Stem cells in liver regeneration: fusion or plasticity

肝再生中的干细胞：融合或可塑性

• 批准号: 7121479
• 负责人: BRYON E PETERSEN
• 金额: $ 24.77万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-15 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7121479
• 关键词: biological models; bone marrow; bone marrow transplantation; cell differentiation; cell fusion; cell proliferation; chemokine; fluorescent in situ hybridization; immunocytochemistry; laboratory rat; liver cells; liver regeneration; polymerase chain reaction; stem cells; stromal cells

DESCRIPTION (provided by applicant): The liver has an enormous capacity to regenerate, as demonstrated by the 2/3 partial hepatectomy model in rodents. In addition, the liver has a stem cell compartment acting as a backup regenerative system. Activation of the stem cell compartment occurs when hepatocytes are functionally compromised, are unable to divide, or both. In stem cell-aided liver regeneration, progeny of the stem cells multiply in an amplification compartment composed of hepatic oval cells. Recent studies have suggested that bone marrow cells can differentiate down the hepatic lineage. We have shown that bone marrow (BM) cells are able to produce hepatic oval cells, while others have only shown that BM cells can contribute to the end product of hepatocytes and bile duct epithelial cells in the rodent. The origins of oval cells thus remain controversial and several key questions remain. The foremost questions are: what is the origin of hepatic oval cells; and what determines the magnitude of their proliferative response to certain hepatic injuries? The studies proposed in this application are designed to determine the contribution of the BM to oval cell-mediated repair of liver injury. These experiments will also evaluate the role of BM-derived stem cell differentiation as opposed to cell fusion in oval cell-mediated liver repair. Finally, involvement of the chemokine stromal cell derived factor- 1 (SDF-1) in BM-derived stem cell migration to the liver, and in oval cell homing within the liver, will be determined. These studies will determine the extent each of these mechanisms play in the oval cell-aided hepatic regenerative process. We will pursue the following specific aims: Specific Aim I. To determine the degree to which BM-derived stem cells contribute to oval cell-mediated liver regeneration and to assess the level of donor repopulation resulting from fusion versus differentiation. Specific Aim II. To determine whether transplanted hepatic oval cells maintain sufficent plasticity to differentiate into mature cells unrelated to liver. Specific Aim III. To determine the functional role of SDF-1 in oval cell activation and as well as targeting BM derived oval cells to specific areas of injury within the liver. It is anticipated that the proposed studies will yield new and significant data about the mechanisms of governing the bone marrow contribution to liver regeneration and signals involved in oval cell activation, proliferation and differentiation.

描述（由申请人提供）：肝脏具有巨大的再生能力，如啮齿动物中2/3部分肝切除术模型所证明的那样。此外，肝脏具有一个干细胞室，充当备用再生系统。当肝细胞在功能上损害，无法分裂或两者兼而有之时，会发生干细胞区室的激活。在干细胞辅助肝脏再生中，干细胞的后代在由肝椭圆形细胞组成的放大室中繁殖。最近的研究表明，骨髓细胞可以区分肝谱系。我们已经表明，骨髓（BM）细胞能够产生肝椭圆形细胞，而其他细胞仅表明BM细胞可以有助于啮齿动物中肝细胞和胆管上皮细胞的最终产物。因此，椭圆形细胞的起源仍然存在争议，并且仍然存在几个关键问题。最重要的问题是：肝椭圆形细胞的起源是什么？是什么决定了它们对某些肝损伤的增殖反应的大小？本应用中提出的研究旨在确定BM对椭圆形细胞介导的肝损伤修复的贡献。这些实验还将评估BM衍生的干细胞分化的作用，而不是椭圆形细胞介导的肝脏修复中的细胞融合。最后，将确定趋化因子基质细胞衍生因子1（SDF-1）参与BM衍生的干细胞迁移到肝脏的迁移，并确定肝脏内的椭圆形细胞归位。这些研究将确定这些机制在椭圆形细胞辅助再生过程中所起的每种机制。我们将追求以下特定目的：具体目的I.确定BM衍生的干细胞有助于椭圆形细胞介导的肝脏再生的程度，并评估融合与分化而导致的供体重新群体的水平。具体目标II。确定移植的肝椭圆形细胞是否保持足够的可塑性，以区分与肝脏无关的成熟细胞。特定目标III。确定SDF-1在椭圆形细胞激活中的功能作用，并将BM衍生的椭圆形细胞靶向肝内的特定损伤区域。预计拟议的研究将产生有关管理骨髓对肝脏再生贡献以及参与椭圆形细胞激活，增殖和分化的信号的机制的新的重要数据。