Biophysical Regulation of Chromatin Architecture Instills a Mechanical Memory in Mesenchymal Stem Cells

Abstract

Mechanical cues direct the lineage commitment of mesenchymal stem cells (MSCs). In this study, we identified the operative molecular mechanisms through which dynamic tensile loading (DL) regulates changes in chromatin organization and nuclear mechanics in MSCs. Our data show that, in the absence of exogenous differentiation factors, short term DL elicits a rapid increase in chromatin condensation, mediated by acto-myosin based cellular contractility and the activity of the histone-lysine N-methyltransferase EZH2. The resulting change in chromatin condensation stiffened the MSC nucleus, making it less deformable when stretch was applied to the cell. We also identified stretch induced ATP release and purinergic calcium signaling as a central mediator of this chromatin condensation process. Further, we showed that DL, through differential stabilization of the condensed chromatin state, established a ‘mechanical memory’ in these cells. That is, increasing strain levels and number of loading events led to a greater degree of chromatin condensation that persisted for longer periods of time after the cessation of loading. These data indicate that, with mechanical perturbation, MSCs develop a mechanical memory encoded in structural changes in the nucleus which may sensitize them to future mechanical loading events and define the trajectory and persistence of their lineage specification.

Differentiation alters stem cell nuclear architecture, mechanics, and mechano-sensitivity

“…This increased calcium mobilization may itself impact lamin processing (Kalinowski et al, 2013), creating a feed-forward loop to ensure that the nucleus remains patent under conditions of high mechanical activity. We recently showed that ATP-purinergic signaling is a central modulator in the load-induced-chromatin condensation in MSCs, as is signaling thorough Smad proteins (Heo et al, 2015, 2016). Further, we have established that the giant isoform of nesprin-1 (a component of the LINC complex that mediates actin connectivity to the nucleus) is essential for mechanical force transfer to the nucleus and activation of the YAP/TAZ pathway in response to exogenous mechanical loading (Driscoll et al, 2015).…”

Cellular adaptation to biomechanical stress across length scales in tissue homeostasis and disease

“…Another proposed mechanism by which a mechanical memory is imprinted onto a cell is by physically altering the chromatin state. Indeed, calcium signaling downstream of cyclic stretch triggers changes in chromatin organization, and is proposed to elicit a mechanical memory in response to environmental mechanics [36]. Of note, multiple rounds and not singular episodes of loading are required to achieve a memory in MSCs, thereby providing flexibility in the system for cells to transiently survey diverse environments without being irreversibly sent down a specific fate pathway.…”

Mechanical stretch and chronotherapeutic techniques for progenitor cell transplantation and biomaterials

“…The authors identified ATP release and calcium signalling induced by mechanical stretch as the mediators of this condensation process. Following being subjected to stretch, it was also found that the cells retained a ‘mechanical memory’, whereby the cells exhibited higher amounts of chromatin condensation that persisted for longer times, when subjected to increasing numbers of loading events and strain levels, which may be a mechanism by which the MSCs sensitize themselves to future loading events [54]. Collectively, these studies emphasise just how far reaching the effects of mechanical stretch can be on MSC physiology and maintenance, and show how tensile loading can affect not only cellular differentiation, but also affect apoptosis, ROS, calcium oscillations and matrix mineralisation.…”