COL1A1 expression induced by overexpression of both a 15‑amino acid peptide from the fibrinogen domain of tenascin‑X and integrin α11 in LX‑2 cells

Abstract

Extracellular matrix tenascin-X (TNX) is the largest member of the tenascin family. Our previous study demonstrated that TNX was involved in hepatic dysfunction, including fibrosis, in mice that were administered a high-fat and high-cholesterol diet with high levels of phosphorus and calcium. The present study investigated whether overexpression of both the fibrinogen domain of TNX (TNX-FG) and integrin α11, one of the TNX cell surface receptors, induces in vitro fibrosis in LX-2 human hepatic stellate cells. Overexpression of both a 15-amino acid peptide (hTNX-FGFFFF) derived from the TNX-FG domain and integrin α11 induced the expression of type I collagen α1 chain (COL1A1). Treatment with verteporfin [YAP (Yes-associated protein) inhibitor] attenuated the elevated COL1A1 expression elicited by overexpression of both hTNX-FGFFFF and integrin α11. In addition, small interfering RNA-mediated knockdown of YAP1 resulted in a decrease in COL1A1 expression induced by overexpression of both hTNX-FGFFFF and integrin α11. These results indicated that overexpression of both hTNX-FGFFFF and integrin α11 induced COL1A1 expression via the YAP signaling pathway.

Tenascin-X as a causal gene for classical-like Ehlers-Danlos syndrome

“…Initially, we speculated that TGF-β and TNX-FBG with integrin α11β1 are involved in the induction of COL1A1 expression since interaction of the TNX-FBG domain and TGF-β was reported previously ( Alcaraz et al, 2014 ) and TGF-β is a well-known central mediator of fibrosis ( Dewidar et al, 2019 ). However, contrary to our initial expectation, we found that the Yes-associated protein 1 (YAP1) signaling pathway through integrin α11β1 plays a major role in the induction of COL1A1 expression by expression of the TNX-FBG domain in human hepatic stellate LX-2 cells and that the minimum 15-amino acid (aa) sequence derived from the TNX-FBG domain is required for the induction of COL1A1 expression in the LX-2 cells ( Matsumoto et al, 2022 ). Since integrin α11β1 is known to be a receptor for type I collagen (COL1) and type II collagen ( Zhang et al, 2003 ), it is yet to be determined whether interaction of the TNX-FBG domain with integrin α11β1 is direct or indirect for the induction of COL1A1 expression.…”

“…Finally, we showed that COL1A1 expression was induced by expression of both the 15-aa peptide in the TNX-FBG domain and integrin α11 in hepatic stellate LX-2 cells in vitro ( Matsumoto et al, 2022 ). Further experiments are needed to determine whether expression of the 15-aa peptide from the TNX-FBG domain in liver can induce COL1A1 expression leading to hepatic fibrosis in vivo .…”