# Mechanopriming for cell engineering

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $508,355

## Abstract

Project Summary
 Cell reprogramming represents a major advancement in biology, and has wide applications in
regenerative medicine, disease modeling and drug screening. Somatic cells such as fibroblasts can be
directly converted into induced neuronal (iN) cells via the forced expression of three transcription factors:
Ascl1, Brn2 and Myt1l (BAM). However, a major challenge of cell reprogramming, especially iN
reprogramming, is the low reprogramming efficiency, which has limited the translation of this technology
for biomedical applications. Biophysical factors from the microenvironment have been shown to regulate
many aspects of cell functions such as cell growth, migration and differentiation. Recently, we have shown
that mechanical deformation of cell nucleus through microfluidic channels can promote open chromatin
structure and enhance cell reprogramming, yet the underlying mechanisms are not well understood. Based
on our recent findings, we hypothesize that a mechanopriming process such as mechanical squeezing of
cell nucleus can induce NL reorganization and a permissive chromatin state to facilitate the activation of
neuronal genes in the heterochromatin of fibroblasts, which promotes iN reprogramming and CRISPR-
mediated gene editing/activation. To test our hypothesis, we propose three Specific Aims: (1) To
investigate how nuclear deformation modulates the epigenetic state to enhance iN reprogramming; (2) To
determine the role of nuclear lamina in mediating nuclear deformation-induced LAD dissociation,
epigenetic changes and iN reprogramming; (3) To investigate the enhancement of CRISPR-mediated
neuronal gene activation by mechanical squeezing. We have assembled a multidisciplinary team with
expertise on cell engineering, microdevice fabrication, high-throughput genomic and epigenomic analysis,
neuroscience, biosensors and CRISPR gene editing to work together and investigate the mechanical
regulation of epigenetic state and cell reprogramming. We propose to optimize a high-throughput
microfluidic device, further investigate the causative mechanisms and profile the genome-wide site-specific
epigenetic changes induced by nuclear deformation, which can provide a rational basis for the design of
site-specific gene editing for cell engineering. Accomplishment of this project will advance our
understanding of how biophysical factors regulate cell reprogramming and the epigenetic state, and
unravel new mechanisms of cell fate determination, which will have wide applications in gene editing, cell
and tissue engineering, disease modeling and drug discovery.

## Key facts

- **NIH application ID:** 10737574
- **Project number:** 1R01NS130677-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Song Li
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $508,355
- **Award type:** 1
- **Project period:** 2023-06-15 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10737574

## Citation

> US National Institutes of Health, RePORTER application 10737574, Mechanopriming for cell engineering (1R01NS130677-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10737574. Licensed CC0.

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