Abstract: The major characteristic of embryonic stem cells (ESCs) is their extensive self-renewal ability in culture and their potential to differentiate. ESCs are capable of differentiating into all cell types of the body as the mesoderm, ectoderm, and endoderm lineage. However, stem cell populations display cell-to-cell variations in multiple attributes such as protein and gene expressions, self... read more-renewal and proclivity for differentiation. Transcription factors (TFs) are important in stem cell fate decisions and TFs themselves can also serve as biomarkers of stem cell state. Cell identity is controlled by the action of transcription factors (TFs) that recognize and bind specific sequences in the genome and regulate gene expression. NANOG, a critical transcription factor among Sox2 and Oct4 which are responsible for self-renewal in embryonic stem cell, is not homogeneously expressed in cultured stem cell. In this study first, I validated the mathematical modeling approach of solving the inverse problem to predict the single-cell growth, division rates and the partition probability density function for the size of human embryonic stem cells (hESCs) with experimental data acquired by flow cytometry. There was an excellent agreement between the original analytical expressions defined for physiological state functions and results from the inverse problem approach. Next, this model was applied to predict gene expression behavior based on single cell analysis during cell growth and division in heterogeneous population of stem cells under self renewal and directed differentiation condition. This model captures population heterogeneity and may facilitate in depth understanding of this complex system while enabling systematic formulation of culture strategies to improve stem cell growth and productivity.
Thesis (Ph.D.)--Tufts University, 2017.
Submitted to the Dept. of Chemical and Biological Engineering.
Advisor: Emmanuel (Manolis) Tzanakakis.
Committee: Panagiotis Kevrekidis, and Bree Aldridge.