UCLA

Cell reprogramming has great potential in biomedical applications, including disease modeling, drug screening, tissue regeneration and personalized medicine. A major limitation of cell reprogramming is the low conversion efficiency due to epigenetic barriers. Extensive research has focused on how to enhance reprogramming; in addition to biochemical cues, mechanical stimulation can also modulate epigenetic state and various cell functions through distinct mechanisms that are not fully understood. Here I developed novel microfluidics devices to induce the deformation of cell nucleus in a high throughput manner, by forcing cells moving through microchannels with well-defined sizes, and studied the direct effect of nuclear deformation on cell reprogramming. This milli-second nuclear deformation promotes the reprogramming of mouse fibroblasts into neuronal cells, which are attributed to the transient decrease of histone H3 lysine 9 trimethylation and DNA methylation after squeezing. This epigenetic change and the enhancement of reprogramming are dependent on the geometric features of microchannels cross-sections. To optimize the microfluidic device design to achieve the highest reprogramming efficiency, I constructed a second-order quadratic model and parabolic response surface. By integrating the experiment results and theoretical prediction, I generated a design guideline for the cross-section geometry of microfluidic channels that can be generalized for various cell types, which was validated by reprogramming mouse macrophages into neuronal cells. This innovative mechanobiology approach using microfluidic device for epigenetic modulation and reprogramming enhancement, together with the parabolic response surface-based optimization process, open a new avenue for cell engineering.