Growth Regulation of the Intrahepatic Biliary Tree

描述（申请人提供）：胆管细胞是原发性胆汁性肝硬化（PBC）、原发性硬化性胆管炎（PSC）等慢性胆汁淤积性肝病的靶细胞，其特点是不同大小（即小、大）胆管细胞的损伤、增殖和分化。在这些破坏性肝脏疾病的发病过程中，胆管细胞分化和胆道重塑对胆道肿块的维持和功能恢复至关重要。阐明调节大小胆管细胞对胆汁淤积和肝损伤/毒素的不同再生反应的细胞内机制，将在制定治疗胆汁淤积性肝病的治疗策略中发挥关键作用。在慢性肝胆损伤期间，一群双能性肝祖细胞被激活以补充胆管细胞和肝细胞。如果人类和啮齿类动物的胆管中存在具有多电位能力的小胆管细胞，那么这些细胞应该在肝损伤期间，例如在大胆管细胞或肝细胞丢失或再生机制受阻的疾病条件下，具有分化为大胆管细胞或肝细胞的能力。肝内胆管细胞的可塑性已经被假设为一个谱系的终末分化细胞可以直接分化到另一个谱系或进行反分化。因此，特定的细胞亚群，如表达已知胆道祖细胞标记的小胆管细胞，可以假设在暴露于某些病理条件下包含多能细胞群。我们提出了一个中心假设，即小胆管细胞通过在病变条件下获得肝祖细胞和大胆管细胞的表型来促进胆道损伤的恢复。系统研究多能基因和microrna作为小胆管细胞中具有治疗胆汁淤积性肝损伤潜力的标志物。中心假设将通过三个具体目标进行评估。首先，我们将区分多能性

DESCRIPTION (provided by applicant): Cholangiocytes are the target cells in chronic cholestatic liver diseases such as primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC), which are characterized by the damage, proliferation and differentiation of cholangiocytes of different sizes (i.e., small and large). Cholangiocyte differentiation and biliar remodeling are critical for the maintenance of biliary mass and the functional recovery during the pathogenesis of these devastating liver diseases. The elucidation of the intracellular mechanisms regulating the differential regenerative responses of small and large cholangiocytes to cholestasis and liver injury/toxins will play a pivotal role in the development o therapeutic strategies for the treatment of cholestatic liver diseases. During chronic hepatobiliary injury, a population of bipotent liver progenitor cells becomes activated to replenis both cholangiocytes and hepatocytes. If small cholangiocytes with multipotential capacity exist within human and rodent bile ducts, these cells should possess the ability to differentiate into either large cholangiocytes or hepatocytes during liver damage, such as diseased conditions in which large cholangiocytes or hepatocytes are lost or regenerative mechanisms are hampered. The plasticity of intrahepatic cholangiocytes has been postulated that terminally differentiated cells of one lineage may directly differentiate into another lineage or undergo trans-differentiation. Therefore, specific subpopulations of cells, such as small cholangiocytes that express known biliary progenitor cell markers, can be hypothesized to contain a multipotent cell population when exposed to certain pathological conditions. We propose the central hypothesis that small cholangiocytes contribute to the recovery of biliary injury through acquiring the phenotypes of liver progenitor cells and large cholangiocytes under diseased conditions. Systematic investigation of pluripotent genes and microRNAs is proposed in this application as markers in small cholangiocytes with the therapeutic potentials for cholestatic liver injury. The central hypothesis will be evaluated by three specific aims. First, we will distinguish pluripotent functional signaling pathways involved in tissue repair-related cellular functions in small and large cholangiocytes. Second, we will identify TGF-� dependent miRNAs involved in differentiation/regeneration-related cellular functions in small cholangiocytes. Last, we will determine the effects of small cholangiocytes and their-associated miRNAs on accelerating the morphologic and functional recovery of transgenic and chronic cholestatic liver injury in specific animal models. Therapeutic effects of cell engraft/miRNA manipulation on biliary cell growth and differentiation will be evaluated in vivo. Novel insights into the physiological roles and mechanisms of molecular and functional heterogeneity in human biliary epithelium will be obtained. Meanwhile, the fundamental knowledge obtained in the regulation of growth, differentiation and remodeling by small cholangiocytes/biliary committed progenitors is expected to advance the field of cholangiocyte biology/ pathophysiology.