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We investigate how matrix stiffness regulates chromatin reorganization and cell reprogramming and find that matrix stiffness acts as a biphasic regulator of epigenetic state and fibroblast-to-neuron conversion efficiency, maximized at an intermediate stiffness of 20 kPa. ATAC sequencing analysis shows the same trend of chromatin accessibility to neuronal genes at these stiffness levels. Concurrently, we observe peak levels of histone acetylation and histone acetyltransferase (HAT) activity in the nucleus on 20 kPa matrices, and inhibiting HAT activity abolishes matrix stiffness effects. G-actin and cofilin, the cotransporters shuttling HAT into the nucleus, rises with decreasing matrix stiffness; however, reduced importin-9 on soft matrices limits nuclear transport. These two factors result in a biphasic regulation of HAT transport into nucleus, which is directly demonstrated on matrices with dynamically tunable stiffness. Our findings unravel a mechanism of the mechano-epigenetic regulation that is valuable for cell engineering in disease modeling and regenerative medicine applications. 

Abstract This article describes the effects of gravity on the response of systems of identical, cyclically arranged, centrifugal pendulum vibration absorbers (CPVAs) fitted to a rotor spinning about a vertical axis. CPVAs are passive devices composed of movable masses suspended on a rotor, suspended such that they reduce torsional vibrations at a given engine order. Gravitational effects acting on the absorbers can be important for systems spinning at relatively low rotation speeds, for example, during engine idle conditions. The main goal of this study is to predict the response of a CPVA/rotor system in the presence of gravity. A linearized model that includes the effects of gravity and an order n torque acting on the rotor is analyzed by exploiting the cyclic symmetry of the system. The results show that a system of N absorbers responds in one or more groups, where the absorbers in each group have identical waveforms but shifted phases. The nature of the waveforms can have a limiting effect on the absorber operating envelope. The number of groups is shown to depend on the engine order n and the ratio N/n. It is also shown that there are special resonant effects if the engine order is n = 1 or n = 2, the latter of which is particularly important in applications. In these cases, the response of the absorbers has a complicated dependence on the relative levels of the applied torque and gravity. In addition, it is shown that for N > 1, the rotor response is not affected by gravity, at least to leading order, due to the cyclic symmetry of the gravity effects. The linear model and the attendant analytical predictions are verified by numerical simulations of the full nonlinear equations of motion. 

Abstract The role of transcription factors and biomolecules in cell type conversion has been widely studied. Yet, it remains unclear whether and how intracellular mechanotransduction through focal adhesions (FAs) and the cytoskeleton regulates the epigenetic state and cell reprogramming. Here, it is shown that cytoskeletal structures and the mechanical properties of cells are modulated during the early phase of induced neuronal (iN) reprogramming, with an increase in actin cytoskeleton assembly induced by Ascl1 transgene. The reduction of actin cytoskeletal tension or cell adhesion at the early phase of reprogramming suppresses the expression of mesenchymal genes, promotes a more open chromatin structure, and significantly enhances the efficiency of iN conversion. Specifically, reduction of intracellular tension or cell adhesion not only modulates global epigenetic marks, but also decreases DNA methylation and heterochromatin marks and increases euchromatin marks at the promoter of neuronal genes, thus enhancing the accessibility for gene activation. Finally, micro‐ and nano‐topographic surfaces that reduce cell adhesions enhance iN reprogramming. These novel findings suggest that the actin cytoskeleton and FAs play an important role in epigenetic regulation for cell fate determination, which may lead to novel engineering approaches for cell reprogramming.