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Pathological matrix stiffness promotes cardiac fibroblast differentiation through the POU2F1 signaling pathway
- Source :
- Science China Life Sciences. 64:242-254
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 2020.
-
Abstract
- Cardiac fibroblast (CF) differentiation into myofibroblasts is a crucial cause of cardiac fibrosis, which increases in the extracellular matrix (ECM) stiffness. The increased stiffness further promotes CF differentiation and fibrosis. However, the molecular mechanism is still unclear. We used bioinformatics analysis to find new candidates that regulate the genes involved in stiffness-induced CF differentiation, and found that there were binding sites for the POU-domain transcription factor, POU2F1 (also known as Oct-1), in the promoters of 50 differentially expressed genes (DEGs) in CFs on the stiffer substrate. Immunofluorescent staining and Western blotting revealed that pathological stiffness upregulated POU2F1 expression and increased CF differentiation on polyacrylamide hydrogel substrates and in mouse myocardial infarction tissue. A chromatin immunoprecipitation assay showed that POU2F1 bound to the promoters of fibrosis repressors IL1R2, CD69, and TGIF2. The expression of these fibrosis repressors was inhibited on pathological substrate stiffness. Knockdown of POU2F1 upregulated these repressors and attenuated CF differentiation on pathological substrate stiffness (35 kPa). Whereas, overexpression of POU2F1 downregulated these repressors and enhanced CF differentiation. In conclusion, pathological stiffness upregulates the transcription factor POU2F1 to promote CF differentiation by inhibiting fibrosis repressors. Our work elucidated the crosstalk between CF differentiation and the ECM and provided a potential target for cardiac fibrosis treatment.
- Subjects :
- Male
0301 basic medicine
Cardiac fibrosis
General Biochemistry, Genetics and Molecular Biology
Extracellular matrix
03 medical and health sciences
0302 clinical medicine
Fibrosis
medicine
Animals
Receptors, Interleukin-1 Type II
Myofibroblasts
Promoter Regions, Genetic
Transcription factor
Cells, Cultured
General Environmental Science
Gene knockdown
Binding Sites
Chemistry
Gene Expression Profiling
Myocardium
Cell Differentiation
Fibroblasts
medicine.disease
Extracellular Matrix
Cell biology
Mice, Inbred C57BL
030104 developmental biology
Gene Expression Regulation
030220 oncology & carcinogenesis
Signal transduction
General Agricultural and Biological Sciences
Chromatin immunoprecipitation
Myofibroblast
Octamer Transcription Factor-1
Protein Binding
Signal Transduction
Subjects
Details
- ISSN :
- 18691889 and 16747305
- Volume :
- 64
- Database :
- OpenAIRE
- Journal :
- Science China Life Sciences
- Accession number :
- edsair.doi.dedup.....8f42c716a0c78c6614c86c252d7ed03e