ASU-Mayo Seed Grant awarded to assistant professor Madeline Andrews and cardiac Dr. Clifford Holmes at Mayo Clinic
Abstract: Target physiologic energy metabolism for high-fidelity patient-specific stem cell models of cardiac and neural disease
In a recent interview, Madeline Andrews, an assistant professor of biomedical engineering at the School of Biological and Health Systems Engineering, part of the Ira A. Fulton Schools of Engineering at ASU, discussed her collaborative research with Dr. Clifford Folmes from Mayo Clinic, Scottsdale. Funded by an ASU-Mayo seed grant, their project aims to develop more accurate human-induced pluripotent stem cell (iPSC) models for the brain and heart—two organs that do not regenerate.
Question: Can you provide me with a brief overview of the project that received the seed grant? What research question(s) or problem(s) are you addressing?
Answer: ASU-Mayo seed grant is in collaboration with Dr. Clifford Folmes at Mayo Clinic, Scottsdale. We are collaborating to develop higher fidelity human-induced pluripotent stem cell (iPSC) models of the human brain and heart, which are two organs that do not regenerate. iPSCs are derived from the skin or blood of patients that have been genetically manipulated until they have the capacity to become any cell in the body – we then use these stem cells to differentiate into cell types of interest. iPSC models are immensely useful tools to study patient-specific disease origins and test therapeutics, however their reflection of the native cells and tissues they resemble is currently limited. The goal of this study is to improve their culture conditions to more accurately model and screen therapeutics for currently intractable neurological and cardiac diseases. We hypothesize that recreating an in vivo-like nutrient environment will increase cellular capacity to differentiate and mature in more adult-like tissues.
Question: What are the primary goals of this project? How do you envision the research impacting your field or the broader scientific community?
Answer: Our goal is to recreate an in vivo-like metabolic environment to produce higher fidelity iPSC models and investigate how metabolites direct normal development and disease pathogenesis. We will leverage my expertise in brain development and single cell transcriptomics and Dr. Folmes’ expertise in cardiac development and stem cell metabolism, combined with our complementary approaches to differentiate iPSC lines into defined cardiac and neural lineages. This strategy will enable us to comprehensively benchmark tissue-specific lineage and maturation state improvements. Under validated culture conditions, we’ll use iPSC lines derived from skin cells of patients with mitochondrial encephalomyopathy, lactic acidosis and stroke like episodes (MELAS) to assess how impaired mitochondrial function influences lineage commitment and maturation under physiologic conditions. This strategy will offer novel insights into disease origins that cannot be observed under standard culture conditions. Together, these studies will establish a temporal metabolic roadmap of human tissue function and leverage validated features to interrogate physiologically relevant metabolic conditions that are intractable due to current model limitations. The improvements in cell culture methodology have widespread implications for how stem cells are used to study a range of diseases and how they are applied as regenerative medicine tools.
Question: What makes your approach in your research innovative? How does it differ from existing research in this area?
Answer: Metabolism is often ignored as a driver of tissue health and function, partly due to the technical challenges of studying it. Metabolic changes occur rapidly and are not optimally evaluated using many standard molecular biology assays. Our strategy is to directly perturb metabolic conditions to make them closer to endogenous nutrient quantities in the body. Then, we will measure changes with various functional readouts to assess metabolic states and their impact on tissue maturation. The culture conditions and the method for analyzing these types of samples are novel and will provide unique insights into this field.
Question: I understand you are working with the Mayo Clinic in Arizona. How does this collaboration align with the Mayo Clinic and ASU Alliance for Health Care to optimize health and the human body?
Answer: This project aligns with the strategic priority of the Mayo Clinic and ASU Alliance for Health Care to optimize health and the human body by defining how nutrient supply regulates iPSC differentiation into discrete lineages for accurate disease models and innovative treatments. Additionally, metabolism is a highly druggable and pliable target for identifying potential therapeutics, which we can test in our improved models.
One-month-old neural organoids form 3D structures resembling features of the brain. Image courtesy of Madeline Andrews.
Organoids containing neural cell types are used to study the brain. In this image, blue marks all cells, red highlights dividing cells, and green identifies dying cells, allowing researchers to assess how changes in cell culture conditions impact tissue growth and health. Image courtesy of Madeline Andrews.