BONE MARROW DERIVED OVAL CELLS FOR LIVER REGENERATION

描述(由申请人提供)：激活、扩散和 分化一种不同表型的肝细胞，称为卵圆细胞， 在严重的肝损伤后观察到，特别是当肝细胞增殖时 肝细胞受到抑制。在这些条件下，椭圆形细胞可以起到 两种类型的肝上皮细胞的双潜能祖细胞 肝细胞和双小管细胞。椭圆形细胞通常被认为是 肝干细胞的后代，原产于肝脏。然而，我们有 获得了明确的证据，在大鼠的肝脏卵圆细胞中，或者至少有一个 它们中的一部分可以来自骨髓起源的前体细胞。这个 因此，该项目的目标是确定骨髓干细胞如何 迁移到肝脏是受调控的，局部肝脏环境促进的 骨髓细胞作为卵圆细胞群的植入，以及什么骨 骨髓来源的细胞群最有可能成为肝卵圆的祖细胞 细胞。为了实现这些目标，我们将进行一系列研究 旨在提高骨髓细胞募集的效率，以测试 假设损伤类型(门静脉周围与中心周围)和趋化因子 (CC与CXC)被调用的响应决定了 骨髓干细胞/前体细胞移植修复大鼠和大鼠肝损伤的实验研究 小鼠模型(特异靶I)；确定归巢趋化因子SDF-1是否 其受体CXCR4对骨髓前体细胞具有导向作用 对肝脏(特定目标Il)；并确定CD-34或CD-34是否- 骨髓细胞亚群包含卵圆细胞祖细胞和 产生更高比例的骨髓源性肝细胞(特定目标 三)。预计拟议研究的执行将产生新的 和重要的数据的整体机制的肝脏重新招募 卵圆细胞及其骨髓的基本表型和特性 前身。这些数据将对开发新的治疗方法至关重要 肝病的治疗策略。

DESCRIPTION (provided by applicant): Activation, proliferation and differentiation of a distinct phenotype of hepatic cells, called oval cells, are observed after severe hepatic injuries, especially when proliferation of hepatocytes is inhibited. Under those conditions, oval cells can act as bipotential progenitors of the two types of epithelial cells of the liver, the hepatocytes and bileductular cells. Oval cells have been usually thought to be the progeny of a hepatic stem cell, native to the liver. However, we have obtained clear evidence that in the rat, hepatic oval cells, or at the least a fraction of them, can derive from a precursor cell of bone marrow origin. The goals of this project are therefore to determine how bone marrow stem cell emigration to the liver is regulated, what local hepatic environment promotes engraftment of bone marrow cells as an oval cell population, and what bone marrow-derived cell population can best act as a progenitor of hepatic oval cells. Towards achievement of these goals, we will perform a series of studies aimed at increasing the efficiency of bone marrow cell recruitment to test the hypothesis that the type of injury (periportal vs. pericentral) and chemokine (CC vs. CXC) response being invoked determines the efficiency with which bone-marrow stem/precursor cells engraft in an injured liver in both rat and mouse models (Specific Aim I); to determine whether the homing chemokine SDF- 1 and its receptor CXCR4 play a role in directing the bone marrow precursor cell to the liver (Specific Aim Il); and to establish whether the CD-34+ or CD-34- sub-population of bone marrow cells contains the oval cell progenitor and produces the higher percentage of bone marrow derived hepatocytes (SpecificAim III). It is anticipated that performance of the proposed studies will yield new and significant data about the overall mechanisms for recruitment of hepatic oval cells, and the basic phenotype and properties of their bone marrow precursor. These data will be critical for developing novel therapeutic strategies for the treatment of liver disease.