Regulation of cell reprogramming by matrix stiffness

通过基质硬度调节细胞重编程

• 批准号: 10687264
• 负责人: Song Li
• 金额: $ 32.47万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687264
• 关键词: Actins; Biocompatible Materials; Biological; Biology; Biophysical Process; Biophysics; Cardiac Myocytes; Cell Nucleus; Cell Reprogramming; Cell physiology; Cells; Cues; Cytoskeleton; Data; Development; Disease model; Distant; Drug Screening; Epigenetic Process; Extracellular Matrix; F-Actin; Fibroblasts; Focal Adhesions; G Actin; Gene Expression; Gene Targeting; Genes; Genomics; Histone Acetylation; Mediating; Microfilaments; Modification; Neurons; Nuclear; Nuclear Translocation; Phenotype; Play; Process; Proliferating; Regenerative Medicine; Regulation; Repression; Role; Site; Somatic Cell; Surface; Testing; Tissue Engineering; Transgenes; Work; cell type; cellular engineering; cofilin; depolymerization; design; drug discovery; epigenomics; experience; histone acetyltransferase; induced pluripotent stem cell; live cell imaging; migration; multidisciplinary; novel; novel strategies; nucleocytoplasmic transport; transcription factor; transcriptomics

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.

项目总结

项目成果

Self-Powered Programming of Fibroblasts into Neurons via a Scalable Magnetoelastic Generator Array.

• DOI: 10.1002/adma.202206933
• 发表时间: 2023-02
• 期刊: ADVANCED MATERIALS
• 影响因子: 29.4
• 作者: Libanori, Alberto;Soto, Jennifer;Xu, Jing;Song, Yang;Zarubova, Jana;Tat, Trinny;Xiao, Xiao;Yue, Shou Zheng;Jonas, Steven J.;Li, Song;Chen, Jun
• 通讯作者: Chen, Jun