Abstract
Liver cirrhosis remains major health problem. Despite the progress in diagnosis of asymptomatic early-stage cirrhosis, prognostic biomarkers are needed to identify cirrhotic patients at high risk developing advanced stage disease. Liver cirrhosis is the result of deregulated wound healing and is featured by aberrant extracellular matrix (ECM) remodeling. However, it is not comprehensively understood how ECM is dynamically remodeled in the progressive development of liver cirrhosis. It is yet unknown whether ECM signature is of predictive value in determining prognosis of early-stage liver cirrhosis. In this study, we systematically analyzed proteomics of decellularized hepatic matrix and identified four unique clusters of ECM proteins at tissue damage/inflammation, transitional ECM remodeling or fibrogenesis stage in carbon tetrachloride-induced liver fibrosis. In particular, basement membrane (BM) was heavily deposited at the fibrogenesis stage. BM component minor type IV collagen α5 chain expression was increased in activated hepatic stellate cells. Knockout of minor type IV collagen α5 chain ameliorated liver fibrosis by hampering hepatic stellate cell activation and promoting hepatocyte proliferation. ECM signatures were differentially enriched in the biopsies of good and poor prognosis early-stage liver cirrhosis patients. Clusters of ECM proteins responsible for homeostatic remodeling and tissue fibrogenesis, as well as basement membrane signature were significantly associated with disease progression and patient survival. In particular, a 14-gene signature consisting of basement membrane proteins is potent in predicting disease progression and patient survival. Thus, the ECM signatures are potential prognostic biomarkers to identify cirrhotic patients at high risk developing advanced stage disease.
Highlights
Types XII and XIV collagens and tenascin C are found throughout skin wound healing, while latent TGF-β binding protein-4 is detected in the later phase of wound repair[11]
Global changes of the hepatic matrisomal proteins in liver fibrosis Repeated carbon tetrachloride (CCl4) treatment leads to iterative wound healing, resulting in deregulated extracellular matrix (ECM) deposition and progressive development of liver fibrosis[22,23]
Weak collagen deposition was observed after 1-week CCl4 treatment (Fig. 1A). 4-week repeated CCl4 treatment resulted in extensive collagen deposition and α-smooth muscle actin-positive myofibroblast accumulation (Fig. 1A and S1)
Summary
It is not comprehensively understood how ECM is dynamically remodeled in the progressive development of liver cirrhosis It is yet unknown whether ECM signature is of predictive value in determining prognosis of early-stage liver cirrhosis. We systematically analyzed proteomics of decellularized hepatic matrix and identified four unique clusters of ECM proteins at tissue damage/inflammation, transitional ECM remodeling or fibrogenesis stage in carbon tetrachloride-induced liver fibrosis. Clusters of ECM proteins responsible for homeostatic remodeling and tissue fibrogenesis, as well as basement membrane signature were significantly associated with disease progression and patient survival. Unique matrisomal proteins were identified for tissue damage/inflammation, transitional ECM remodeling and fibrogenesis Such matrisomal protein signatures, including basement membrane signature, are predictive of Child-Pugh Class A earlystage cirrhosis progression and patient survival. A 14-gene signature, present in both cluster 4 and basement membrane signatures, predicts progression and patient survival of Child-Pugh Class A early-stage cirrhosis
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