# Regulation of cell reprogramming by matrix stiffness

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $324,716

## Abstract

Project Summary
 Cell reprogramming represents a major advancement in biology, and has wide applications in
regenerative medicine, disease modeling and drug screening. During cell reprogramming, cells experience
epigenetic changes that result in a cell phenotype switch. However, whether and how biophysical factors
regulate cell reprogramming through epigenetic modifications are not well understood. We have found that
biophysical factors, specifically extracellular matrix (ECM) stiffness, has profound effects on epigenetic
state and the conversion of fibroblasts into induced neuronal (iN) cells, with the highest efficiency at an
intermediate ECM stiffness, which is regulated by focal adhesions and the cytoskeleton. In addition, we
have discovered that actin assembly and transport into nucleus plays an important role in epigenetic
modulation. Based on our preliminary data, we hypothesize that (1) biophysical cues such as ECM
stiffness regulates FAs, actin assembly/disassembly, nuclear transport of actin, and thus, HAT activity to
modulate the epigenetic state and cell reprogramming process and (2) an intermediate level of stiffness is
optimal for epigenetic remodeling and cell reprogramming. To test our hypothesis, we propose three
Specific Aims: (1) Investigate how matrix stiffness regulates iN reprogramming through FAs and actin
cytoskeleton, (2) Elucidate how matrix stiffness modulates HAT and the epigenetic state to turn on neuronal
genes during iN reprogramming, and (3) Determine the role of actin nuclear transport in matrix stiffness-
modulation of HAT and epigenetic state during iN reprogramming. We have assembled a multidisciplinary
team with expertise on mechanobiology, cell engineering, high throughput genomic and epigenomic
analysis, and live cell imaging to work together and investigate the underlying biophysical and biological
mechanisms. Our proposed studies will be one of the first to elucidate how ECM stiffness regulates
transcriptomic and epigenetic changes for cell reprogramming, and how ECM stiffness modulates focal
adhesions and the cytoskeleton for cell reprogramming. Findings from this project will unravel new
mechanisms of cell fate determination, which will have wide applications in cell and tissue engineering,
disease modeling and drug discovery, and provide a rational basis for the optimization and development of
novel biomaterials for somatic cell reprogramming.

## Key facts

- **NIH application ID:** 10687264
- **Project number:** 5R01GM143485-03
- **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:** $324,716
- **Award type:** 5
- **Project period:** 2021-09-20 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10687264

## Citation

> US National Institutes of Health, RePORTER application 10687264, Regulation of cell reprogramming by matrix stiffness (5R01GM143485-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10687264. Licensed CC0.

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