Hepatic stellate cells in NASH fibrosis and HCC

NASH 纤维化和 HCC 中的肝星状细胞

• 批准号: 10182514
• 负责人: SCOTT L. FRIEDMAN
• 金额: $ 49.58万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 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/10182514
• 关键词: Address; Affect; American; Animal Model; Animals; Behavior; CD8-Positive T-Lymphocytes; Cells; Cellular biology; Cessation of life; Chronic; Cicatrix; Cirrhosis; Clinical; Coupled; Data; Development; Disease; Extracellular Matrix; Fibroblasts; Fibrosis; Goals; Green Fluorescent Proteins; Growth Factor; Health; Hepatic Stellate Cell; Histologic; Histology; Homeostasis; Human; Hypertension; Individual; Inflammation; Knowledge; Ligation; Link; Liver; Liver Fibrosis; Liver diseases; Malignant Neoplasms; Malignant neoplasm of liver; Metabolic syndrome; Metagenomics; Methods; Mission; Modeling; Mus; Myofibroblast; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathogenesis; Pathogenicity; Patients; Phenotype; Plasminogen; Platelet-Derived Growth Factor beta Receptor; Positioning Attribute; Prevalence; Primary Malignant Neoplasm of Liver; Primary carcinoma of the liver cells; Public Health; Regulator Genes; Reproducibility; Research; Role; Source; Stromal Change; System; T-Cell Depletion; T-Lymphocyte; Testing; Tissues; Transgenic Mice; Urokinase; Viral hepatitis; Vitamin A; bile duct; carcinogenicity; cell killing; chimeric antigen receptor T cells; clinically relevant; cytokine; defined contribution; engineered T cells; hepatocyte injury; improved; innovation; insight; liver injury; morphometry; mouse model; new therapeutic target; nonalcoholic steatohepatitis; prevent; promoter; public health priorities; receptor; senescence; single-cell RNA sequencing; therapeutic target; tool; transcriptome; transcriptomics; tumor

Non-alcoholic steatohepatitis (NASH) is a rising public health threat characterized by progression from steatosis, to hepatocyte injury, inflammation, fibrosis and hepatocellular carcinoma (HCC). A key unanswered question is how inflammation and hepatic fibrosis create a ‘pro-carcinogenic stroma’ that promotes the development of hepatocellular carcinoma (HCC), even without co-existent cirrhosis. Central to these stromal changes is the activation of hepatic stellate cells (HSCs), which are resident perisinusoidal, vitamin A-rich cells that transdifferentiate into myofibroblasts (cancer-associated fibroblasts, or CAFs) to secrete a host of extracellular matrix constituents, growth factors, and cytokines. The objective of this research is to clarify the role of hepatic stellate cells in the pathogenesis of NASH and HCC. We and our collaborators have developed two highly efficient, complementary models of HSC depletion that can address critical gaps in understanding their role in NASH fibrosis and HCC: 1) JEDI (“Just EGFP death inducing”) T-cells, in which CD8+ T cells engineered to kill cells that express green fluorescent protein (GFP) are administered to transgenic mice, in which GFP is driven by the b-PDGF receptor promoter, killing 99% of HSCs; 2) CAR T cells targeting urokinase plasminogen activated receptor (uPAR), which eliminate only senescent HSCs in murine liver. Concurrently, we have created a highly reproducible murine NASH model that faithfully replicates the histology, fibrosis progression and HCCs of human NASH. Our central hypothesis is that activated and senescent HSCs in NASH express unique drivers that contribute to a tumor-prone stromal microenvironment. Thus, this proposal concurrently investigates the dynamics and unique contributions of HSCs to NASH, and the stromal abnormalities they generate that give rise to HCC. We will address this hypothesis in three interrelated, but distinct Specific Aims:1) To define the dynamics, origin and cellular features of HSC repopulation before and after their depletion in normal and NASH mice; 2) To establish the relative contributions of senescent and non-senescent HSCs to NASH fibrosis and HCC; 3) To identify HSC-derived stromal drivers of HCC in murine and human NASH. This innovative approach leveraging unique animal models is significant because it will yield fundamental new insights into HSC biology in health and disease, define specific stromal drivers that they regulate, and link abnormalities from mouse models to human NASH-HCC to establish their clinical relevance as potential therapeutic targets.

非酒精性脂肪性肝炎 (NASH) 是一种日益严重的公共卫生威胁，其特征是脂肪变性、 肝细胞损伤、炎症、纤维化和肝细胞癌（HCC）。一个尚未回答的关键问题是 炎症和肝纤维化如何产生“促癌基质”，促进癌症的发展 肝细胞癌（HCC），即使没有共存的肝硬化。这些基质变化的核心是 肝星状细胞 (HSC) 的激活，这些细胞是常驻于窦周、富含维生素 A 的细胞， 转分化为肌成纤维细胞（癌症相关成纤维细胞，或 CAF）以分泌大量细胞外 基质成分、生长因子和细胞因子。本研究的目的是阐明肝脏的作用 星状细胞在 NASH 和 HCC 发病机制中的作用。我们和我们的合作者开发了两种高度 高效、互补的 HSC 消耗模型，可以解决理解其作用的关键差距 NASH 纤维化和 HCC：1) JEDI（“Just EGFP 死亡诱导”）T 细胞，其中 CD8+ T 细胞被设计用于杀死 将表达绿色荧光蛋白（GFP）的细胞给予转基因小鼠，其中 GFP 被驱动 通过b-PDGF受体启动子，杀死99%的HSC； 2）靶向尿激酶纤溶酶原的CAR T细胞 激活受体（uPAR），仅消除小鼠肝脏中衰老的 HSC。同时，我们创建了 高度可重复的小鼠 NASH 模型，忠实地复制组织学、纤维化进展和 HCC 人类NASH。我们的中心假设是 NASH 中激活和衰老的 HSC 表达独特的驱动因素 有助于形成易发肿瘤的基质微环境。因此，本提案同时研究了 HSC 对 NASH 的动态和独特贡献，以及它们产生的基质异常 至肝癌。我们将通过三个相互关联但又不同的具体目标来解决这个假设：1）定义 正常和 NASH 中 HSC 耗竭前后的动态、起源和细胞特征 老鼠； 2) 确定衰老和非衰老 HSC 对 NASH 纤维化的相对贡献 肝癌； 3) 鉴定小鼠和人类 NASH 中 HCC 的 HSC 衍生基质驱动因素。这种创新方法 利用独特的动物模型意义重大，因为它将产生对 HSC 生物学的基本新见解 在健康和疾病中，定义它们调节的特定基质驱动因素，并将小鼠的异常联系起来 人类 NASH-HCC 模型，以确定其作为潜在治疗靶点的临床相关性。