Redox Regulation of Canine Embryonic Stem Cells

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Stem cells are characterized by their capacity for prolong cell division and their ability to differentiate into multiple cell types. As such, stem cells help preserve tissue functions throughout life. Aerobic metabolism, while enabling efficient energy production, also generates reactive oxygen species (ROS). Stem cell biology has primarily focused on the harmful effects of ROS, which include cell/tissue aging, cancer development and activation of anti-stress repair mechanisms. In contrast, exciting new data that we have contributed to generating, indicates that the characteristic traits of stem cells are in fact regulated by ROS. My NSERC funded research program (continuously since 2001) has resulted in the novel development of several canine embryonic stem cell (cESC) lines. Interestingly, our cESCs appear to require both leukemia inhibitory factor (LIF) and basic fibroblast growth factor (bFGF) in their culture medium to survive, proliferate and maintain their stem cell characteristics - unlike mouse or human ESCs, which solely require LIF or bFGF, respectively. The next critical step in characterizing these novel canine stem cells is to understand how ROS govern their stem cell attributes. Using canine embryonic stem cell culture models that mimic physiological low and high oxidative conditions, we will characterize the redox status and signaling pathways that control canine embryonic stem cell division in the undifferentiated state. Using a novel protein separation technique, we will determine the spectrum of disulfide-linked proteins that are affected by increased ROS levels and by modulating the levels of ROS aim to increase the efficiency of producing induced pluripotent stem cells from canine fibroblasts. Identification and analysis of ROS sensing proteins will provide insight into how oxidative cellular conditions influence stem cell functions. Support for these studies will place Canada in the forefront of these emerging biotechnologies, providing high-tech training for numerous highly qualified personnel (HQP) while enhancing the biomedical and commercial potential for implementing stem cell therapies in the dog.