Ross Hall #643
Keynote Speaker Information
Satdarshan (Pal) Singh Monga, M.D., FAASLD
Director, Pittsburgh Liver Research Center,
Professor of Pathology and Medicine
Endowed Chair for Experimental Pathology
Vice Chair and Chief of the Division of Experimental Pathology
Assistant Dean for the Medical Scientist Program
University of Pittsburgh, Pittsburgh, PA
Equipped to perform a multitude of complex functions daily, hepatocytes, the chief effector cells of the liver, need to possess resilience. However, unlike intestinal or dermal epithelia, which have high turnover, the liver epithelia, are rarely found to be in mitosis. How then does liver, an organ with the highest metabolic and synthetic demand, replenish and sustain itself, both during homeostasis and in an event of injury? There are specific strategies liver utilizes to ensure that injury is restricted to a subset of cells, always allowing remnant cells to proliferate and expand. One such way liver restricts damage to specific zone is through the process of metabolic zonation. Zonation restricts expression of specific genes to specific location along the porto-central axis in a liver lobule. Such genes may be involved in generation of toxic metabolites or impart protective features to a specific zone thereby allowing liver to regenerate. One master regulator of zonation is the Wnt-b-catenin signaling pathway, which directs expression of the genes in zone-3 of hepatic lobule.
Liver regeneration (LR), ensured by redundant signaling pathways, is an evolutionarily conserved phenomenon, and highly relevant in patients in the setting of both surgical or toxicant-induced injury. Further understanding of the cellular and molecular basis of the process of LR is thus relevant in devising treatments for end stage liver disease and has implications in transplant hepatology. Wnt-b-catenin pathway also plays a key role in the LR process.
Almost 2 decades of work using multiple GEMM has allowed us to elucidate the cell-molecule circuitry of this pathway both in metabolic zonation and in LR. Endothelial cells lining the central vein seem to be the source of Wnt signals at baseline and regulate the process of metabolic zonation. Sinusoidal endothelial cell (SEC) and to a lesser extent macrophages, are the key sources of specific Wnt proteins that regulate b-catenin-TCF complex in hepatocytes to in turn regulate cyclin-D1 expression and control hepatocyte proliferation during LR.
We have also exploited the role of b-catenin in hepatocyte proliferation to demonstrate that cholangiocytes can give rise to hepatocytes following liver injury. When hepatocyte specific-b-catenin-KO also labeled genetically with EYFP were fed hepatotoxic choline-deficient, ethionine supplemented (CDE) diet for 2 weeks, there was a significant increase in injury in KO over controls. Upon allowing recovery, due to a defect in hepatocyte proliferation, smalls clusters of cholangiocyte-derived hepatocytes are evident and demonstrate transdifferentiation. After allowing recovery for 6 months, more than 70% of the liver was composed of cholangiocyte-derived hepatocytes without any overt pathology.
Liver repair is thus ensured by mechanisms that restrict hepatic injury such as metabolic zonation, ensuring survival and proliferation of remnant cells within parenchyma, to capabilities of mature hepatocytes and cholangiocytes to transdifferentiate into each other to ensure hepatobiliary repair.