Mechanical memory and dosing influence stem cell fate

Abstract

We investigated whether stem cells remember past physical signals and whether these can be exploited to dose cells mechanically. We found that the activation of the Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding domain (TAZ) as well as the pre-osteogenic transcription factor RUNX2 in human mesenchymal stem cells (hMSCs) cultured on soft poly(ethylene glycol) (PEG) hydrogels (Young’s modulus E ~ 2 kPa) depended on prior culture time on stiff tissue culture polystyrene (TCPS; E ~ 3 GPa). Additionally, mechanical dosing of hMSCs cultured on initially stiff (E ~ 10 kPa) and then soft (E ~ 2 kPa) phototunable PEG hydrogels resulted in either reversible - or above a threshold mechanical dose, irreversible - activation of YAP/TAZ and RUNX2. We also found that increased mechanical dosing on supraphysiologically stiff TCPS biases hMSCs toward osteogenic differentiation. We conclude that stem cells possess mechanical memory - with YAP/TAZ acting as an intracellular mechanical rheostat - that stores information from past physical environments and influences the cells’ fate.

Adaptable Fast Relaxing Boronate‐Based Hydrogels for Probing Cell–Matrix Interactions

“…Recent investigations have shown that YAP/TAZ behaves as cellular rheostats, which largely influence mechanosensing and affect cell function and fate 2, 40. For hMSCs in elastic hydrogels, YAP/TAZ mainly remained in the cytoplasm throughout the 7 d culture (Figure 5a,f and more representative images in Figure S11, Supporting Information), reminiscent of previous findings in slowly relaxing9 or nondegradable gels 38.…”

“…By incorporating various biochemical, biophysical, and mechanical cues into a single system, hydrogels provide a powerful in vitro model to probe and understand the fundamentals of cell‐niche interactions2 and to provide information for testing hypotheses related to developmental and disease‐related processes 3, 4…”

“…Accumulating evidence in the literature suggests that the modulus of synthetic extracellular matrices (ECMs) can have a significant influence on cell function and fate 2, 5. However, more recently, it has been realized that other time‐dependent mechanical properties, such as viscoelasticity, can also substantially impact cellular responses 6, 7, 8, 9.…”

PLLA/ZnO nanocomposites: Dynamic surfaces to harness cell differentiation

“…Cell morphology after 3 h of culture was very similar, and cells presented a well-developed actin cytoskeleton with tension fibres (Figure 4g) typical of cells cultured on 2D rigid substrates [51] (stiffness measured via indentation with the AFM was 3.417 ± 1.037 GPa for PLLA and 3.027 ± 0.760 GPa for PLLA/ZnO, Figure S3). Cell shape descriptors were calculated and shown in Figure 4h.…”

Material‐Driven Fibronectin Assembly Promotes Maintenance of Mesenchymal Stem Cell Phenotypes

“…[ 3,4 ] Material systems that mimic the natural niche environment of MSCs may offer an alternative to the use of complex cocktails of soluble factors used in the culture media. Previous studies show that the cell/material interface plays an essential role on MSC function and differentiation, encompassing promising approaches to manipulate differentiation of stem cells ranging from chemistry, [5][6][7] surface modifi cations, [ 8,9 ] topography, [10][11][12] stiffness, [ 13,14 ] and even dynamic material properties such as stress relaxation. [ 15 ] While we are starting to identify the range of materials properties that can be used to drive stem cell differentiation, there is much left to discover and understand.…”