Viscoelastic extracellular matrix enhances epigenetic remodeling and cellular plasticity

Yifan Wu, Yang Song, Jennifer Soto, Tyler Hoffman, Xiao Lin, Aaron Zhang, Siyu Chen, Ramzi N. Massad, Xiao Han, Dongping Qi, Kun-Wei Yeh, Zhiwei Fang, Joon Eoh, Luo Gu, Amy C. Rowat, Zhen Gu and Song Li ()
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Yifan Wu: University of California Los Angeles
Yang Song: University of California Los Angeles
Jennifer Soto: University of California Los Angeles
Tyler Hoffman: University of California Los Angeles
Xiao Lin: University of California Los Angeles
Aaron Zhang: University of California Los Angeles
Siyu Chen: University of California Los Angeles
Ramzi N. Massad: University of California Los Angeles
Xiao Han: University of California Los Angeles
Dongping Qi: University of California Los Angeles
Kun-Wei Yeh: University of California Los Angeles
Zhiwei Fang: Johns Hopkins University
Joon Eoh: Johns Hopkins University
Luo Gu: Johns Hopkins University
Amy C. Rowat: University of California Los Angeles
Zhen Gu: University of California Los Angeles
Song Li: University of California Los Angeles

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: Abstract Extracellular matrices of living tissues exhibit viscoelastic properties, yet how these properties regulate chromatin and the epigenome remains unclear. Here, we show that viscoelastic substrates induce changes in nuclear architecture and epigenome, with more pronounced effects on softer surfaces. Fibroblasts on viscoelastic substrates display larger nuclei, lower chromatin compaction, and differential expression of distinct sets of genes related to the cytoskeleton and nuclear function, compared to those on elastic surfaces. Slow-relaxing viscoelastic substrates reduce lamin A/C expression and enhance nuclear remodeling. These structural changes are accompanied by a global increase in euchromatin marks and local increase in chromatin accessibility at cis-regulatory elements associated with neuronal and pluripotent genes. Consequently, viscoelastic substrates improve the reprogramming efficiency from fibroblasts into neurons and induced pluripotent stem cells. Collectively, our findings unravel the roles of matrix viscoelasticity in epigenetic regulation and cell reprogramming, with implications for designing smart materials for cell fate engineering.

Date: 2025
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DOI: 10.1038/s41467-025-59190-7

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