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: 7908385
• 负责人: BRYON E PETERSEN
• 金额: $ 10万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-10 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7908385
• 关键词: 2-Acetylaminofluorene; Abbreviations; Acute; Adult; Animals; Area; Bile Duct Epithelium; Bile fluid; Biochemical; Blood Circulation; Bone Marrow; Bone Marrow Cells; Bone Marrow Transplantation; CXCR4 Receptors; CXCR4 gene; Carbon Tetrachloride; Cell Adhesion Molecules; Cell Proliferation; Cell Separation; Cell Transplantation; Cell fusion; Cells; Chemicals; Chemotactic Factors; Choline; Chronic; DAPM; Data; Diet; Dipeptidyl-Peptidase IV; Endothelium; Epithelial Cells; Ethionine; Event; Female; Fluorescence-Activated Cell Sorting; Gamma-glutamyl transferase; Gene Expression; Goals; Hematopoiesis; Hematopoietic Stem Cell Mobilization; Hematopoietic stem cells; Hepatic; Hepatic Mass; Hepatic Tissue; Hepatocyte; Homing; Immunohistochemistry; Inborn Genetic Diseases; Individual; Infarction; Injury; Karyotype determination procedure; Laboratories; Ligation; Liver; Liver Regeneration; Liver parenchyma; Magnetism; Mediating; Metabolism; Methods; Modeling; Molecular; Natural regeneration; Nature; Partial Hepatectomy; Pathway interactions; Play; Process; Proliferating; Proteins; Rattus; Research; Research Personnel; Rodent; Role; Signal Pathway; Signal Transduction; Small Interfering RNA; Southern Blotting; Staging; Stem cells; Stromal Cell-Derived Factor 1; System; Techniques; Testing; Transforming Growth Factor alpha; Transforming Growth Factor beta; Transplantation; allyl alcohol; alpha-Fetoproteins; bile duct; carbene; cell motility; chemokine; clinical application; cytokine; design; fetal; liver cell proliferation; male; migration; monocyte; mouse model; oval cell; pathogen; programs; reconstitution; regenerative; repaired; research study; response; stem cell differentiation

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2/3部分肝切除模型所示。此外，肝脏有一个干细胞隔室作为后备再生系统。当肝细胞功能受损、不能分裂或两者兼而有之时，干细胞区室的激活发生。在干细胞辅助的肝再生中，干细胞的后代在由肝卵圆细胞组成的扩增区室中繁殖。最近的研究表明，骨髓细胞可以分化为肝细胞。我们已经表明，骨髓（BM）细胞能够产生肝卵圆细胞，而其他人只表明，骨髓细胞可以有助于肝细胞和胆管上皮细胞在啮齿动物的最终产品。因此，卵圆细胞的起源仍然存在争议，还有几个关键问题。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大小？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BM衍生的干细胞分化相对于卵圆细胞介导的肝修复中的细胞融合的作用。最后，将确定趋化因子基质细胞衍生因子-1（SDF-1）参与BM衍生的干细胞向肝脏的迁移以及肝内卵圆细胞归巢。这些研究将确定这些机制中的每一种在卵圆细胞辅助的肝再生过程中发挥的作用。我们将努力实现以下具体目标：具体目标一。确定骨髓源性干细胞促进卵圆细胞介导的肝再生的程度，并评估融合与分化导致的供体再增殖水平。具体目标二。目的：观察移植的肝卵圆细胞能否保持足够的可塑性，分化为与肝脏无关的成熟细胞。具体目标三。确定SDF-1在卵圆细胞活化中的功能作用，以及将BM衍生的卵圆细胞靶向至肝脏内的特定损伤区域。预计拟议的研究将产生新的和重要的数据有关的机制，管理骨髓的贡献，肝再生和信号参与卵圆细胞活化，增殖和分化。