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-肝祖细胞在肝脏再生中的作用 急性和慢性肝病会导致肝功能衰竭，是发病率和 死亡率。新冠肺炎疫情进一步加剧了这一问题的严重性。肝脏 是一种高度再生的器官，但存在专门的干细胞群体 有争议的。在我们的初步工作中，我们描述了一种近乎完全的肝细胞消融模型 器官再生来源于胆管上皮细胞的斑马鱼。我们在这里的目标是 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临时性的 胆管上皮细胞的干细胞潜能。这一过程似乎是由EGFR、PI3K、 和mTOR信令。提出了两个具体的目标来定义产生和贡献 兼性肝干细胞。在特定目标1中，我们将利用单细胞转录和 近全肝细胞消融术后的高分辨率成像分析 当胆管上皮细胞经历转录和形态变化时 肝细胞。在这个过程中，我们将生成斑马鱼中所有肝细胞的清单，并 通过与小鼠和小鼠的比较来确定细胞特性和功能的进化保守性 人类肝脏数据集。特异性AIM2将决定胆管上皮细胞的增殖程度 肝细胞分化前肝母细胞转录因子基因的表达及意义 参与这一兼性细胞的产生、功能和增殖的信号通路 干细胞种群。鉴定类似EGFR的信号可导致胆管上皮细胞 成为肝细胞对肝功能衰竭患者具有显著的治疗潜力。