PROTEIN SYNTHESIS IN NORMAL AND REGENERATING LIVER

近年来，人们对鉴定不同来源的祖细胞或干细胞有相当大的兴趣。 组织及其在组织再繁殖中的潜在用途。使用自然产生的、独特的细胞 肝移植系统(DPPIV突变型Fischer 344大鼠)的实验室研究 已经证明，早期胎肝上皮细胞可以重新填充多达10？4的实质 在正常肝脏中肿块，产生肝细胞和胆管上皮细胞后代并显示 细胞移植后持续增殖活动长达六个月(一般特性 归因于干细胞)。我们假设使用正常的基于肝脏的细胞移植系统， 在确定分离细胞的干细胞潜能方面起着至关重要的作用 和细胞系以及促进它们在肝脏中增殖和分化的因素。 在这一背景下，实验被提出：1)使用细胞因子和药理学试剂来 在我们的基于肝脏的细胞移植模型中促进移植的胎肝细胞的增殖， 2)研究不同群体增殖期胎儿的分子和细胞特征 肝移植后肝上皮细胞表型、增殖潜能、谱系的确定 衍生能力和自我更新的能力；3)确定成熟肝细胞是否可以 从实质进入胆管室，表现出足够的可塑性以切换 它们的表型并结合到胆管中，表明植入部位在 肝小叶决定了移植肝细胞的最终命运。我们还将使用最近的 建立的DPPIV-/-小鼠模型与大鼠相当，但现在也免疫受损 (Rag2-/-)，允许对选定的转基因和基因敲除动物进行再繁殖研究 修改细胞周期调控，促进生长因子或依赖细胞因子的增殖。这个 这些研究的总体目标是找到通过移植肝脏来促进肝脏再繁殖的方法。 最终将导致临床应用于人类的衍生细胞。

In recent years, there has been considerable interest in identifying progenitor or stem cells in various tissues and their potential use for tissue repopulation. Using a naturally occurring, unique cell transplantation system for the liver (the DPPIV- mutant Fischer 344 rat), studies in our laboratory have demonstrated that early fetal liver epithelial cells can repopulate up to 10¿,4 of the parenchymal mass in normal liver, produce both hepatocytic and bile duct epithelial cell progeny and show continued proliferative activity for up to six months after cell transplantation (properties generally attributed to stem cells). We hypothesize that use of a normal liver-based cell transplantation system, such as the one we have established, is critical in determining the stem cell potential of isolated cells and cell lines and the factors that contribute to their proliferation and differentiation in the liver. Within this context, experiments are proposed: 1) to use cytokines and pharmacological agents to augment proliferation of transplanted fetal hepatic cells in our liver-based cell transplantation model, 2) to study the molecular and cellular characteristics of different populations of proliferating fetal liver epithelial cells after transplantation to define their phenotype, proliferative potential, lineage deriving capacity and ability for self renewal and 3) to determine whether mature hepatocytes can pass from the parenchyma into the biliary compartment and exhibit sufficient plasticity to switch their phenotype and become incorporated into bile ducts, demonstrating that the engraftment site in the liver iobule determines the ultimate fate of transplanted hepatic cells. We will also use a recently established DPPIV -/- mouse model comparable to the rat, but now also immunocompromised (Rag2-/-), to permit repopulation studies with selected transgenic and knockout animals exhibiting modified cell cycle regulation, growth factor enhanced or cytokine dependent proliferation. The overall goal of these studies is to find methods to enhance liver repopulation by transplanted hepatic derived cells that will ultimately lead to clinical application in humans.