Journal Article

A mathematical model of mechanotransduction reveals how mechanical memory regulates mesenchymal stem cell fate decisions

MacLean, Adam L, Liu, Linan, Zhao, Weian, Peng, Tao, Wong, Chi Wut, Nie, Qing

2017

Overview

Background Mechanical and biophysical properties of the cellular microenvironment regulate cell fate decisions. Mesenchymal stem cell (MSC) fate is influenced by past mechanical dosing (memory), but the mechanisms underlying this process have not yet been well defined. We have yet to understand how memory affects specific cell fate decisions, such as the differentiation of MSCs into neurons, adipocytes, myocytes, and osteoblasts. Results We study a minimal gene regulatory network permissive of multi-lineage MSC differentiation into four cell fates. We present a continuous model that is able to describe the cell fate transitions that occur during differentiation, and analyze its dynamics with tools from multistability, bifurcation, and cell fate landscape analysis, and via stochastic simulation. Whereas experimentally, memory has only been observed during osteogenic differentiation, this model predicts that memory regions can exist for each of the four MSC-derived cell lineages. We can predict the substrate stiffness ranges over which memory drives differentiation; these are directly testable in an experimental setting. Furthermore, we quantitatively predict how substrate stiffness and culture duration co-regulate the fate of a stem cell, and we find that the feedbacks from the differentiating MSC onto its substrate are critical to preserve mechanical memory. Strikingly, we show that re-seeding MSCs onto a sufficiently soft substrate increases the number of cell fates accessible. Conclusions Control of MSC differentiation is crucial for the success of much-lauded regenerative therapies based on MSCs. We have predicted new memory regions that will directly impact this control, and have quantified the size of the memory region for osteoblasts, as well as the co-regulatory effects on cell fates of substrate stiffness and culture duration. Taken together, these results can be used to develop novel strategies to better control the fates of MSCs in vitro and following transplantation.

• Publisher: BioMed Central
• Subject: Accessibility / Adipocytes / Algorithms / Bifurcations / Biocompatibility / Bioinformatics / Biomechanical Phenomena / Biomedical and Life Sciences / Biomedical materials / Cancer / Cell Adhesion / Cell culture / Cell cycle / Cell Differentiation / Cell fate / Cell Lineage / Cellular and Medical Topics / Computational Biology/Bioinformatics / Computer simulation / Decisions / Differentiation / Empirical systems biology / Extracellular matrix / Feedback, Physiological / Fractures / Gene expression / Gene Regulatory Networks / Homeostasis / In vitro methods and tests / Life Sciences / Mathematical analysis / Mathematical models / Mechanical Phenomena / Mechanotransduction / Mechanotransduction, Cellular / Mesenchymal Stem Cells - cytology / Mesenchymal Stem Cells - metabolism / Mesenchyme / Models, Biological / Myocytes / Neurons / Osteoblastogenesis / Osteoblasts / Physiological / Predictive control / Probability theory / Randomness / Research Article / Simulation and Modeling / Stem cells / Stiffness / Studies / Substrates / Systems Biology / Transcription factors / Transplantation