Protective and fibrosis-independent functions of hepatic stellate cells

肝星状细胞的保护性和纤维化独立功能

• 批准号: 10597076
• 负责人: Robert F. Schwabe
• 金额: $ 51.8万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597076
• 关键词: Acute; Affect; Anatomy; Bioinformatics; Cell Communication; Cell Death; Cell physiology; Cell secretion; Cells; Cessation of life; Cirrhosis; Clinical Trials; Coculture Techniques; Collagen; Complex; Data; Deposition; Development; Disease; Disease Progression; Endothelial Cells; Esters; Extracellular Matrix; Fibrosis; Functional disorder; Gene Deletion; Genetic; Hepatic; Hepatic Stellate Cell; Hepatocyte; Homeostasis; Injury; Knock-out; Kupffer Cells; Ligands; Link; Liver; Liver Fibrosis; Liver Regeneration; Liver diseases; Long-Term Effects; Macrophage; Mechanics; Mediator; Metabolism; Mus; Myofibroblast; Natural regeneration; Outcome; Partial Hepatectomy; Pathogenicity; Pathologic; Pathway interactions; Patients; Perisinusoidal Space; Physiological; Positioning Attribute; Proliferating; Regulation; Role; Signal Transduction; Testing; Therapeutically Targetable; Tissues; candidate identification; cell type; chronic liver disease; cost; functional restoration; hepatocyte injury; in vitro Model; in vivo; injured; insight; liver cell proliferation; liver development; liver injury; nonalcoholic steatohepatitis; novel; novel therapeutics; receptor; response to injury; single cell sequencing; single-cell RNA sequencing; tool

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.

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生。 肝纤维化的发展在广泛的疾病。虽然人们普遍认为， 病理性肝纤维化是“适应不良”或HSC过度激活的结果，该领域还认为， “生理性”HSC激活在急性和/或慢性肝病中提供益处。但 目前还不清楚HSC激活的确切益处是什么，以及是否可能 除了长期纤维化的负面长期影响之外，这些益处的“成本”。 HSC活化的预期功能包括损伤组织的机械稳定和促进HSC活化。 肝细胞存活率由HSC分泌的胶原决定。然而，这些保护功能并没有被 在体内实验验证，迄今为止，尚不知道哪些肝功能，损伤反应和细胞 类型受到HSC的影响。此外，除了细胞外，对HSC在体内平衡中的作用几乎没有了解。 事实上，它们储存了大量的身体的视黄酯。这些基本差距主要是由于 该领域的重点是致病性HSC激活和纤维化作为结果的关键决定因素;以及缺乏工具来 在体内研究HSC及其衍生介质的保护功能。与该领域对致病性的关注有关 在纤维化中，HSC通常被视为最终和最下游的执行者，其响应来自 损伤的肝细胞和/或活化的巨噬细胞，因此代表损伤级联的最后一步。 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有助于HSC 与几乎所有的肝细胞类型密切相关，表明HSC是肝脏的潜在中心， 蜂窝网络我们已经开发了几种工具，包括HSC耗尽、HSC选择性基因缺失和 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神经的作用。 信号，通过该信号HSC可以在稳态和损伤状态下协调细胞-细胞通信。这些 工具使我们能够生成初步数据，支持HSC在调节肝细胞中的关键作用 增殖和损伤，并将使我们能够揭示HSC的保护性和纤维化独立的功能， vivo.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）， 重点是负责任的机制和介质和假设，HSC和肝细胞形成一个 功能单位在目标2中，我们将研究HSC作为肝细胞死亡调节因子的作用，重点是潜在的 介质和机制和我们的假设，HSC既可以促进和保护损伤。除了 为了更好地理解HSC在肝脏复杂细胞串扰中的新功能，我们的研究可能 (i)揭示急性和慢性肝病的治疗靶向途径，以及（ii）提供相关的 关于如何靶向HSC活化或促进HSC死亡的信息，这是最直接的抗纤维化药物的主要策略 目前正在开发或在NASH的临床试验中，可能会影响肝脏，而不仅仅是减少纤维化。