BONE MARROW DERIVED OVAL CELLS FOR LIVER REGENERATION

骨髓来源的卵圆细胞用于肝脏再生

• 批准号: 6517832
• 负责人: BRYON E PETERSEN
• 金额: $ 24.65万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6517832
• 关键词: CD34 molecule; allyl compound; biological models; bone marrow transplantation; carbon tetrachloride poisoning; cell migration; cell population study; cell proliferation; chemokine; cytokine receptors; disease /disorder model; enzyme linked immunosorbent assay; flow cytometry; hematopoietic stem cells; hepatectomy; immunocytochemistry; in situ hybridization; laboratory mouse; laboratory rat; liver cells; liver disorder; liver regeneration; model design /development; nonhuman therapy evaluation; protein structure function; western blottings

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.

描述（由申请人提供）：激活、增殖和 肝细胞独特表型的分化，称为卵圆细胞， 在严重肝损伤后观察到，特别是当肝细胞增殖时 肝细胞受到抑制。在这些条件下，卵圆细胞可以充当 肝脏两种类型上皮细胞的双能祖细胞 肝细胞和胆管细胞。卵形细胞通常被认为是 肝脏原生的肝干细胞的后代。然而，我们有 获得明确的证据表明，在大鼠中，肝卵圆细胞，或至少有一个 其中一部分可以源自骨髓来源的前体细胞。这 因此，该项目的目标是确定骨髓干细胞如何 向肝脏的迁移受到调节，局部肝脏环境促进什么 骨髓细胞作为卵圆细胞群植入，以及什么骨 骨髓来源的细胞群最能充当肝卵圆的祖细胞 细胞。为了实现这些目标，我们将进行一系列研究 旨在提高骨髓细胞招募的效率来测试 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响应的效率 骨髓干细胞/前体细胞移植到大鼠和小鼠受损的肝脏中 小鼠模型（具体目标 I）；确定归巢趋化因子SDF-1是否 其受体CXCR4对骨髓前体细胞发挥导向作用 到肝脏（具体目标 II）；并确定 CD-34+ 或 CD-34- 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来源肝细胞（SpecificAim 三）。预计拟议研究的实施将产生新的成果 以及有关肝细胞募集总体机制的重要数据 卵圆细胞及其骨髓的基本表型和特性 前驱。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。