BONE MARROW DERIVED OVAL CELLS FOR LIVER REGENERATION

描述（由申请人提供）：活化、增殖和 肝细胞的不同表型的分化，称为卵圆细胞， 在严重肝损伤后观察到，特别是当 肝细胞受到抑制。在这些条件下，卵圆细胞可以作为 两种类型的肝上皮细胞的双能祖细胞， 肝细胞和胆管细胞。卵圆细胞通常被认为 肝干细胞的后代，肝脏原生的。但我们 获得明确的证据表明，在大鼠中，肝卵圆细胞，或至少 它们中的一部分可以源自骨髓来源的前体细胞。的 因此，该项目的目标是确定骨髓干细胞 向肝脏的迁移受到调节，局部肝脏环境促进 移植骨髓细胞作为卵圆细胞群，什么骨 骨髓来源的细胞群最适合作为肝卵圆的祖细胞 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， 假设损伤类型（门静脉周围vs.中心周围）和趋化因子 (CC vs. CXC）响应的调用决定了 骨髓干/前体细胞移植到大鼠和大鼠的损伤肝脏中， 小鼠模型（特异性目标I）;以确定归巢趋化因子SDF- 1是否 及其受体CXCR 4在指导骨髓前体细胞 肝脏（特异性目的II）;并确定CD-34+或CD-34- 骨髓细胞亚群含有卵圆细胞祖细胞， 产生更高百分比的骨髓源性肝细胞（SpecificAim III）。预计拟议研究的执行将产生新的 以及关于肝细胞募集的总体机制的重要数据， 卵圆细胞及其骨髓的基本表型和性质 先驱这些数据对于开发新的治疗方法至关重要。 治疗肝病的策略。

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.