Reprogramming of liver cell fate by Hippo signaling

通过 Hippo 信号重新编程肝细胞命运

• 批准号: 8676791
• 负责人: Fernando Camargo
• 金额: $ 38.23万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8676791
• 关键词: Adult; Biliary; Biological Assay; Biology; Cell Transplantation; Cells; Characteristics; Data; Development; Gene Expression; Genes; Genetic Epistasis; Goals; Growth; Hepatic; Hepatocyte; In Situ; In Vitro; Laboratories; Lead; Liver; Liver Regeneration; Liver Stem Cell; Liver diseases; Maintenance; Mammals; Mediating; Modeling; Molecular; Mus; Natural regeneration; Nature; Normal tissue morphology; Organ; Organ Size; Organ Transplantation; Organoids; Outcome Study; Pathway interactions; Patients; Population; Process; Property; Proteins; Reporter; Signal Transduction; Solid; Staging; Stem cells; Structure; Testing; Therapeutic; Transducers; Transplantation; Work; base; cell type; cellular targeting; chromatin immunoprecipitation; empowered; in vivo; insight; liver cell proliferation; liver transplantation; matrigel; member; notch protein; novel; oval cell; overexpression; primitive cell; progenitor; public health relevance; research study; response; restoration; self-renewal; tissue culture; tumorigenesis

DESCRIPTION (provided by applicant): Liver transplantation is the second most common form of solid organ transplant with more than a quarter of listed patients expiring prior to receiving an organ. Developing a means to either stimulate liver regeneration or cultivate liver cells under tissue culture conditions could potentially abrogate the need for transplantation. While several groups have attempted to cultivate liver stem cells in the laboratory, robust conditions that could fulfill the current transplantation needs have yet to be developed. Our laboratory has made two recent discoveries that may be useful for the expansion of liver stem cells. First, we have found that changes in Hippo signaling can reprogram mature hepatocytes into cells displaying characteristics of bipotential liver progenitor cells. Hippo signaling has ben previously described as a potent growth regulator, but this finding suggests this pathway also confers increased plasticity upon differentiated cells. Secondly, we have developed culture conditions in which manipulation of Hippo signaling allows for long-term growth and enormous expansion of liver progenitors and reprogrammed hepatocytes. We propose to investigate the nature of these findings in three parts: 1) Utilize a novel Hippo reporter mouse line to determine whether endogenous Hippo activity can mark the elusive liver progenitor cell in situ. 2) Elucidate whether reprogrammed-hepatocytes contain bona fide stem cells as tested functionally in vitro and in vivo; and 3) Investigate the downstream mechanisms by which YAP reprograms hepatocytes. Completion of this project would elucidate the nature of the liver progenitor/stem cell compartment; and explore the plasticity of liver cell fate as a strategy to develop transplantable cells for transplantation.

描述（由申请人提供）：肝移植是固体器官移植的第二大最常见形式，在接收器官之前已有四分之一以上的患者到期。开发一种刺激肝脏再生或在组织培养条件下培养肝细胞的方法可能会消除移植的需求。尽管几个小组试图在实验室中培养肝脏干细胞，但可以满足当前移植需求的稳健条件尚未开发。我们的实验室已经进行了两个最近的发现，这些发现可能对肝干细胞的扩展有用。首先，我们发现河马信号的变化可以将成熟的肝细胞重新编程到显示两局肝脏祖细胞特征的细胞中。 Hippo信号传导先前已将BEN描述为有效的生长调节剂，但是这一发现表明该途径也使分化细胞上的可塑性增加。其次，我们开发了培养条件，在这种情况下，对河马信号的操纵允许长期生长和肝脏祖细胞的巨大扩张和重编程的肝细胞。我们建议在三个部分中研究这些发现的性质：1）利用新型的河马记者小鼠系来确定内源性河马活性是否可以标记难以捉摸的肝脏祖细胞原位。 2）阐明重编程的羊皮细胞是否包含真正在体外和体内测试的真正的干细胞； 3）研究YAP重编程肝细胞的下游机制。该项目的完成将阐明肝脏祖细胞/干细胞室的性质；并探索肝细胞命运的可塑性，作为发展可移植细胞进行移植的策略。