Serum response factor (SRF) is a transcription factor that plays a vital role in growth factor-mediated cell proliferation as well as the development and function of many organs including the heart, skeletal muscle, and the nervous system. Recently, our lab has demonstrated that SRF also plays a crucial role in the liver by maintaining normal liver function. When SRF is knocked out specifically in the liver, mice exhibit metabolic defects, including disrupted glucose and triglyceride homeostasis. Poorly maintained triglycerides and glucose are just a couple of factors that increase the risk for cardiovascular disease. One possibility to overcome this genetically based liver dysfunction is to combine gene therapy with cell transplantation. Immune rejection and lack of transplantable cells makes this a very difficult task. However, research has demonstrated that embryonic stem (ES) cells, which are capable of developing into any cell type in vitro and in vivo, could be a promising source of cells and tissues for transplantation. However, obtaining ES cells is lethal to the embryo from which they are derived, which raises many ethical concerns and puts limitations on their use for research purposes. In addition, immunological differences between the donor ES cells and the patient raise the possibility of immune rejection. Recent advances in the field of stem cell research have demonstrated that mouse and human fibroblasts can be reprogrammed to a pluripotent state in vitro by ectopically expressing four transcription factors. These induced pluripotent stem (iPS) cells can differentiate into all cell types of the body just as ES cells can and will not only overcome the ethical issues that come with obtaining ES cells, but might also provide a customizable cell to be used for transplantation on a patient-specific basis. To determine if hepatocytes derived from iPS cells can efficiently engraft into and repopulate a damaged liver, we propose to rescue the defect seen in the conditional SRF knockout model by combining gene therapy with iPS cell-based therapy. As alcohol- related liver disease is a prevalent problem, iPS cell-based therapies, most importantly transplantation with hepatocytes derived from iPS cells, could one day help cure those with liver disease and circumvent the issue of the limited supply of donor organs. Furthermore, demonstrating that iPS cell-derived hepatocytes can effectively rescue a dysfunctional liver could pave the way for the use of iPS cells to produce a variety of cell types to be used to regenerate other damaged organs, such as the heart or nervous system.

Public Health Relevance

In this project, we aim to study the therapeutic potential of induced pluripotent stem (iPS) cells, which are very similar in characteristics to embryonic stem cells, except that iPS cells originate from somatic cells, such as skin, stomach, or liver cells. iPS cells will be used to produce more mature cell types, such as liver cells, to be studied in transplantation experiments in animal models of disease to determine their therapeutic potential. The therapeutic use of iPS cells is relevant to public health in that they may provide us with a source of cells to be used in cell-based therapies for regenerative medicine to overcome disease and the shortage of donor organs.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Predoctoral Individual National Research Service Award (F31)
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Health Services Research Review Subcommittee (AA)
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Murray, Gary
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Medical College of Wisconsin
Anatomy/Cell Biology
Schools of Medicine
United States
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Noto, Fallon K; Determan, Megan R; Cai, Jun et al. (2014) Aneuploidy is permissive for hepatocyte-like cell differentiation from human induced pluripotent stem cells. BMC Res Notes 7:437
Gundry, Rebekah L; Riordon, Daniel R; Tarasova, Yelena et al. (2012) A cell surfaceome map for immunophenotyping and sorting pluripotent stem cells. Mol Cell Proteomics 11:303-16
Cayo, Max A; Cai, Jun; DeLaForest, Ann et al. (2012) JD induced pluripotent stem cell-derived hepatocytes faithfully recapitulate the pathophysiology of familial hypercholesterolemia. Hepatology 56:2163-71