Response of Hepatic Stellate Cells to TGFB1 Differs from the Response of Myofibroblasts. Decorin Protects against the Action of Growth Factor

Abstract

Regardless to the exact nature of damage, hepatic stellate cells (HSCs) and other non-parenchymal liver cells transform to activated myofibroblasts, synthesizing the accumulating extracellular matrix (ECM) proteins, and transforming growth factor-β1 (TGF-β1) plays a crucial role in this process. Later it was discovered that decorin, member of the small leucin rich proteoglycan family is able to inhibit this action of TGF-β1. The aim of our present study was to clarify whether HSCs and activated myofibroblasts of portal region exert identical or different response to TGF-β1 exposure, and the inhibitory action of decorin against the growth factor is a generalized phenomenon on myofibroblast of different origin? To this end we measured mRNA expression and production of major collagen components (collagen type I, III and IV) of the liver after stimulation and co-stimulation with TGF-β1 and decorin in primary cell cultures of HSCs and myofibroblasts (MFs). Production of matrix proteins, decorin and members of the TGF-β1 signaling pathways were assessed on Western blots. Messenger RNA expression of collagens and TIEG was quantified by real-time RT-PCR. HSCs and MFs responded differently to TGF-β1 exposure. In contrast to HSCs in which TGF-β1 stimulated the synthesis of collagen type I, type III, and type IV, only the increase of collagen type IV was detected in portal MFs. However, in a combined treatment, decorin seemed to interfere with TGF-β1 and its stimulatory effect was abolished. The different mode of TGF-β1 action is mirrored by the different activation of signaling pathways in activated HSCs and portal fibroblasts. In HSCs the activation of pSMAD2 whereas in myofibroblasts the activation of MAPK pathway was detected. The inhibitory effect of decorin was neither related to the Smad-dependent nor to the Smad-independent signaling pathways.

Systemic inhibition of BMP1-3 decreases progression of CCl4-induced liver fibrosis in rats

“…As a previously proven molecule with antifibrotic activity, BMP7 also reduced Tgfb1, Itgb1, Itgb6, and Acta2 gene expression, Following BMP1-3 inhibition, endogenous expression of Dcn mRNA and protein was increased. Decorin is a small leucine-rich proteoglycan and downregulates the expression and the biological activity of TGFb1 (Full ar et al, 2016;Yamaguchi et al, 1990). It has been demonstrated that three BMP1 isoforms (BMP1-1, BMP1-3, and BMP1-5) can effectively remove the pro-peptide from the human prodecorin resulting in a well-established mature proteoglycan (von Marschall and Fisher, 2010).…”

“…It has been demonstrated that three BMP1 isoforms (BMP1-1, BMP1-3, and BMP1-5) can effectively remove the pro-peptide from the human prodecorin resulting in a well-established mature proteoglycan (von Marschall and Fisher, 2010). Previous studies indicate the efficacy of decorin in antagonizing the TGFb1 effect on HSCs by suppression of ECM production (Full ar et al, 2016), migration of fibroblasts, trophoblasts, and differentiation of myocytes (Baghy et al, 2012;Droguett et al, 2006;Fischer et al, 2001). Decorin has an evident anti-fibrotic activity in the liver after injury with CCl 4 (Cai et al, 2014) and Dcn silencing caused an increased activation of HSCs both in vivo and in vitro (Baghy et al, 2011).…”

RNA sequencing of LX-2 cells treated with TGF-β1 identifies genes associated with hepatic stellate cell activation

“…Genes whose role within HSCs is unknown are listed as "not characterised" therefore its reduced expression in this context would inhibit TGF-β1 signalling and subsequent HSC activation. The expression of COL17A1 and COL4A6 were also downregulated, despite COL4 having been shown previously to be upregulated in HSCs following TGF-β1 exposure [41]. One previous study has shown that COL17 and COL4 interact together in skin and oral keratinocytes to assist cell-ECM adhesion [42].…”

Expression of fibrosis‐related genes in liver allografts: Association with histology and long‐term outcome after pediatric liver transplantation

“…29 Overproduced TGFβ, ECM deposition, and inflammatory activity (in chronic hepatitis) are all known to induce decorin expression, which probably explains the elevated decorin mRNA levels in the liver grafts. 50 The expression of SMAD2 and latent transforming growth factorβ-binding protein 1 was increased in patients with fibrosis but no inflammation when compared with controls. SMAD2 is a part of the TGFβ intracellular signaling pathway, and latent transforming growth factorβ-binding protein 1 is a protein that is bonded to TGFβ before its secretion from the cell.…”