Stem Cells in Liver Regeneration: Fusion or Plasticity

描述（由申请人提供）：啮齿动物的2/3部分肝切除术模型证明，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。干细胞室的激活发生在肝细胞功能受损、无法分裂或两者兼而有之时。在干细胞辅助肝再生中，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，我们也发现骨髓细胞能够产生肝卵圆细胞。最重要的问题是：卵形细胞生理学涉及哪些分子机制，这些途径是否可以被操纵以提高其治疗肝脏疾病的治疗价值？本提案中描述的实验旨在解决上述问题。具体目的1：我们假设G-CSF与细胞膜上G-CSF受体的相互作用激活了JAK2和MAPK信号转导通路，从而增强了肝卵圆细胞的增殖和迁移。特异性目的2：我们假设在SDF-1与细胞膜上的CXCR4受体结合后，MEK和PI3K信号转导通路的激活促进了肝卵圆细胞的增殖和迁移。具体目的3：我们假设G-CSF和SDF-1对卵形细胞表型的调节将积极影响代偿卵形细胞在患有遗传性疾病的小鼠肝脏中的植入和扩增，从而导致肝脏功能的可测量增强。我们预计，这些研究将为骨髓对肝脏再生的调控机制和参与卵圆细胞活化、增殖和分化的信号提供新的重要数据。

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 mouse 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.