Modeling hiPSC-to-Early Cardiomyocyte Differentiation Process using Microsimulation and Markov Chain Models

Cardiomyocytes (CMs), the contractile heart cells that can be derived from human induced pluripotent stem cells (hiPSCs). These hiPSC derived CMs can be used for cardiovascular disease drug testing and regeneration therapies, and they have therapeutic potential. Currently, hiPSC-CM differentiation cannot yet be controlled to yield specific heart cell subtypes consistently. Designing differentiation processes to consistently direct differentiation to specific heart cells is important to realize the full therapeutic potential of hiPSC-CMs. A model that accurately represents the dynamic changes in cell populations from hiPSCs to CMs over the differentiation timeline is a first step towards designing processes for directing differentiation. This paper introduces a microsimulation model for studying temporal changes in the hiPSC-to-early CM differentiation. The differentiation process for each cell in the microsimulation model is represented by a Markov chain model (MCM). The MCM includes cell subtypes representing key developmental stages in hiPSC differentiation to early CMs. These stages include pluripotent stem cells, early primitive streak, late primitive streak, mesodermal progenitors, early cardiac progenitors, late cardiac progenitors, and early CMs. The time taken by a cell to transit from one state to the next state is assumed to be exponentially distributed. The transition probabilities of the Markov chain process and the mean duration parameter of the exponential distribution were estimated using Bayesian optimization. The results predicted by the MCM agree with the data.