Deciphering Cellular Reprogramming: Mechanistic Insights for Disease Modeling, Pharmaceutical Testing, and AI-Driven Drug Discovery
Abstract
iPSC reprogramming is a process that converts somatic cells, such as fibroblasts, into induced pluripotent stem cells (iPSCs). iPSCs exhibit the properties of embryonic stem cells, including the ability to give rise to every cell type in an organism. iPSCs are of prime interest in the field of regenerative medicine because they can be used to generate a wide range of cells, which can potentially replace damaged cells in a patient without the threat of immune rejection. Reprogramming involves dynamic changes in chromatin accessibility, which are critical for the conversion of fibroblast cells to iPSCs. Recent technological advances in sequencing and machine learning can be applied to further explore the mechanisms by which cells are able to silence somatic genes and activate pluripotent gene networks. The following chapters investigate the mechanism of cellular reprogramming and the practical applications of stem cell properties. In Chapter 1, a meta-analysis of comparable epigenomic and transcriptomic human and murine data sets was conducted to identify consistent changes in chromatin accessibility regions during reprogramming. Integrative approaches were then used to construct stage-specific regulatory networks of human cellular reprogramming from gene expression and chromatin accessibility data. In Chapter 2, stem cells were utilized for disease modeling and pharmaceutical testing. In Chapter 3, artificial intelligence methods were employed to aid in discovery of potential pharmaceuticals for preclinical, in vitro testing. The primary focus of regenerative medicine is to efficiently derive human stem cells in order to treat a host of diseases and disabilities. Overall, this dissertation provides a significant contribution to understanding the process by which cells become pluripotent, which will aid in surmounting current challenges associated with stem cell technology and potentially lead to revolutionary therapeutics. In attempt to help actualize this, this dissertation also heavily investigates the practical applications of stem cells and AI-driven drug discovery as avenues to propose, develop and test medical solutions.