The Origin and Fate of Liver Myofibroblasts

Abstract

Liver fibrosis of different etiologies is a serious health problem worldwide. There is no effective therapy available for liver fibrosis except the removal of the underlying cause of injury or liver transplantation. Development of liver fibrosis is caused by fibrogenic myofibroblasts that are not present in the normal liver, but rather activate from liver resident mesenchymal cells in response to chronic toxic or cholestatic injury. Many studies indicate that liver fibrosis is reversible when the causative agent is removed. Regression of liver fibrosis is associated with the disappearance of activated myofibroblasts and resorption of the fibrous scar. In this review, we discuss the results of genetic tracing and cell fate mapping of hepatic stellate cells and portal fibroblasts, their specific characteristics, and potential phenotypes. We summarize research progress in the understanding of the molecular mechanisms underlying the development and reversibility of liver fibrosis, including activation, apoptosis, and inactivation of myofibroblasts.

Keywords: Hepatic Stellate Cells; Liver Fibrosis; Portal Fibroblasts.

Figure 1

Contribution of HSCs and PFs to hepatic myofibroblasts. (A) Representative markers that can differentiate aHSCs from aPFs. (B) HSCs are located in the space of Disse (between sinusoidal endothelial cells and hepatocytes) and store vitamin A. PFs are located around portal triads, and under physiological conditions maintain the integrity of the portal tract. There are no myofibroblasts in the normal liver. In response to chronic liver injury HSCs rapidly activate and give rise to collagen type I–producing myofibroblasts. PFs activate into myofibroblasts mainly in response to cholestatic injury.

Figure 2

Characterization of phenotypic changes in HSCs in response to chronic injury and fibrosis recovery. Under physiological conditions, HSCs exhibit a quiescent state (qHSCs). In response to chronic liver injury, release of TGF-β1, qHSCs activate into collagen type I–expressing aHSCs. Upon removal of the underlying etiological cause of injury, liver fibrosis can regress, and aHSCs can senesce and apoptose, or inactivate. Inactivation of HSCs (iHSCs) downregulates expression of fibrogenic genes and upregulates expression of some but not all quiescence-associated genes. Phenotype-specific expression of the signature genes (blue boxes) and transcription factors (yellow boxes), and senescence-associated secretory phenotype (SASP) (green box) are shown.

Figure 3

Potential similarities and differences in responses of embryonic and adult HSCs to injury and inactivation. (A) Based on the data analysis of Col-GFP mice (that express collagen type I in real time) and cell fate mapping of collagen type I–expressing HSCs throughout the embryonic development (E14–E16) into the adulthood (2 months), dynamic changes in the HSC composition in normal liver, in response to fibrogenic injury (2 months of CCl₄), and during regression of liver fibrosis (1 month after CCl₄ cessation), were identified. (B) The heatmap depicts the top genes uniquely expressed in eHSCs, eHSCs that escape apoptosis and persist into the adulthood in healthy mouse livers (peHSCs), the classical qHSCs, activated fibrogenic myofibroblasts (aHSCs), and HSCs detected during fibrosis resolution (HSCs that survive apoptosis and inactivate [iHSCs] and newly generated recovery-associated HSCs [rqHSCs]). Upregulated (red) and downregulated (blue) genes are shown.