Stellate Cell Contraction: Role, Regulation, and Potential Therapeutic Target

Abstract

SynopsisThe contraction of hepatic stellate cells has been proposed to mediate fibrosis by regulating sinusoidal blood flow and extracellular matrix remodeling. Abundant data from diverse, yet complementary, experimental methods support a robust model for the regulation of contractile force generation by stellate cells. In this model, soluble factors associated with liver injury, including endothelin-1 and nitric oxide, are transduced primarily through rho signaling pathways that promote the myosin IIpowered generation of contractile force by stellate cells. The enhanced knowledge of the role and differential regulation of stellate cell contraction may facilitate the discovery of new and targeted strategies for the prevention and treatment of hepatic fibrosis. Keywordshepatic stellate cell; contraction; fibrosis; pericyte; rho-associated kinase; sinusoid IntroductionContractile force generation by hepatic stellate cells is recognized to play a key role in the liver's response to injury. This cellular behavior is consequently believed to contribute to normal healing as well as the development of hepatic fibrosis. Therefore, improved understanding of stellate cell contraction and its regulation would be predicted to facilitate development of clinical strategies for the treatment of liver disease. Despite more than 15 years of study, however, effective therapies based on targeting the generation of contractile force by stellate cells have remained elusive. This chapter will examine the current state of knowledge regarding stellate cell contraction, its role, its regulation, and its potential as a therapeutic target, by addressing three fundamental questions:1. What do we believe we know? Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. In summary, conventional wisdom holds that hepatic stellate cells are contractile, and their capacity to generate contractile force mediates the liver's injury response through modulation of sinusoidal blood flow and scar contracture (Fig. 1). This current understanding of the role of stellate cell contraction is, however, largely based on circumstantial evidence and common logic. In the following section we will dissect the scientific methods that have been employed to study stellate cell contraction, as well as discuss the model (Fig. 2) for the regulation of stellate cell contraction that is best supported by the evidence. NIH Public AccessWhat do we really know about hepatic stellate cell contraction? [20][21][22][23]. In this assay stellate cells in culture were grown to sub-confluence on a glass cover slip and visualized with transmissio...

MR Imaging of activated hepatic stellate cells in liver injured by CCl4 of rats with integrin-targeted ultrasmall superparamagnetic iron oxide

“…The findings indicate that the activated HSCs in liver fibrosis can be targeted and imaged in vivo by a specific probe when using MR imaging. Since the activated HSCs are responsible for the overproduction of the ECM during the hepatic fibrogenesis, targeting the HSCs is a reasonable option for the cellspecific therapy of liver fibrosis [10,24]. The first HSC-specific carrier, mannose 6-phosphate/ insulin-like growth factorII receptor modified with human serum albumin (M6P/IGFII-HSA), has been reported in 1999 [25].…”

Vitamin A and lipid metabolism: relationship between hepatic stellate cells (HSCs) and adipocytes

“…Vitamin A storage and metabolism [9] Lipid storage and metabolism [59] Lipid storage and metabolism [41] Vitamin A storage and metabolism [10] Hepatic blood flow regulation [51,58] Endocrine regulation of metabolism [49,64] Tissue repairing [28] Tissue repairing [72] Enzymatic and protein equipment…”

Murine junctional adhesion molecules JAM-B and JAM-C mediate endothelial and stellate cell interactions during hepatic fibrosis

“…7 LSECs form a discontinuous barrier without classical TJs and their open fenestrations allow transvascular exchange between blood and the perisinusoidal space of Diss e, which is further populated by Kupffer cells and hepatic stellate cells (HSCs). The latter are considered liver-specific pericytes since several ultrastructural and physiological features of HSCs are similar to those of pericytes in other organs 7,8 : HSCs have long cytoplasmic processes, which embrace the abluminal surface of the endothelium wall surrounding the sinusoids; when activated, they differentiate into myofibroblasts, which express a-smooth muscle actin (a-SMA); and they show vasomotor activity in response to endothelin, angiotensin II or transforming growth factor-b: [9][10][11] Thus, HSCs influence the sinusoid diameter and stabilize vessel walls. The close proximity between LSECs and HSCs allows for paracine signaling via endothelial heparin-binding EGF-like growth factor or platelet derived growth factor-BB (PDGF-BB), which attract HSCs to vessels or via HSC-secreted vascular endothelial growth factor supporting angiogenesis.…”