Transient nuclear deformation primes epigenetic state and promotes cell reprogramming

Abstract

Cell reprogramming has wide applications in tissue regeneration, disease modeling and personalized medicine, but low reprogramming efficiency remains a challenge. In addition to biochemical cues, biophysical factors can modulate the epigenetic state and a variety of cell functions. However, how biophysical factors help overcome the epigenetic barrier for cell reprogramming are not well understood. Here we utilized microfluidic channels to induce a transient deformation of the cell nucleus, which caused the disassembly of nuclear lamina and a downregulation of DNA methylation and histone (H3K9) for 12-24 hours. These global decreases of heterochromatin marks at the early stage of cell reprogramming strikingly enhanced the conversion of fibroblasts into neurons and induced pluripotent stem cells. Consistently, inhibition of DNA methylation and H3K9 methylation partially mimicked the effects of mechanical squeezing on iN reprogramming efficiency. Knocking down lamin A had similar effects to squeezing on enhancing reprogramming efficiency. Based on these findings, we developed a scalable microfluidic system that enabled a continuous cell processing to effectively prime epigenetic state for cell reprogramming, demonstrating the potential of mechano-biotechnology for cell engineering.

Coordinated Biophysical Stimulation of MSCs via Electromagnetized Au‐Nanofiber Matrix Regulates Cytoskeletal‐to‐Nuclear Mechanoresponses and Lineage Specification

“…For instance, transient nuclear squeezing of fibroblasts through forced passing through microchannels or cyclic stretch-induced nuclear deformation of epidermis stem cells led to chromatin decondensation and enhanced gene accessibility. [28] Furthermore, one recent study highlighted the chromatin decondensation in MSCs with decreased nuclear size induced by subcellular microtopographical constriction. [29] On the other hand, experiments utilizing confined matrices with varying geometries -systems that affect cell spreading area and cytoskeletal processes, thus altering nuclear shape and size -reported that the reduction in nuclear size does not lead to chromatin decondensation.…”