Protective and fibrosis-independent functions of hepatic stellate cells

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Hepatic stellate cells (HSC) are well-characterized as key fibrogenic cell type of the liver, contributing to the development of liver fibrosis in a wide range of diseases. While it widely believed that the development of pathological liver fibrosis is the result of “maladaptive” or overshooting HSC activation, the field also believes that “physiological” HSC activation serve provides benefits in acute and/or chronic liver disease. However, there is currently no understanding of what precisely the benefits of HSC activation constitute and whether there may be “costs” at which these benefits come in addition to the negative long-term effects of prolonged fibrosis. Purported functions of HSC activation include the mechanical stabilization of injured tissue and promotion of hepatocyte survival by HSC-secreted collagen. However, these protective functions have not been experimentally validated in vivo, and to date, it is not known which hepatic functions, injury responses and cell types are affected by HSC. Moreover, there is little understanding on the role of HSC in homeostasis beyond the fact that they store a large amount of the body’s retinyl esters. These fundamental gap are mostly due to the field’s focus on pathogenic HSC activation and fibrosis as key determinant of outcomes; and the lack of tools to study protective functions of HSC and HSC-derived mediators in vivo. Related to the field’s focus on pathogenic fibrosis, HSC are commonly viewed as final and most downstream executors, which respond to signals from injured hepatocytes and/or activated macrophages and thus represent the last step of an injury cascade. However, this view ignores the fact that their anatomical position and prototypical protrusions endeavors HSC with close connection to almost all hepatic cell types, pointing towards HSC as a potential hub in the liver’s cellular network. We have generated several tools including HSC depletion, HSC-selective gene deletion, and single cell RNA-sequencing based bioinformatics allowing us to determine the role of HSC in vivo and the efferent signals through which HSC may orchestrate cell-cell communication in the homeostatic and injured state. These tools have enabled us to generate a preliminary data supporting a key role for HSC in modulating hepatocyte proliferation and injury, and will enable us to uncover protective and fibrosis-independent functions of HSC in vivo. In Aim 1, we seek to test the contribution of HSC-hepatocyte crosstalk to liver regeneration (Aim 1), focusing on responsible mechanisms and mediators and the hypothesis that HSC and hepatocytes form a functional unit. In Aim 2, we will study the role of HSC as regulators of hepatocyte death, focusing on underlying mediators and mechanisms and our hypothesis that HSC can both promote and protect from injury. Besides providing better understanding novel HSC functions in the complex cellular crosstalk of the liver, our studies may (i) reveal therapeutically targetable pathways in acute and chronic liver disease, and (ii) provide relevant information on how targeting HSC activation or promoting HSC death, a main strategy for most direct antifibrotics currently under development or in clinical trials in NASH, may affect the liver beyond simple reduction of fibrosis.