Mechanisms of oval cell activation and differentiation

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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.