Magnesium ions regulate mesenchymal stem cells population and osteogenic differentiation: A fuzzy agent-based modeling approach.

Jalil Nourisa,Regine Willumeit-Römer,Berit Zeller-Plumhoff,Vladimir Ivannikov,Heike Helmholz,Bérengère Luthringer-Feyerabend

doi:10.1016/j.csbj.2021.07.005

Abstract

Mesenchymal stem cells (MSCs) are proliferative and multipotent cells that play a key role in the bone regeneration process. Empirical data have repeatedly shown the bioregulatory importance of magnesium (Mg) ions in MSC growth and osteogenesis. In this study, we propose an agent-based model to predict the spatiotemporal dynamics of the MSC population and osteogenic differentiation in response to Mg2+ ions. A fuzzy-logic controller was designed to govern the decision-making process of cells by predicting four cellular processes of proliferation, differentiation, migration, and mortality in response to several important bioregulatory factors such as Mg2+ ions, pH, BMP2, and TGF-β1. The model was calibrated using the empirical data obtained from three sets of cell culture experiments. The model successfully reproduced the empirical observations regarding live cell count, viability, DNA content, and the differentiation-related markers of alkaline phosphate (ALP) and osteocalcin (OC). The simulation results, in agreement with the empirical data, showed that Mg2+ ions within 3-6mM concentration have the highest stimulation effect on cell population growth. The model also correctly reproduced the stimulatory effect of Mg2+ ions on ALP and its inhibitory effect on OC as the early and late differentiation markers, respectively. Besides, the numerical simulation shed light on the innate cellular differences of the cells cultured in different experiments in terms of the proliferative capacity as well as sensitivity to Mg2+ ions. The proposed model can be adopted in the study of the osteogenesis around Mg-based implants where ions released due to degradation interact with local cells and regulate bone regeneration.

Highlights

Mesenchymal stem cells (MSCs) are the key players in bone fracture healing [1]
MSCs increase cell population through a fast proliferation process and differentiate into multiple cell types involved in bone tissue regeneration, in particular osteoblasts [2]
MSCs experience a decline in proliferative capacity and gain osteoblastic properties [4]

Summary

Introduction

Mesenchymal stem cells (MSCs) are the key players in bone fracture healing [1]. MSCs increase cell population through a fast proliferation process and differentiate into multiple cell types involved in bone tissue regeneration, in particular osteoblasts [2]. The proliferation process occurs through a cascade of cell cycle events including the two major processes of DNA synthesis and actual division of the parent cell into two daughter cells [2]. The specialization of MSCs toward osteoblasts involves a complex intracellular interaction and is shown to occur continuously with recognizable intermediate cells such as osteoprogenitors and preosteoblasts [3]. MSCs experience a decline in proliferative capacity and gain osteoblastic properties [4]. The onset of MSC differentiation to osteoblasts and the

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