A general mathematical framework for understanding the behavior of heterogeneous stem cell regeneration.

Stem cell heterogeneity is essential for homeostasis in tissue development. This paper establishes a general mathematical framework to model the dynamics of stem cell regeneration with cell heterogeneity and random transitions of epigenetic states. The framework generalizes the classical G0 cell cycle model and incorporates the epigenetic states of individual cells represented by a continuous multidimensional variable. In the model, the kinetic rates of cell behaviors, including proliferation, differentiation, and apoptosis, are dependent on their epigenetic states, and the random transitions of epigenetic states between cell cycles are represented by an inheritance probability function that describes the conditional probability of cell state changes. Moreover, the model can be extended to include genotypic changes and describe the process of gene mutation-induced tumor development. The proposed mathematical framework provides a generalized formula that helps us to understand various dynamic processes of stem cell regeneration, including tissue development, degeneration, and abnormal growth.