The role of liver progenitor cells in liver regeneration

肝祖细胞在肝再生中的作用

• 批准号: 10607301
• 负责人: Wolfram Goessling
• 金额: $ 66.91万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10607301
• 关键词: Ablation; Acetaminophen; Acute; Adult; Affect; Atlases; Bile fluid; Biliary; Blood; COVID-19 pandemic; Cells; Cessation of life; Chemicals; Chronic; Data Set; Dedications; Development; Endoderm Cell; Epidermal Growth Factor Receptor; Epithelial Cell Proliferation; Epithelial Cells; Equipment and supply inventories; Experimental Autoimmune Encephalomyelitis; FRAP1 gene; Fibrosis; Fishes; Gallbladder; Gene Expression; Generations; Genetic; Genetic Transcription; Goals; Hepatic; Hepatocyte; Homeostasis; Human; Inflammation; Injury; Intestines; Liver; Liver Failure; Liver Regeneration; Liver Stem Cell; Maps; Mediating; Metabolic; Methods; Microscopy; Modeling; Molecular; Morbidity - disease rate; Morphology; Mus; Muscle; Natural regeneration; Organ; Outcome; PIK3CG gene; Partial Hepatectomy; Pathway interactions; Patients; Phenotype; Population; Process; Proliferating; Rattus; Regenerative capacity; Regenerative response; Reporter; Resolution; Role; Signal Pathway; Signal Transduction; Skin; Therapeutic; Therapeutic Intervention; Tissues; Work; Zebrafish; adult stem cell; airway epithelium; cell type; chronic liver disease; experimental study; hepatocyte injury; high resolution imaging; insight; liver development; liver function; liver injury; liver repair; mTOR Signaling Pathway; mortality; novel; organ growth; organ regeneration; oval cell; progenitor; regenerative; response to injury; self-renewal; single-cell RNA sequencing; stem cell population; stem cells; timeline; tool; transcription factor; transcriptomics

Project Summary - The role of liver progenitor cells in liver regeneration Acute and chronic liver disease causes liver failure and is a growing cause for morbidity and mortality. The COVID-19 pandemic has further increased the magnitude of this problem. The liver is a highly regenerative organ, yet the presence of a dedicated stem cell population remains controversial. In our preliminary work, we describe a near-total hepatocyte ablation model in zebrafish where organ regeneration is derived from biliary epithelial cells. Our objective here is to characterize the functional implications and molecular mechanisms of EAE to affect organ development. Our central hypothesis is that severe hepatocyte injury will reveal the facultative stem cell potential of biliary epithelial cells. This process appears to be driven by EGFR, PI3K, and mTOR signaling. Two Specific Aims are proposed to define the generation and contribution of facultative hepatic stem cells. In Specific Aim 1 we will utilize single-cell transcriptomic and high-resolution imaging analyses after near-total hepatocyte ablation to investigate whether and when biliary epithelial cells undergo transcriptional and morphological changes to become hepatocytes. In the process, we will generate an inventory of all liver cells in the zebrafish and determine evolutionary conservation of cell identity and function by comparison to murine and human liver datasets. Specific Aim2 will determine the degree of biliary epithelial cell proliferation hepatoblast transcription factors gene expression prior to hepatocyte differentiation and define the signaling pathways involved in the generation, function and proliferation of this facultative stem cell population. Identification of a signal like EGFR that can cause biliary epithelial cells to become hepatocytes has significant therapeutic potential for patients with liver failure.

项目摘要 - 肝祖细胞在肝再生中的作用 急性和慢性肝病会导致肝功能衰竭，并且是发病率和死亡率日益增长的原因 死亡。 COVID-19 大流行进一步加剧了这一问题的严重性。肝脏 是一个高度再生的器官，但仍然存在专用的干细胞群 有争议的。在我们的前期工作中，我们描述了一种近乎完全的肝细胞消融模型 斑马鱼的器官再生源自胆管上皮细胞。我们的目标是 描述 EAE 影响器官的功能含义和分子机制 发展。我们的中心假设是严重的肝细胞损伤将揭示兼性 胆道上皮细胞的干细胞潜力。这个过程似乎是由 EGFR、PI3K、 和 mTOR 信号传导。提出了两个具体目标来定义生成和贡献 兼性肝干细胞。在具体目标 1 中，我们将利用单细胞转录组学和 近乎全部肝细胞消融后进行高分辨率成像分析，以研究是否和 当胆道上皮细胞经历转录和形态学变化时 肝细胞。在此过程中，我们将生成斑马鱼所有肝细胞的清单，并 通过与小鼠和小鼠的比较来确定细胞身份和功能的进化保守性 人类肝脏数据集。具体的Aim2将决定胆道上皮细胞增殖的程度 肝细胞分化前的成肝细胞转录因子基因表达并定义 参与这种兼性的产生、功能和增殖的信号通路 干细胞群。鉴定像 EGFR 这样的信号，可以导致胆管上皮细胞 成为肝细胞对于肝功能衰竭患者具有显着的治疗潜力。