Defense Date


Document Type


Degree Name

Master of Science


Physiology and Biophysics

First Advisor

Dr. Martin Mangino

Second Advisor

Dr. Ru Li


Organ transplants are a vital intervention for many diseases that result in end stage organ failure. Currently, the donation pool is not meeting the demands of the transplant list. Expanding this pool to include donation after cardiac death (DCD) is highly sought-after. However, the use of DCD livers can lead to increased odds of graft failure and ischemic cholangiopathy. The loss of epithelialization and fibrosis that occurs during ischemic cholangiopathy is characteristic of these cells undergoing epithelial-to-mesenchymal transition (EMT). The biological changes the cell experiences enhance migratory capacity, invasiveness, and increased resistance to apoptosis. Our earlier studies have shown differential gene expression patterns in these cells, consistent with an EMT, after they have been exposed to conditions associated with DCD liver donation (cold and warm ischemia). In that, epigenetic modifications by HDAC can influence E-Cadherin gene expression, which is thought to be necessary for EMT. We sought to investigate the role of HDAC in cholangiocyte EMT, evoked by exposure to DCD conditions. Cell migration assays were performed with human cholangiocytes exposed to warm and cold ischemia (DCD conditions) and tested for HDAC expression with relevant gene/proteins using RT-PCR and immunocytochemistry. The effects of HDAC on EMT genotype, migratory behaviour, and cell morphometry characteristics was determined by using two structurally different, but selective HDAC-1 inhibitors, Trichostatin-A and Romidepsin. Human cholangiocytes displayed migratory behaviour following exposure to DCD conditions. Cell morphology also transitioned with a loss of epithelial and cuboidal characteristics, and a gain of mesenchymal, spindle-shaped characteristics. The use of both selective HDAC inhibitors prevented these changes in ischemic cholangiocytes and reversed changes in mesenchymal cells, changed by an existing EMT – they induced an MET. Our findings indicate that HDAC plays a major and causative role in the transition of cholangiocytes into mesenchymal cells exposed to DCD conditions. These data have implications for liver preservation in DCD donors.


© Priyanshi Parikh

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