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）：正如啮齿类动物 2/3 部分肝切除模型所证明的那样，肝脏具有巨大的再生能力。此外，肝脏还有一个干细胞室作为备用再生系统。当肝细胞功能受损、无法分裂或两者兼而有之时，干细胞区室就会被激活。在干细胞辅助肝脏再生中，干细胞的后代在由肝卵圆细胞组成的扩增室中繁殖。最近的研究表明，骨髓细胞可以分化为肝谱系。我们已经证明骨髓（BM）细胞能够产生肝卵圆细胞，而其他人仅表明BM细胞可以在啮齿动物中产生肝细胞和胆管上皮细胞的最终产物。因此，卵圆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：肝卵圆细胞的起源是什么？是什么决定了它们对某些肝损伤的增殖反应的程度？本申请中提出的研究旨在确定 BM 对卵圆细胞介导的肝损伤修复的贡献。这些实验还将评估骨髓来源的干细胞分化相对于细胞融合在卵圆细胞介导的肝脏修复中的作用。最后，将确定趋化因子基质细胞衍生因子-1 (SDF-1) 参与骨髓衍生干细胞向肝脏迁移以及卵圆细胞在肝脏内归巢的过程。这些研究将确定这些机制在卵圆细胞辅助肝脏再生过程中发挥的作用程度。我们将追求以下具体目标： 具体目标 I. 确定骨髓来源的干细胞对卵圆细胞介导的肝再生的贡献程度，并评估融合与分化导致的供体再增殖水平。具体目标二。确定移植的肝卵圆细胞是否保持足够的可塑性以分化为与肝脏无关的成熟细胞。具体目标 III.确定 SDF-1 在卵圆细胞激活以及将 BM 来源的卵圆细胞靶向肝脏内特定损伤区域中的功能作用。预计所提出的研究将产生关于控制骨髓对肝再生的贡献的机制以及涉及卵圆细胞活化、增殖和分化的信号的新的重要数据。