Metabolic regulation of cardiac differentiation and maturation
Cells in the body take up nutrients from their environment and metabolize them in a complex set of biochemical reactions to generate energy and replicate. Control of these processes is particularly important for heart cells, which need large amounts of energy to drive blood flow throughout the body. Not surprisingly, the nutritional requirements of heart cells are very different than those of stem cells. This proposal will investigate the metabolism of pluripotent stem cells and how this changes during differentiation to cardiac cells. We will determine which nutrients are important to make functional heart cells and use this information to optimize growth conditions for producing heart cells for regenerative medicine and basic biology applications. We accomplish this by feeding cells nutrients (sugar, fat) labeled with isotopes. As these labeled molecules are consumed, the isotopes are incorporated into different metabolites which we track using mass spectrometry. This advanced technique will allow us to see how sugars and fat are metabolized inside stem cells and cardiac cells obtained through differentiation. We will also study the electrical activity of these heart cells to ensure that adequate nutrients are provided for the generation of cells with optimal function. Ultimately, this project will lead to new methods for producing functional heart cells for regenerative medicine and may also lead to insights into how cardiac cells malfunction in heart disease.
Heart disease is one of the leading causes of death in California. As a result, much of the regenerative medicine community in the state and the many Californians suffering from heart failure are interested in obtaining functional heart cells from stem cells. Our work will identify the most important nutrients required to coax stem cell-derived heart cells to behave like true adult heart cells. This information will make more effective cell models for researchers and companies to study how this disease affects heart cell metabolism. Since enzymes are highly targetable with drugs, the basic scientific findings from our work will be of great interest to California biotechnology companies and can stimulate job growth in the state. Our findings will also provide insight into very specific types of genetic heart disease, and this work may lead to additional grants from federal funding sources, bringing about additional revenue and job growth in California. A better understanding of how different nutrients influence heart cell function may provide guidance into new treatment strategies for heart disease. Finally, this work will highlight the importance of diet, nutrition, and healthy heart function, providing useful information relating to public health.
Growing up we have all heard the phrase, “You are what you eat.” Just like our bodies, stem cells require large quantities of fuel for energy and growth. The same is true for heart cells that continually drive blood flow. Therefore, understanding how stem cells and cardiac cells they generate consume and use different foods is important for characterizing their clinical potential. This grant aims to study how different nutritional fuels influence stem cell and cardiomyocyte (heart cell) growth, differentiation, and function. Using advanced methods that allow us to track how sugar (carbs), protein, and fat are consumed and produced by stem cells, we have identified key nutritional factors that affect stem cell performance and function. Surprisingly, most advanced stem cell media are lacking in several important factors. This deficiency negatively impacts stem cell metabolism in a number of ways, causing increased nutrient consumption, decreased respiration, and oxidative stress. Using this information we have developed improved stem cell growth conditions that mitigates these effects. Finally, we have compared the metabolism of stem cell-derived heart cells to parental stem cells, identifying key differences that will serve as benchmarks to functionally validate the performance and “maturity” of cardiac cells.