Abstract
Hepatic stellate cells (HSCs) exist in the liver’s perisinusoidal space, are phenotypically activated, and acquire myofibroblast-like phenotype. This phenotypic transformation is accountable for the accumulation and production of various extracellular matrix (ECM) proteins, involving different fibril-forming collagens in the perisinusoidal space, producing altered hepatic function and portal hypertension and increased vascular resistance, fibrosis, cirrhosis, and hepatocellular carcinoma. The activated HSCs/myofibroblasts are principal collagen-producing cells in the damaged liver. Therefore, fibrosis treatments are often targeting HSCs. HSCs store most of the total body’s retinol in their cytoplasm, and hence, antifibrotic nanomedicines are often targeted with vitamin A decoration. Vitamin A-decorated nanomedicines with siRNAs for transforming growth factor-beta, collagen, and connective tissue growth factors target to inhibit fibrogenesis and the ECM-associated gene expressions, leading to fibrosis regression. Similarly, a variety of miRNAs play pro- and antifibrotic function. In the fibrotic liver, the profibrotic miRNAs are targeted with their respective antagomir and the antifibrotic miRNAs are targeted with their respective agomirs along with HSC-specific nanodecoration. These miRNA treatments reduce fibrogenesis by downregulation of ECM-related gene expressions. However, liver fibrosis is caused by the upregulation of a different type of profibrotic signaling pathways associated with ECM accumulation in the fibrotic liver. Therefore, specific gene silencing by siRNAs or targeting particularly miRNA may also not effectively reduce fibrosis to a greater extent. However, nanodecoration of a drug is useful to deliver drugs into activated HSCs in the injured liver. Therefore, the aim of this review is to focus on targeted drug delivery towards activated HSCs in the persistently damaged liver.
Highlights
Chronic liver diseases are the main cause of universal health problem
Increased extracellular matrix (ECM) synthesis and scar formation are considered as the initial event of liver fibrosis mediated by the hepatic stellate cell (HSC), which is the principal collagen-producing cell in the chronically injured liver [5]
HSCs activation often leads to the overexpression of several cell surface receptors such as collagen type 4, transforming expressing growth factor-β (TGF-β), connective tissue growth factor receptors, PDGFRβ, retinol binding protein (RBP) receptor, synaptophysin, cluster of differentiation 44 (CD44), insulin-like growth factor-II receptor (IGF2R), and low-density lipoprotein receptor [24]
Summary
Chronic liver diseases are the main cause of universal health problem. Approximately, 2 million annual deaths are attributed to cirrhosis and its associated complications, hepatocellular carcinoma (HCC) and viral hepatitis [1]. Hepatic fibrosis is the common sequel of chronic liver diseases. If fibrosis is not properly treated, it progresses into cirrhosis and its related complications like portal hypertension and HCC. Increased ECM synthesis and scar formation are considered as the initial event of liver fibrosis mediated by the hepatic stellate cell (HSC), which is the principal collagen-producing cell in the chronically injured liver [5]. Chronic liver diseases are often reversible after the withdrawal of underlying etiology, and their treatment mainly focused on etiology-specific. HSCs are one of the prime targets for treating fibrotic liver [8]. Studies have principally targeted HSCs with several nanoformulations to control or regress the ongoing liver fibrosis. This review is primarily focusing on novel nano-based drug delivery systems targeting HSCs in the fibrosed liver
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