Figure 3 – HSCs during liver injury and regeneration.

HSCs become activated by liver injury. Activation involves downregulation of the adipogenic transcription factors, and loss of the retinoid-storing lipid droplets. HSCs differentiate into contractile myofibroblasts, proliferate, and can respond to chemotactic signals. A number of secreted factors participate in the response to injury. For example, tumor growth factor beta (TGFβ) activates immune cells, but also enhances HSC activation via autocrine signaling. The HSCs continue to produce hepatocyte growth factor (HGF), but also degrade the basal extracellular matrix (ECM) by matrix metalloproteinase 2 (MMP2), which frees sequestered HGF and stimulates hepatocyte proliferation. HSCs also produce vascular endothelial growth factor (VEGF), as well as fibroblast growth factor, platelet-derived growth factor, and TGFβ which can all enhance angiogenesis. Activated HSCs also synthesize the collagen-rich fibrosis, as well as proteoglycans, glycosaminoglycans, and tissue-inhibitor of matrix metalloproteinases which all participate in the formation of the fibrotic scar. Lastly, HSCs participate in the termination of liver regeneration by re-establishing the basal ECM which sequesters HGF. Likewise, TGFβ from HSCs can inhibit hepatocyte proliferation to help terminate liver regeneration.