Decreased Substrate Stiffness Promotes a Hypofibrotic Phenotype in Cardiac Fibroblasts
A hypofibrotic phenotype has been observed in cardiac fibroblasts (CFs) isolated from a volume overload heart failure model, aortocaval fistula (ACF). This paradoxical phenotype results in decreased ECM synthesis despite increased TGF-β presence. Since ACF results in decreased tissue stiffness relat...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-06-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/12/6231 |
| _version_ | 1797530832509861888 |
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| author | Rachel C. Childers Pamela A. Lucchesi Keith J. Gooch |
| author_facet | Rachel C. Childers Pamela A. Lucchesi Keith J. Gooch |
| author_sort | Rachel C. Childers |
| collection | DOAJ |
| description | A hypofibrotic phenotype has been observed in cardiac fibroblasts (CFs) isolated from a volume overload heart failure model, aortocaval fistula (ACF). This paradoxical phenotype results in decreased ECM synthesis despite increased TGF-β presence. Since ACF results in decreased tissue stiffness relative to control (sham) hearts, this study investigates whether the effects of substrate stiffness could account for the observed hypofibrotic phenotype in CFs isolated from ACF. CFs isolated from ACF and sham hearts were plated on polyacrylamide gels of a range of stiffness (2 kPa to 50 kPa). Markers related to cytoskeletal and fibrotic proteins were measured. Aspects of the hypofibrotic phenotype observed in ACF CFs were recapitulated by sham CFs on soft substrates. For instance, sham CFs on the softest gels compared to ACF CFs on the stiffest gels results in similar CTGF (0.80 vs. 0.76) and transgelin (0.44 vs. 0.57) mRNA expression. The changes due to stiffness may be explained by the observed decreased nuclear translocation of transcriptional regulators, MRTF-A and YAP. ACF CFs appear to have a mechanical memory of a softer environment, supported by a hypofibrotic phenotype overall compared to sham with less YAP detected in the nucleus, and less CTGF and transgelin on all stiffnesses. |
| first_indexed | 2024-03-10T10:34:36Z |
| format | Article |
| id | doaj.art-e0950bed259e45728f951b286479e2f8 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T10:34:36Z |
| publishDate | 2021-06-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-e0950bed259e45728f951b286479e2f82023-11-21T23:24:57ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-06-012212623110.3390/ijms22126231Decreased Substrate Stiffness Promotes a Hypofibrotic Phenotype in Cardiac FibroblastsRachel C. Childers0Pamela A. Lucchesi1Keith J. Gooch2Department of Biomedical Engineering, The Ohio State University, Columbus, OH 43210, USADepartment of Pharmacology, New York Medical College, Valhalla, NY 10595, USADepartment of Biomedical Engineering, The Ohio State University, Columbus, OH 43210, USAA hypofibrotic phenotype has been observed in cardiac fibroblasts (CFs) isolated from a volume overload heart failure model, aortocaval fistula (ACF). This paradoxical phenotype results in decreased ECM synthesis despite increased TGF-β presence. Since ACF results in decreased tissue stiffness relative to control (sham) hearts, this study investigates whether the effects of substrate stiffness could account for the observed hypofibrotic phenotype in CFs isolated from ACF. CFs isolated from ACF and sham hearts were plated on polyacrylamide gels of a range of stiffness (2 kPa to 50 kPa). Markers related to cytoskeletal and fibrotic proteins were measured. Aspects of the hypofibrotic phenotype observed in ACF CFs were recapitulated by sham CFs on soft substrates. For instance, sham CFs on the softest gels compared to ACF CFs on the stiffest gels results in similar CTGF (0.80 vs. 0.76) and transgelin (0.44 vs. 0.57) mRNA expression. The changes due to stiffness may be explained by the observed decreased nuclear translocation of transcriptional regulators, MRTF-A and YAP. ACF CFs appear to have a mechanical memory of a softer environment, supported by a hypofibrotic phenotype overall compared to sham with less YAP detected in the nucleus, and less CTGF and transgelin on all stiffnesses.https://www.mdpi.com/1422-0067/22/12/6231cardiac fibroblaststiffnessvolume overload |
| spellingShingle | Rachel C. Childers Pamela A. Lucchesi Keith J. Gooch Decreased Substrate Stiffness Promotes a Hypofibrotic Phenotype in Cardiac Fibroblasts International Journal of Molecular Sciences cardiac fibroblast stiffness volume overload |
| title | Decreased Substrate Stiffness Promotes a Hypofibrotic Phenotype in Cardiac Fibroblasts |
| title_full | Decreased Substrate Stiffness Promotes a Hypofibrotic Phenotype in Cardiac Fibroblasts |
| title_fullStr | Decreased Substrate Stiffness Promotes a Hypofibrotic Phenotype in Cardiac Fibroblasts |
| title_full_unstemmed | Decreased Substrate Stiffness Promotes a Hypofibrotic Phenotype in Cardiac Fibroblasts |
| title_short | Decreased Substrate Stiffness Promotes a Hypofibrotic Phenotype in Cardiac Fibroblasts |
| title_sort | decreased substrate stiffness promotes a hypofibrotic phenotype in cardiac fibroblasts |
| topic | cardiac fibroblast stiffness volume overload |
| url | https://www.mdpi.com/1422-0067/22/12/6231 |
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