ABSTRACT
Maintaining tissue homeostasis requires appropriate regulation of stem cell differentiation. The Waddington landscape posits that gene circuits in a cell form a potential landscape of different cell types, wherein cells follow attractors of the probability landscape to develop into distinct cell types. However, how adult stem cells achieve a delicate balance between self-renewal and differentiation remains unclear. We propose that random inheritance of epigenetic states plays a pivotal role in stem cell differentiation and present a hybrid model of stem cell differentiation induced by epigenetic modifications. Our comprehensive model integrates gene regulation networks, epigenetic state inheritance, and cell regeneration, encompassing multi-scale dynamics ranging from transcription regulation to cell population. Through model simulations, we demonstrate that random inheritance of epigenetic states during cell divisions can spontaneously induce cell differentiation, dedifferentiation, and transdifferentiation. Furthermore, we investigate the influences of interfering with epigenetic modifications and introducing additional transcription factors on the probabilities of dedifferentiation and transdifferentiation, revealing the underlying mechanism of cell reprogramming. This in silico model provides valuable insights into the intricate mechanism governing stem cell differentiation and cell reprogramming and offers a promising path to enhance the field of regenerative medicine.
Subject(s)
Cellular Reprogramming , Epigenesis, Genetic , Cell Differentiation/genetics , Computer Simulation , Transcription Factors/geneticsABSTRACT
Coculture of mesenchymal stem cells (MSCs) and vascular endothelial cells (ECs) in vitro leads to the formation of a capillary-like reticular structure by ECs, which has great potential as a better substitute for artificial blood vessels in terms of stability and functionality. To investigate the mechanisms of the early neovascularization induced by MSCs, we analyzed the kinematic features of the motion of ECs and concluded that the dynamic interaction between cells and the extracellular matrix would reveal the capillary-like structure formation. Based on this hypothesis, we proposed a mathematical model to simulate the vascular-like migration pattern of ECs in silico, which was confirmed by in vitro studies. These in vitro studies validated that the dynamic secretion and degradation of collagen I is the critical factor for capillary structure formation. The model proposed based on cell tracking, single cell sequencing, and mathematical simulation provides a better understanding of the neovascularization process induced by MSCs and a possible simple explanation guiding this important cellular behavior.-Yu, Y., Situ, Q., Jia, W., Li, J., Wu, Q., Lei, J. Data driven mathematical modeling reveals the dynamic mechanism of MSC-induced neovascularization.
Subject(s)
Mesenchymal Stem Cells/pathology , Neovascularization, Pathologic/pathology , Capillaries/metabolism , Capillaries/pathology , Cells, Cultured , Coculture Techniques/methods , Collagen Type I/metabolism , Endothelial Cells/pathology , Extracellular Matrix/metabolism , HEK293 Cells , Human Umbilical Vein Endothelial Cells , Humans , Mesenchymal Stem Cells/metabolism , Models, Theoretical , Neovascularization, Pathologic/metabolismABSTRACT
In this paper, we study a mathematical model of stem cell regeneration with epigenetic state transitions. In the model, the heterogeneity of stem cells is considered through the epigenetic state of each cell, and each epigenetic state defines a subpopulation of stem cells. The dynamics of the subpopulations are modeled by a set of ordinary differential equations in which epigenetic state transition in cell division is given by the transition probability. We present analysis for the existence and linear stability of the equilibrium state. As an example, we apply the model to study the dynamics of state transition in breast cancer stem cells.
