Stem Cells in Liver Regeneration: Fusion or Plasticity

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。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）细胞能够产生肝卵圆细胞。最重要的问题是：卵圆细胞生理学中涉及哪些分子机制，这些途径能否被操纵以增强其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。我们将追求以下具体目标：具体目标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JAK 2和MAPK信号转导途径，增强肝卵圆细胞的增殖和迁移。具体目标2：我们推测，激活MEK和PI 3 K信号转导途径后，SDF-1结合到细胞膜上的CXCR 4受体增强肝卵圆细胞的增殖和迁移。具体目标3：我们假设，通过G-CSF和SDF-1调节卵圆细胞表型将积极影响补偿性卵圆细胞在患有遗传疾病的小鼠肝脏中的植入和扩增，从而导致肝功能的可测量增强。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。公共卫生相关性：目前约有18，000名患者计划进行肝移植。由于每年只有4,000- 5,000个器官可供使用，许多人将无法在等待中生存。显然，需要一种替代整个器官移植的方法。本申请中提出的研究旨在确定驱动干细胞修复受损肝脏的机制。我们将利用这些机制来促进病变肝脏的干细胞再生，从而产生健康的组织。我们希望有一天类似的疗法可以作为肝移植的替代方案。

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. PUBLIC HEALTH RELEVANCE: About 18,000 patients are currently scheduled for a liver transplant. With only 4,000- 5,000 organs becoming available each year, many will not survive the wait. Clearly, an alternative to whole organ transplant is needed. The studies proposed within this application are designed to identify mechanisms that drive stem cell repair of the damaged liver. We will utilize these mechanisms to facilitate the repopulation of diseased liver with stem cells that will generate healthy tissue. It is our hope that a similar therapy may someday be used as an alternative to liver transplant.