The role of liver progenitor cells in liver regeneration

项目概要-肝祖细胞在肝再生中的作用 急性和慢性肝病导致肝功能衰竭，并且是发病率和死亡率不断增长的原因。 mortality. COVID-19疫情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，然而，一个专门的干细胞群体的存在仍然存在， 争议在我们的初步工作中，我们描述了一个接近全肝细胞消融模型， 斑马鱼，其中器官再生来源于胆管上皮细胞。我们的目标是 研究EAE影响器官功能的意义和分子机制 发展我们的中心假设是，严重的肝细胞损伤将揭示兼性 胆管上皮细胞的干细胞潜能。这个过程似乎是由EGFR，PI 3 K， 和mTOR信号。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 高分辨率成像分析后，近全肝细胞消融，以调查是否和 当胆管上皮细胞经历转录和形态变化， 肝细胞在这个过程中，我们将生成斑马鱼所有肝细胞的清单， 通过与小鼠和小鼠相比，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Aim 2将决定胆管上皮细胞增殖的程度 肝细胞分化前成肝细胞转录因子基因表达及其意义 参与这种兼性细胞的产生、功能和增殖的信号通路 干细胞群体鉴定一种类似EGFR的信号，可导致胆管上皮细胞 成为肝细胞对肝衰竭患者具有显著的治疗潜力。

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.