Liver Repopulation for Liver Injury and Gene Therapy

这项计划旨在获得对细胞和基因治疗方法如何 为肝病提供新的治疗方法。一般的假设是移植的肝细胞会存活下来。 并在允许的微环境中发挥作用，这是由肝脏提供的最佳微环境。后面的单元格 移植，移植细胞和天然肝脏之间的各种相互作用是必要的 移植细胞进行移植和增殖。这些相互作用包括其他类型的肝细胞，并可 由各种细胞类型释放的因子，这些细胞通常驻留在肝脏中，或在细胞后进入肝脏 已经被移植了。这些机制可能会改变移植细胞能否植入、存活、 功能或在肝脏中增殖。细胞和基因治疗需要开发合适的大量 用于疾病矫正的移植细胞，尽管这些要求可能因疾病而异。 因此，有关移植细胞在特定环境中的植入和增殖的多种机制 疾病必须在合适的动物模型中进行研究。此类研究需要包括对成熟度的分析 肝细胞，以及评估干细胞/祖细胞特性的分析，以获得适当的 临床策略。在过去的二十年里，我们实验室的进步导致了工作模型的产生 移植细胞在肝脏内的植入和增殖。有几个重要的机制 发现在细胞移植后的早期阶段也调节移植细胞的存活 由于移植后的细胞已成为肝实质不可分割的一部分。中的特定扰动 促进细胞植入的宿主肝脏包括对肝窦内细胞间相互作用的分析， 肝脏微环境的调节与移植细胞生物学特性的研究 他们自己。为移植细胞提供竞争优势的天然肝细胞的遗传毒性损伤 开始增殖是肝脏再繁殖的有效策略。因此，我们提出了一系列 进一步确定在肝脏正常或正常情况下移植细胞植入的研究 病态的。我们将研究啮齿动物体内移植的肝细胞的命运，包括免疫缺陷小鼠，以 产生更多的动物模型。我们将确定移植的细胞是否会在下列情况下增殖 在细胞移植前诱导受体动物肝脏损伤的进一步方法。我们将使用这些 纠正动物获得性和遗传性疾病的原则。完成我们的学业 将在肝脏重新繁殖以及细胞和基因治疗机制方面产生新的知识。这将导致 更有效的肝脏导向细胞和基因治疗。

This program has been directed at obtaining insights into how cell and gene therapy approaches can provide novel therapies for liver disorders. The general hypothesis is that transplanted liver cells will survive and function in the context of a permissive microenvironment, which is best provided by the liver. After cell transplantation, a variety of interactions between transplanted cells and the native liver are necessary for transplanted cells to engraft and proliferate. These interactions encompass other liver cell types and soluble factors released by various cell types that are normally resident in the liver or could enter the liver after cells have been transplanted. These mechanisms may alter whether transplanted cells can engraft, survive, function or proliferate in the liver. Cell and gene therapy requires development of suitable masses of transplanted cells for disease correction, although these requirements can vary from disease-to-disease. Therefore, a variety of mechanisms concerning engraftment and proliferation of transplanted cells in specific disorders must be studied in suitable animal models. Such studies need to include analysis of mature hepatocytes, as well as assays to assess the properties of stem/progenitor cells for obtaining appropriate clinical strategies. Progress in our laboratory over the past two decades has led to working models of transplanted cell engraftment and proliferation in the liver. Several important mechanisms have been identified that regulate survival of transplanted cells during the early period after cell transplantation, as well as after transplanted cells have become an integral part of the liver parenchyma. Specific perturbations in the host liver that promote cell engraftment include analysis of cell-cell interactions in liver sinusoids, modulations in the liver microenvironment and aspects of the biological properties of transplanted cells themselves. Genotoxic injury in native hepatocytes that offers competitive advantages for transplanted cells to begin proliferating constitutes an effective strategy for liver repopulation. Therefore, we propose a series of studies to further define transplanted cell engraftment in settings where the liver is either normal or diseased. We will study the fate of transplanted liver cells in rodents, including immunodeficient mice, to generate further animal models. We will determine whether transplanted cells will proliferate following further ways to induce liver injury in recipient animals prior to cell transplantation. We will use these principles to approach correction of acquired and genetic disorders in animals. Completion of our studies will generate new knowledge in liver repopulation and cell and gene therapy mechanisms. This will lead to more effective liver-directed cell and gene therapy in people.