cells (rCSCs) were transfected with overexpressed S100A4 or silencing S100A4 to examine the effect of S100A4 on corneal wound healing in vitro. The effect of S100A4 on cell viability, proliferation, migration, invasion, fibrosis, and autophagy of rCSCs after alkali burn was analyzed. Then the functional rescue experiments were carried out. The PI3K inhibitor, LY294002, was used to elucidate the PI3K/Akt/mTOR signaling pathway in rCSCs. Results S100A4 silencing promoted rabbit corneal wound healing by inhibiting fibrosis and inflammation and promoting autophagy in alkali-burned cornea, corresponding to increased levels of LC3, Beclin 1, and Atg4B but lowered α-smooth muscle actin, TNF-ɑ, and p62 levels. Moreover, silencing S100A4 inhibited proliferation, migration, invasion, and fibrosis of NaOH-treated rCSCs and promoted the differentiation of rCSCs into corneal cells and the autophagy of damaged rCSCs. The inhibitory role of S100A4 in wound healing was achieved via activation of the PI3K/Akt/mTOR pathway. Conclusions S100A4 silencing confers a promising effect on wound healing of alkali-burned cornea by blocking the PI3K/Akt/mTOR pathway, supporting the advancement of corneal gene therapies for wound healing.

Time- and Stimulus-Dependent Characteristics of Innate Immune Cells in Organ-Cultured Human Corneal Tissue

“…1; for all online suppl. material, see www.karger.com/doi/10.1159/000516669) revealed various genes being strongly expressed in corneal tissue, including genes that are known to be relevant in corneal cell signaling, such as S100A6 and S100A4 [25], KERA , coding for keratocan, a protein essential for maintaining corneal shape and transparency [26], TGFBI , mutations of which are involved in various corneal dystrophies [27], and ANGPTL7 , which maintains corneal avascularity [28]. Profiles of different adaptive and innate immune cell types were identified in the transcriptional profile of 3 healthy corneas using the xCell deconvolution tool.…”

Proteomic Characterization of Plasma Rich in Growth Factors and Undiluted Autologous Serum

“…The p70S6K is a downstream target of mTOR signaling and the mTOR is a serine/threonine protein kinase that has been found to affect many cellular functions, including cell growth, proliferation, and metabolism [58]. In addition, in a recent study of a rabbit alkali burn model, it was shown that the inhibition of the mTOR pathway promoted the autophagy and inhibited the proliferation, invasion, and migration of corneal stromal cells, promoting corneal wound healing [59]. Furthermore, it has been shown that mTOR signaling may induce scarring, neovascularization, and inflammation in the cornea [60,61].…”

Chitosan/Gelatin Composite Nonwoven Fabric Scaffold Seeding Minimal Function Unit of Skin for Functional Skin Regeneration

“…Immunofluorescence staining results of CD34 were associated with angiogenesis [ 27 ] and S100A4 was relevant to fibroblast cell migration and scar formation [ 28 ] ( Figure 6 A,B). Compared with the interior of MFUS tissue‐engineered skin (CS+GEL scaffolds, MFUS, and wound edge) and normal wound: 1.…”