(199e) Development of a Stochastic Model of Heterogeneity of Human Pluripotent Stem Cell Populations Under Conditions Promoting Self-Renewal or Differentiation

Heterogeneity is an intrinsic feature of stem cell populations giving rise to different cell fate potentials under conditions promoting differentiation. Better understanding of the dynamics of heterogeneous stem cell populations can be achieved through coupling of sophisticated experimental techniques with computational modeling. In this study, we constructed a population balance equation (PBE) system for human embryonic stem cells (hESCs) under self-renewal and differentiation. Model development was accompanied by experimental studies conducted with hESCs under self-renewing and directed differentiation conditions.

A system of PBEs was constructed with each PBE representing different populations of cells depending on their differentiation state. The state vector comprised attributes such as cell size and expression level of lineage markers specific to the differentiated progeny. The heterogeneity within the same population stemmed from gene expression noise and stochastic partitioning at cell division. The model results are in excellent agreement with the experimental data obtained in our laboratory via different methods including flow cytometry. For hESCs undergoing self-renewal, the model predicted that both gene expression noise and partitioning at cell division have comparable contributions to the heterogeneity of hESC populations. Under differentiation conditions, the cell transition kinetics were modeled with respect to cell fate determinants such as gene expression noise and growth factor concentration.

The PBE framework captures the dynamics of stem cell populations with cell-to-cell variability. For self-renewing hESCs, we provide for the first time a quantitative account of the effects gene expression noise and cell division on population heterogeneity. The PBE system presented here also describes the evolution of stem cells and their progeny under conditions promoting cell commitment.