期刊
NATURE BIOMEDICAL ENGINEERING
卷 5, 期 12, 页码 1485-1499出版社
NATURE PORTFOLIO
DOI: 10.1038/s41551-021-00709-w
关键词
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资金
- National Institutes of Health [R01 HL132353, R21 AR067469, T32 HL007822-20, K99 HL148542, RHL117138-05, R01 GM29090)., RO1 GM125871, F31HL142223]
- National Science Foundation [IGERT 1144807]
- Department of Education GAANN Biomaterials Fellowship
- Human Frontiers Science Program fellowship [LT001449/2017-L]
- American Heart Association postdoctoral fellowship [20POST3521111]
- Burroughs Welcome Fund Postdoctoral Enrichment Program
- NIST-CU Cooperative Agreement [70NANB15H226]
- BioFrontiers Institute
- Howard Hughes Medical Institute
- BioFrontiers' IT [NIH 1S10OD012300]
Increased extracellular stiffness activates fibroblasts, leading to the transformation of transiently activated fibroblasts into myofibroblasts with condensed chromatin. The condensed chromatin structure of myofibroblasts is associated with cytoskeletal stability, and nuclear mechanosensing plays a key role in driving distinct chromatin signatures in persistently activated fibroblasts.
Cumulative tension on the nuclear membrane of aortic fibroblasts resulting from increases in the stiffness of the extracellular matrix transforms transiently activated fibroblasts into fibrosis-driving myofibroblasts with condensed chromatin. Fibrotic disease is caused by the continuous deposition of extracellular matrix by persistently activated fibroblasts (also known as myofibroblasts), even after the resolution of the injury. Using fibroblasts from porcine aortic valves cultured on hydrogels that can be softened via exposure to ultraviolet light, here we show that increased extracellular stiffness activates the fibroblasts, and that cumulative tension on the nuclear membrane and increases in the activity of histone deacetylases transform transiently activated fibroblasts into myofibroblasts displaying condensed chromatin with genome-wide alterations. The condensed structure of the myofibroblasts is associated with cytoskeletal stability, as indicated by the inhibition of chromatin condensation and myofibroblast persistence after detachment of the nucleus from the cytoskeleton via the displacement of endogenous nesprins from the nuclear envelope. We also show that the chromatin structure of myofibroblasts from patients with aortic valve stenosis is more condensed than that of myofibroblasts from healthy donors. Our findings suggest that nuclear mechanosensing drives distinct chromatin signatures in persistently activated fibroblasts.
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