BRIGE: Modeling metabolism in embryonic stem cell growth and differentiation

Georgia Tech Research Corporation, Atlanta GA

Investigators

Abstract

PI: Styczynski, Mark Proposal Number: 1125684 The research objective of this proposal is to measure and model the metabolism of embryonic stem cells during proliferation and differentiation. The PI's group is dedicated to understanding and controlling metabolism by studying and modeling metabolite concentrations. Here, we apply metabolite profiling and machine-learning techniques to create the first-ever descriptive models of metabolism in embryonic stem cell differentiation. We will also study the regulatory potential of metabolites we identify as significantly correlated with cellular differentiation. Intellectual Merit Stem cells are poised to make a revolutionary impact on modern medicine. Given recent successes, attention has begun to turn to the looming biomanufacturing problem inherent in developing stem cell treatments. Difficulties expanding stem cell populations from small numbers and controlling their differentiation are such significant roadblocks to scale-up that stem cell therapies may be technically or economically infeasible on a large scale. One promising route for controlling stem cell behavior during scale-up is monitoring and manipulating metabolism and metabolic signals in these cells -yet there has been little research in this area. This transformative research plan will help fill this knowledge gap, specifically addressing three key issues in the field of stem cell culture and engineering. By performing a pioneering longitudinal metabolomics study, we will (1) establish an initial dataset and models demonstrating the importance of metabolism in stem cell expansion and differentiation, and that can be used in guiding culture scale-up. By identifying metabolites capable of promoting specific differentiation lineages, we will (2) enable more precise control of ES cells during expansion and differentiation, also facilitating scale-up. Finally, our extracellular metabolite profiling techniques and models will (3) provide non-invasive, non-destructive methods for stem cell culture monitoring and quality control that are capable of detecting changes in cell state long before morphological changes are evident. Broader Impacts By expanding capabilities in controlling stem cell fate using our systems-level analysis of metabolism, we will enable development of novel and more complex stem cell engineering therapeutics that can save or greatly improve the lives of people facing debilitating diseases. The direct application of our research results to the scale-up of stem cell culture technologies to industrial production levels will circumvent a critical economic roadblock in the field, enabling the development of therapeutic candidates into products that can heal not just those who are rich or fortunate, but anyone facing such a disease regardless of socioeconomic status. Such systems level analysis also has the potential to make a significant impact on future engineers; in this vein, the PI proposes a broadening participation program with a primary focus of encouraging female participation in engineering. The centerpiece of this effort is the development of an activity and event for Girl Scout troops that stokes interest in engineering and introduces them to the systems-level mindset that defines engineering. The PI will collaborate with a local teacher to develop this activity and align it with Georgia state educational standards. Female undergraduates and graduate students will help develop and implement this activity. Other key activities planned by the PI include continuing work with an all-female dormitory, collaboration with the campus Society of Women Engineers chapter in developing outreach activities, and recruiting and mentoring female students. Additionally, the PI's group will host underrepresented minority undergraduate students through an REU program; the first and third aims have been formulated to easily integrate undergraduate researchers in a rewarding project.