Mechanisms of oval cell activation and differentiation

总结：肝脏具有巨大的再生能力，如2/3部分 啮齿类动物肝切除模型。此外，肝脏有一个干细胞室作为备份 再生系统当肝细胞在功能上被激活时， 无法分裂，或者两者兼而有之。在干细胞辅助肝再生中，干细胞的后代 在由所谓的卵圆细胞组成的扩增室中繁殖。最近的研究也 表明骨髓细胞可以向肝细胞分化，而其他研究表明， 不要。不管它们的起源如何，卵圆细胞表达的表型通常被称为过渡型。 肝细胞和胆管细胞之间的细胞。首要问题是，哪些系统性信号是 负责确定这种类型的肝细胞内卵圆细胞活化的程度和效率， 修理？卵圆细胞生物学中的另外两个问题是：卵圆细胞是如何被激活的？ 细胞外因子在它们的植入和分化到肝脏结构中起作用吗？的 拟议的研究将探讨这些过程中涉及的三种具体分子机制。在 初步实验，我们已经表明，结缔组织生长因子（CTGF），Notch-1和 生长抑制素均参与卵圆细胞辅助的肝脏再生。这表明我们可以利用这些因素 作为破译卵圆细胞如何以及为什么参与肝脏的潜在机制的起点， 再生本申请中提出的研究将确定这些分子中的每一种发挥的程度 在卵圆细胞辅助再生过程中的作用，从而更好地了解肝脏再生 整个过程。我们将努力实现以下具体目标：具体目标一。为了验证这个假设， CTGF和星状细胞是促进肝脏卵圆细胞增殖的必要成分。具体 Aim II.探讨Notch-1及其受体Jagged-1在卵圆细胞辅助肝再生中的作用。 具体目的III.确定生长抑素（SST）是否在卵圆细胞活化中起作用，是否能增强卵圆细胞的增殖， 骨髓干细胞/前体细胞移植入受损肝脏的效率。预计，随着 信心，拟议的研究将产生新的和重要的数据有关的机制， 卵圆细胞活化、增殖和分化。

Summary: 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 occurs when the 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 the so-called oval cells. Recent studies have also suggested that bone marrow cells can differentiate down the hepatic lineage, while other studies show they do not. Regardless of their origins, oval cells express the phenotype usually referred to as the transitional cell between hepatocytes and biliary cells. The overarching question is, which systemic signals are responsible for determining the magnitude and efficiency of oval cell activation within this type of hepatic repair? Two additional questions in oval cell biology are; how do oval cells become activated; and what role do extracellular factors play in their engraftment and differentiation into the hepatic architecture? The proposed research will explore three specific molecular mechanisms involved in these processes. In preliminary experiments, we have shown that Connective Tissue Growth Factor (CTGF), Notch-1 and Somatostatin all participate in oval cell-aided liver regeneration. This suggests that we can use these factors as starting points for deciphering the underlying mechanisms of how and why oval cells participate in liver regeneration. The studies proposed in this application will determine the extent each of these molecules play in the oval cell aided regenerative process, thus leading to a better understanding of the liver regeneration process as a whole. We will pursue the following specific aims: Specific Aim I. To test the hypothesis that CTGF and stellate cells are necessary components needed to facilitate oval cell proliferation in liver. Specific Aim II. To determine the role of Notch-1 and its receptor Jagged-1 in oval cell aided liver regeneration. Specific Aim III.To determine if somatostatin (SST) has a role in oval cell activation and can enhance the efficiency with which bone-marrow stem/precursor cells engraft in an injured liver. It is anticipated, with confidence, that the proposed studies will yield new and significant data about the mechanisms of governing oval cell activation, proliferation and differentiation.