Stem Cells in Liver Regeneration: Fusion or Plasticity

肝脏再生中的干细胞：融合或可塑性

• 批准号: 7992495
• 负责人: BRYON E PETERSEN
• 金额: --
• 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 2010-07-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7992495
• 关键词: AKT Signaling Pathway; Address; Affect; Autologous Transplantation; Behavior; Bilirubin; Binding; Bone Marrow; Bone Marrow Cells; CSF3 gene; CXCR4 Receptors; Cell Proliferation; Cell Therapy; Cell Transplants; Cell membrane; Cell physiology; Cells; Complex; Data; Development; Disease model; Engraftment; Ensure; Genetic; Goals; Granulocyte Colony-Stimulating Factor Receptors; Hematopoietic System; Hepatic; Hepatocyte; Hereditary Disease; In Vitro; Inborn Genetic Diseases; Injury; JAK2 gene; Knowledge; Laboratories; Liver; Liver Regeneration; Liver diseases; MAP Kinase Gene; MEKs; Measurable; Mediating; Metabolic; Metabolism; Methods; Modeling; Molecular; Natural regeneration; PI3K/AKT; Partial Hepatectomy; Pathway interactions; Phenotype; Play; Property; Protein Isoforms; Rattus; Relative (related person); Research; Rodent; Role; Serum; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Small Interfering RNA; Source; Stem cells; Stromal Cell-Derived Factor 1; System; Technology; Testing; Therapeutic; Transplantation; base; cell motility; clinically relevant; cytokine; design; experience; in vivo; injured; liver function; migration; oval cell; public health relevance; regenerative; research study; response; therapy development; trafficking; treatment strategy

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 takes place 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. Several studies have shown that bone marrow cells can differentiate into hepatocytes, and we have also shown that bone marrow (BM) cells are able to produce hepatic oval cells. The foremost questions are: what molecular mechanisms are involved in oval cell physiology, and can these pathways be manipulated to enhance their therapeutic value in treating liver disorders? The experiments described within this proposal are designed to address the above stated questions. We will pursue the following specific aims: Specific Aim 1: We hypothesize that activation of the JAK2 and MAPK signal transduction pathways by G-CSF interaction with G-CSF receptor on the cell membrane enhances both proliferation and migration of liver oval cells. Specific aim 2: We hypothesize that activation of the MEK and PI3K signal transduction pathways following SDF-1 binding to CXCR4 receptor on the cell membrane enhances both proliferation and migration of liver oval cells. Specific aim 3: We hypothesize that modulation of the oval cell phenotype by G-CSF and SDF-1 will positively affect engraftment and expansion of compensatory oval cells into rat liver afflicted with a genetic disorder, resulting in a measurable enhancement of liver function. 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. PUBLIC HEALTH RELEVANCE: 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 takes place 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. Several studies have shown that bone marrow cells can differentiate into hepatocytes, and we have also shown that bone marrow (BM) cells are able to produce hepatic oval cells. The foremost questions are: what molecular mechanisms are involved in oval cell physiology, and can these pathways be manipulated to enhance their therapeutic value in treating liver disorders? The experiments described within this proposal are designed to address the above stated questions. We will pursue the following specific aims: Specific Aim 1: We hypothesize that activation of the JAK2 and MAPK signal transduction pathways by G-CSF interaction with G-CSF receptor on the cell membrane enhances both proliferation and migration of liver oval cells. Specific Aim 2: We hypothesize that activation of the MEK and PI3K signal transduction pathways following SDF-1 binding to CXCR4 receptor on the cell membrane enhances both proliferation and migration of liver oval cells. Specific Aim 3: We hypothesize that modulation of the oval cell phenotype by G-CSF and SDF-1 will positively affect engraftment and expansion of compensatory oval cells into rat liver afflicted with a genetic disorder, resulting in a measurable enhancement of liver function. 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，干细胞室的激活发生。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。几项研究表明，骨髓细胞可以分化为肝细胞，我们还表明骨髓（BM）细胞能够产生肝椭圆形细胞。最重要的问题是：椭圆形细胞生理中涉及哪些分子机制，并且可以操纵这些途径以增强其治疗肝脏疾病的治疗价值吗？本提案中描述的实验旨在解决上述问题。我们将追求以下特定目的：特定目标1：我们假设通过G-CSF与G-CSF受体在细胞膜上与G-CSF相互作用通过与G-CSF相互作用激活JAK2和MAPK信号转导途径，从而增强了肝椭圆形细胞的增殖和迁移。具体目标2：我们假设在SDF-1结合细胞膜上SDF-1与CXCR4受体结合后，MEK和PI3K信号转导途径的激活增强了肝椭圆形细胞的增殖和迁移。具体目的3：我们假设G-CSF和SDF-1对椭圆形细胞表型的调节将积极影响植入并扩展代偿性椭圆形细胞到患有遗传疾病的大鼠肝脏中，从而导致可测量的肝功能增强。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。 公共卫生相关性：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，干细胞室的激活发生。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。几项研究表明，骨髓细胞可以分化为肝细胞，我们还表明骨髓（BM）细胞能够产生肝椭圆形细胞。最重要的问题是：椭圆形细胞生理中涉及哪些分子机制，并且可以操纵这些途径以增强其治疗肝脏疾病的治疗价值吗？本提案中描述的实验旨在解决上述问题。我们将追求以下特定目的：特定目标1：我们假设通过G-CSF与G-CSF受体在细胞膜上与G-CSF相互作用通过与G-CSF相互作用激活JAK2和MAPK信号转导途径，从而增强了肝椭圆形细胞的增殖和迁移。具体目标2：我们假设在SDF-1结合细胞膜上SDF-1与CXCR4受体结合后，MEK和PI3K信号转导途径的激活增强了肝椭圆形细胞的增殖和迁移。具体目的3：我们假设G-CSF和SDF-1对椭圆形细胞表型的调节将积极影响植入并扩展代偿性椭圆形细胞到患有遗传疾病的大鼠肝脏中，从而导致可测量的肝功能增强。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。