Mechanical memory in cells emerges from mechanotransduction with transcriptional feedback and epigenetic plasticity

Abstract

Emerging evidence shows that cells are able to sense and store a memory of their past mechanical environment. Since existing mechanotransduction models are based on adhesion and cytoskeletal dynamics that occurs over seconds and minutes, they do not capture memory observed over days or weeks. We postulate that transcriptional activity and epigenetic plasticity, upstream of adhesion-based signaling, need to be invoked to explain long-term mechanical memory. Here, we present a theory for mechanical memory in cells governed by three key components. First, cells on a stiff matrix are primed by a transcriptional reinforcement of cytoskeletal signaling. Second, longer stiff-priming progressively produces more memory-regulating factors and reduces epigenetic plasticity. Third, when stiff-primed cells move to soft matrix, the reduced epigenetic plasticity blocks new transcription required for cellular adaptation to the new matrix. This stalled transcriptional state gives rise to memory. We validate this model against previous experimental findings of memory storage and decay in epithelial cell migration and stem cell differentiation. We also predict wide-ranging memory responses for different cell types of varying protein kinetics and priming conditions. This theoretical framework for mechanical memory expands the timescales of mechanotransduction captured by conventional models by integrating cytoskeletal signaling with transcriptional activity and epigenetic plasticity. Our model predictions explain mechanical memory and propose new experiments to test spatiotemporal regulation of cellular memory in diverse contexts ranging from cell differentiation to migration and growth.

Actuation Enhances Patterning in Human Neural Tube Organoids

“…In particular, we observed a linear dependency on stretch magnitudes and a mechanical temporal competence window between days 3-7 when mechanical stimulation had the greatest and irreversible effect on enhancing FP patterning. These observations suggest that hNTOs retain a mechanical memory of applied forces, in line with emerging experimental 37 and theoretical 38 results in other systems. To test whether stretch direction would bias the direction or frequency of patterning, we built a device which allowed us to stretch organoids uniaxially at the same rate as that applied with the equibiaxial device.…”

Metastasis: crosstalk between tissue mechanics and tumour cell plasticity

“…Notably, cells appear to possess a "mechanical memory" i.e., prolonged exposure to a stiff ECM causes EMT-like behaviour with nuclear localisation of YAP, high actomyosin contractility, and large cell matrix adhesions and this phenotype is maintained when the cells move to a soft environment for as long as the factors mediating the mechanical memory suppress a transcriptional switch. [113][114][115] EMT and tumour cell mechanics Whereas stiffening of the TME drives EMT and the aggressive behaviour of tumours, 116 tumour cells themselves have been observed to be "more deformable" or "softer". 117 EMT might play a role in such softening of tumour cells.…”

Characterizing and Engineering Biomimetic Materials for Viscoelastic Mechanotransduction Studies

“…For example, stem cell priming on stiff substrates reduces their epigenetic plasticity (i.e. the ability to modify their phenotype), blocking the transcription of new genes required for the adaptation to a new environment 75,76 . This type of memory has also been observed for other cells such as lung fibroblasts, which showed persistent myofibroblast activity after three weeks on PDMS substrates with a pathological stiffness, even after switching to a softer substrate 77 .…”

“…The longer cells are cultured on stiff substrates, the less they respond to substrates with different mechanical properties (Figure 6C). In particular conditions, depending on the combination of substrate stiffness and culture duration, cell mechanical memory can be restored 75,78 . The promoter of this reversible memory effect is thought to be the YAP/TAZ complex, which is thought to act as a mechanical rheostat mediating the mechanical dosing.…”