Deciphering the Drug Synergy in Pharmacological Rejuvenation of Mesenchymal Stromal Cells

Cell rejuvenation can be achieved, in principle. The process involves interconnected biological processes. The major challenge is to understand which drugs can stimulate and coordinate these processes. The mechanisms of stimulation and regulation must also be discovered and described. Artificial intelligence (AI) will be utilized to identify effective drug combinations and understand their working mechanisms. The initial objective is to delay aging in lab-grown mesenchymal stromal cells (MSCs). Specifically, the research team will decipher the metabolic responses to combinations of rejuvenating drugs. To promote diversity in engineering, the research team will advise underrepresented undergraduates both in project-based courses and in research labs. This project integrates tissue engineering, drug screening, and machine learning. The aim is to develop a pharmacological approach for mitigating the in vitro senescence progression in MSCs. MSCs hold great promise for treating many currently uncurable diseases, but their therapeutic function decays rapidly during expansion. Identifying the appropriate pharmacologic factors that effectively mitigates senescence remains challenging. A “combination therapy” approach for reducing MSC senescence will be pursued and evaluated. This will entail deciphering the nonlinear and high-dimensional relationship between the major senescence signaling pathways (i.e., mTOR, EGF, FGF, PDGF, and insulin). The research team will first utilize AI to identify the combination of pharmacological factors that reduces senescence. Subsequently, transcriptome analyses of the rejuvenated MSCs will be performed to identify how the induced transcriptional response mitigates senescence. By performing a targeted drug screening that perturbs the AI-predicted factor combination, the research team will identify the underlying drug synergism that amplifies the efficacy of the “combination therapy”. The outcome sought it to identify an effective rejuvenation trajectory that can be reproducibly induced by perturbing the cell culture medium supplements. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.