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2015 ; 5
(ä): 16895
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Biophysical Regulation of Chromatin Architecture Instills a Mechanical Memory in
Mesenchymal Stem Cells
#MMPMID26592929
Heo SJ
; Thorpe SD
; Driscoll TP
; Duncan RL
; Lee DA
; Mauck RL
Sci Rep
2015[Nov]; 5
(ä): 16895
PMID26592929
show ga
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.