Obesity is a huge burden to society with its increasing trend unstopped. Obesity significantly increases risk factors for type 2 diabetes, high blood pressure, and cardiovascular diseases. A pathological recruitment of new fat cells, or adipocytes, contributes to obesity, and a source of adipocytes can be mesenchymal stem cells(MSCs). However, there is a significant knowledge gap in understanding the environmental factors that control MSC differentiation into adipocytes, and research is needed on how to prohibit the differentiation of MSCs into fat cells. This seriously limits therapeutic ways to treat obesity. The goal of this study is to gain a thorough insight on how mechanical signals regulate the propensity of MSCs to differentiate into adipocytes, and on the basis of this knowledge propose novel therapeutic approaches to prevent and treat obesity. Therefore, the proposed studies are expected to address in the long run the unmet needs in obesity and relieve the high medical spending over obesity and related diseases. Research will be integrated with educational efforts to offer engineering students a basic foundation on stem cell bioengineering. This educational goal will be achieved by curriculum development on stem cell-based bioengineering, graduate student training, training undergraduates via Undergraduate Creative Activities and Research Experiences (UCARE) program at the University of Nebraska-Lincoln, and the Lab Experience Program for Homeschool Students (LEPHS) developed by the PI.
A pathological recruitment of new adipocytes to form adipose tissue hyperplasia induces obesity, and one of the main causes of adipocyte number growth is the recruitment of newly formed preadipocytes from MSC sources. Since MSCs have plasticity to commit and differentiate into various lineages, it is critical to understand how MSCs determine their fate to adipocytes to deal with obesity. However, there is a huge knowledge barrier in regard to complex adipogenesisleading milieus, biochemical, mechanical and physical, and how to prohibit the adipogenesis of MSCs. This seriously limits therapeutic ways to treat obesity. The long-term goal of this study isto gain a thorough insight on how mechanical signals regulate MSC adipogenesis for potential therapeutic attempts targeting molecular mechanosensors. For this goal, this CAREER study exploits a novel adipocytic mechanotransduction theme. It is proposed to inhibit MSC adipogenesis via applying mechanical cell stretch and unveil primary molecular mechanisms that govern MSC stretch mechanotransduction during the course of adipogenesis. Two Specific Aims are proposed. 1. To examine the effects of mechanical stretch at varying regimens in inhibiting MSC adipocytic commitment and differentiation. 2. To determine the role of cellsubstrate and cell-cell interactions in the stretch inhibition of MSC adipogenesis. The hypothesis to be tested is that mechanical stretch will induce inhibitory effects on MSC adipogenesis via cell-substrate and/or cell-cell interaction-mediated mechanotransduction mechanisms. The proposed studies may suggest a novel adipocytic mechanotransduction strategy to treat obesity. Specifically, sensitizing molecular mechanosensors, for example, focal adhesion kinase(FAK) and cadherin cell-cell adherens junction, may enhance mechanical inhibitory effects acting on MSC adipogenesis. This may suggest potential molecular therapeutic targets for dealing with obesity. Research efforts will be integrated with educational and outreach efforts at the high school, undergraduate and graduate student levels.
