Protective and fibrosis-independent functions of hepatic stellate cells

肝星状细胞(HSC)是肝脏的关键纤维化细胞类型，有助于 肝纤维化的发展涉及多种疾病。虽然它普遍认为， 病理性肝纤维化是“不适应”或过度激活HSC的结果，该领域也认为 这种“生理性”的HSC激活服务对急性和/或慢性肝病有好处。然而，在那里 目前还不了解激活HSC的确切好处是什么，以及是否可能 除了长期纤维化带来的负面长期影响外，这些好处还需要付出“代价”。 据称肝星状细胞激活的功能包括损伤组织的机械稳定和促进 肝细胞靠HSC分泌的胶原蛋白存活。然而，这些保护功能并没有得到 经体内实验验证，到目前为止，尚不清楚哪些肝功能、损伤反应和细胞 类型受HSC的影响。此外，对于HSC在动态平衡中的作用，除了 事实上，它们储存了人体内大量的视黄酸酯。这些根本性的差距主要是由于 外地对致病性HSC激活和纤维化作为结果关键决定因素的关注；以及缺乏工具来 研究HSC及其衍生介质在体内的保护作用。与该领域对致病的关注有关 纤维化，HSC通常被视为最终的和大多数下游的执行者，它们对来自 损伤的肝细胞和/或激活的巨噬细胞，因此是损伤级联反应的最后一步。 然而，这种观点忽略了这样一个事实，即它们的解剖位置和原型突起努力促进HSC 与几乎所有类型的肝细胞密切相关，表明HSC是肝脏的潜在枢纽 蜂窝网络。我们已经产生了几种工具，包括HSC耗尽，HSC选择性基因缺失，以及 基于单细胞RNA测序的生物信息学使我们能够确定HSC在体内的作用和传出 信号，通过这些信号，肝星状细胞可以协调处于内稳态和损伤状态的细胞间通信。这些 工具使我们能够生成支持HSC在调节肝细胞中的关键作用的初步数据 增殖和损伤，并将使我们能够揭示HSC的保护性和纤维化非依赖性功能 活着。在目标1中，我们试图测试HSC-肝细胞串扰对肝再生的贡献(目标1)， 关注责任机制和介体，以及肝星状细胞和肝细胞形成 功能单元。在目标2中，我们将研究HSC作为肝细胞死亡的调节者的作用，重点是潜在的 中介物和机制，以及我们的假设，即HSC既可以促进损伤，也可以保护免受损伤。此外 为了更好地理解HSC在复杂的肝脏细胞串扰中的新功能，我们的研究可能 (I)揭示急慢性肝病的治疗靶向途径；及。(Ii)提供相关 关于如何靶向HSC激活或促进HSC死亡的信息，这是大多数直接抗纤维化药物的主要策略 目前正在开发或正在进行NASH的临床试验，可能会影响肝脏，而不仅仅是减少纤维化。

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.