Liver development is a complex and temporal process, which entails a balanced regulation of proliferation, survival and differentiation of the bipotential stem cells or hepatoblasts. Understanding this process will be critical for applications in regenerative medicine and cancer biology. We have identified peak expression of Platelet derived growth factor receptor-a (PDGFRa) during early stages of liver development at embryonic days 11 (E11) to E14. The exact role and regulation of PDGFRa during this stage in liver development remains to be delineated. Interestingly, this robust PDGFRa expression coincides with time of peak hepatoblast proliferation. At late developmental stages and in normal adult liver, low PDGFRa expression is observed and coincides with decreased hepatocyte turnover. The current proposal is aimed at performing a comprehensive analysis of PDGFRa signaling during early development through balanced in vitro and in vivo models that currently exist in the lab. We propose to study upstream effector and divergent PDGFRa signaling in depth in embryonic livers to address the state of signaling. Utilizing embryonic liver cultures with which our lab has considerable experience, we will modulate PDGFRa signaling to directly address its impact on various developmental events such as cell proliferation, apoptosis, lineage specification and differentiation. Finally, we will utilize cre-lox strategy to conditionally delete PDGFRa gene in hepatoblasts to address the in vivo significance of PDGFRa in liver development. We provide strong preliminary data to demonstrate the ongoing signaling of PDGFRa in liver development and also demonstrate embryonic lethality due to PDGFRa loss in hepatoblasts, which mandates a detailed analysis. Understanding the process of liver development will unravel the cellular and molecular mechanisms that may be critical in successful generation of hepatocytes from alternate cell types such as embryonic or induced pluripotent stem cells. This is significant because of the shortage of organs for transplantation mandating careful research on alternate sources of hepatocytes. In addition, based on commonalities between the processes of development and cancer, understanding liver development will shed light on the basis of Hepatocellular carcinoma (HCC). HCC is a disease of poor prognosis affecting at least half a million people worldwide and ranks as the third most common cause of cancer- related death. There is significant evidence of the role of PDGFRa in HCC in patients and in preclinical studies. Thus, through the execution of this proposal will be able to address the central hypothesis of the proposal that PDGFRa is an important mediator of hepatoblast/hepatocyte proliferation and survival during liver development.
The work described in this proposal has great implications for understanding molecular mechanisms underlying liver diseases. Studying the function and role of platelet derived growth factor receptor alpha during liver development may allow us to further understand its role and regulation in both liver health and in liver diseases.
|Awuah, Prince K; Nejak-Bowen, Kari N; Monga, Satdarshan P S (2013) Role and regulation of PDGFR* signaling in liver development and regeneration. Am J Pathol 182:1648-58|