Stem Cells in Liver Regeneration: Fusion or Plasticity

描述(申请人提供)：如啮齿类动物2/3部分肝切除模型所示，肝脏具有巨大的再生能力。此外，肝脏有一个干细胞室，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，干细胞室就会被激活。在干细胞辅助的肝脏再生中，干细胞的后代在由肝卵圆细胞组成的扩增室中繁殖。一些研究表明，骨髓细胞可以分化为肝细胞，我们也证明了骨髓(BM)细胞能够产生肝卵圆细胞。最重要的问题是：卵圆细胞生理学涉及哪些分子机制，这些途径能否被操纵以提高它们在治疗肝脏疾病中的治疗价值？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的目标：特定的目标1：我们假设通过G-CSF与细胞膜上的G-CSF受体相互作用激活JAK2和MAPK信号转导通路，促进肝卵圆细胞的增殖和迁移。具体目的2：我们假设SDF-1与细胞膜上的CXCR4受体结合后激活的MEK和PI3K信号转导通路促进了肝卵圆细胞的增殖和迁移。具体目标3：我们假设G-CSF和SDF-1对卵圆细胞表型的调节将积极影响代偿性卵圆细胞在患有遗传性疾病的大鼠肝脏中的植入和扩增，从而导致肝功能的显著增强。预计拟议的研究将产生关于骨髓对肝脏再生的调控机制以及涉及卵圆细胞激活、增殖和分化的信号的新的和重要的数据。 公共卫生相关性：肝脏具有巨大的再生能力，啮齿类动物的2/3部分肝切除模型证明了这一点。此外，肝脏有一个干细胞室，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，干细胞室就会被激活。在干细胞辅助的肝脏再生中，干细胞的后代在由肝卵圆细胞组成的扩增室中繁殖。一些研究表明，骨髓细胞可以分化为肝细胞，我们也证明了骨髓(BM)细胞能够产生肝卵圆细胞。最重要的问题是：卵圆细胞生理学涉及哪些分子机制，这些途径能否被操纵以提高它们在治疗肝脏疾病中的治疗价值？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的目标：特定的目标1：我们假设通过G-CSF与细胞膜上的G-CSF受体相互作用激活JAK2和MAPK信号转导通路，促进肝卵圆细胞的增殖和迁移。具体目的2：我们假设SDF-1与细胞膜上的CXCR4受体结合后激活的MEK和PI3K信号转导通路促进了肝卵圆细胞的增殖和迁移。具体目标3：我们假设G-CSF和SDF-1对卵圆细胞表型的调节将积极影响代偿性卵圆细胞在患有遗传性疾病的大鼠肝脏中的植入和扩增，从而导致肝功能的显著增强。预计拟议的研究将产生关于骨髓对肝脏再生的调控机制以及涉及卵圆细胞激活、增殖和分化的信号的新的和重要的数据。

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.