Abstract
BackgroundMechanical 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.ResultsWe 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.ConclusionsControl 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.
Highlights
Mechanical and biophysical properties of the cellular microenvironment regulate cell fate decisions
Stiff substrates promote cellECM adhesion interactions via integrins [6]. These adhesive interactions control the localization of downstream transcriptional factors Yesassociated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), which have been identified as mechanical sensors and mediators of such signals [6, 18]
We first assessed whether the model is able to recapitulate experimental studies, and find that it does agree with evidence showing Mesenchymal stem cell (MSC) differentiation into neurons or adipocytes on softer substrates, and myocytes or osteoblasts on stiffer substrates
Summary
Mechanical and biophysical properties of the cellular microenvironment regulate cell fate decisions. The signals arising at the stem cell/substrate interface are complex and dynamic [7], it has been shown that stiffness alone is enough to direct MSC differentiation [3, 4]. Seeding MSCs on a phototunable substrate demonstrates that osteogenic patterns of gene expression persist even after decreasing the stiffness of the substrate [8].
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