HSC in Physiology and Pathology
Hepatic Stellate Cells (HSCs) are vitamin A storing perisinusoidal pericytes that undergo phenotypic changes characterized as “myofibroblastic activation” during liver cirrhosis. Activated HSCs produce fibrosis factors such as collagen, which leads to the formation of scar tissue in the liver and therefore increases intra hepatic resistance to blood flow. This is how stressed liver ultimately slips into hepatic insufficiency and portal hypertension.
The hepatic Stellate cell number increases from the normal 3% to 15% during liver cirrhosis. HSCs and sinusoidal endothelial cells exist in close proximity to each other in hepatic sinusoid. The hepatic stellate cells (HSC) are now well established as the key cellular element involved in the development of hepatic fibrosis. Liver fibrosis is a histological change in the liver due to inflammation that causes HSCs to undergo activation with the synthesis of excess ECM proteins. HSCs play an important role that facilitates the process of fibrosis and thereby liver cirrhosis. HSCs are liver specific pericytes that usually store fat and vitamin A in normal liver. Under inflammation, HSCs undergoes a trans-differentiated stage leading to liver cirrhosis (Friedman et al 2004). Under normal conditions, HSCs remain in a dormant state, has protrusions extending from the cell body that wraps around the sinusoids. In pathological conditions such as liver fibrosis or liver cirrhosis, activated HSCs undergo cell proliferation, cell migration, loses retinoids, secrete proinflammatory cytokines and synthesize a large amount of extracellular matrix (ECM) components including collagen, proteoglycan and adhesive glycoproteins. Morphology of these cells also changes from the star shaped stellate cells to that of the fibroblasts or myofibroblasts and acquires contractile properties. HSCs show remarkable changes in the secretory pattern after activation.
Leptin, PPAR, SREBP-1c are the markers expressed in quiescent HSCs. Upon activation, HSCs express mostly alpha smooth muscle actin, c-myb, and myocyte enhancer factor–2 (Bataller and Brenner, 2005). About 5-8% of the total number of liver cells is represented by quiscent HSCs while it increases to 15-20% during cirrhotic condition (Geerts, 2001). Activation of HSC consists of 2 major phases: (1) initiation (also called a preinflammatory stage) and (2) perpetuation. Initiation refers to early paracrine-mediated changes in gene expression and phenotype that render the cells responsive to other cytokines and stimuli. Perpetuation results from the effects of these stimuli on maintaining the activated phenotype and generating fibrosis (Friedman, 2000).
The liver is composed of several cell types which are given in the form of a table:
|Name of the Cell||Property||Function||Image|
|Hepatocytes/biliary cells||Polyploid, highly polarized, parenchymal cells||Metabolism, produce bile salts, participates in liver regeneration||
Source:Wilkening et al 2003
|Hepatic stellate cells (Ito cells)||Pericytes||Store fat and vitamin A in normal liver. Produces collagen under pathology|
|Kupffer cells||Liver resident macrophages||Innate immune system||
Source: Sunman et al 2004
|Endothelial cells||Proliferation, migration||Line the sinusoids||
Source: LRSU – AUKBC
|Liver stem cells||Highly plastic||regeneration||
Source: LRSU – AUKBC
- Wilkening S, Stahl F, Bader A. Comparison of primary human hepatocytes and hepatoma cell line Hepg2 with regard to their biotransformation properties. Drug Metab Dispos. 2003 Aug; 31(8):1035-42.
- Sunman JA, Hawke RL, LeCluyse EL, Kashuba AD Kupffer cell-mediated IL-2 suppression of CYP3A activity in human hepatocytes. Drug Metab Dispos. 2004 Mar;32(3):359-63.
- Friedman SL. Mechanisms of disease: Mechanisms of hepatic fibrosis and therapeutic implications. Nat Clin Pract Gastroenterol Hepatol. 2004 Dec;1(2):98-105.
- Geerts, A. “History, heterogeneity, developmental biology and functions of quiescent HSC”, Semin. Liver Dis., Vol. 21, pp. 311-335, 2001.
- Friedman SL Molecular regulation of hepatic fibrosis, an integrated cellular response to tissue injury. J Biol Chem. 2000 Jan 28;275(4):2247.