Knockout of thyroid hormone receptor alpha a (thraa) enhances cardiac regeneration in zebrafish through metabolic and hypoxic regulation
Abstract Background Thyroid hormone (TH) signaling drives cardiomyocyte (CM) maturation in endothermic animals. Elevated TH levels, coupled with increased basal metabolism, promote CM cell cycle exit and polyploidization, thus limiting heart regenerative potential. However, a comprehensive understan...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-07-01
|
| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12964-025-02350-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849343383440457728 |
|---|---|
| author | Man Yee Cheung Chunmei Jiang Imtiaz Ul Hassan Hui Wang Donghao Guo Daniel Wuyang Dio Huan Yan Jianmin Sun Xufeng Qi Dongqing Cai Wei Ge Sheue-yann Cheng Wai-Yee Chan Hui Zhao |
| author_facet | Man Yee Cheung Chunmei Jiang Imtiaz Ul Hassan Hui Wang Donghao Guo Daniel Wuyang Dio Huan Yan Jianmin Sun Xufeng Qi Dongqing Cai Wei Ge Sheue-yann Cheng Wai-Yee Chan Hui Zhao |
| author_sort | Man Yee Cheung |
| collection | DOAJ |
| description | Abstract Background Thyroid hormone (TH) signaling drives cardiomyocyte (CM) maturation in endothermic animals. Elevated TH levels, coupled with increased basal metabolism, promote CM cell cycle exit and polyploidization, thus limiting heart regenerative potential. However, a comprehensive understanding of TH and its receptors, thyroid hormone receptors (TRs), orchestrating with other regulatory processes for heart regeneration, such as the hypoxia signaling pathway and post-injury metabolic switches, remains elusive. Results Here, we investigated the molecular mechanisms of TH signaling in heart regeneration using a time-course sequencing experiment. We assessed heart regeneration capacity in thyroid hormone receptor alpha a (thraa) mutant zebrafish, which carry an 8-bp insertion that leads to truncation of the Thraa protein and impaired TH signaling. The thraa + 8 bp mutant zebrafish exhibited an enhanced heart regenerative response. Our study showed that, in thraa +/– mutants, a transiently augmented inflammatory response and an extended CM proliferative window are associated with metabolic switches across different phases. Moreover, we found that thraa transcriptionally regulates hypoxia-inducible factor 3 subunit alpha (hif3a), and its knockout in zebrafish impairs heart regeneration. Conclusions In conclusion, our study highlights the role of TH signaling via thraa in modulating zebrafish heart regeneration through metabolic regulation, inflammation, cardiac tissue regeneration, and its interplay with hif3a. |
| format | Article |
| id | doaj-art-35cc647d2f9c4debb418d893421326b2 |
| institution | Kabale University |
| issn | 1478-811X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj-art-35cc647d2f9c4debb418d893421326b22025-08-20T03:43:01ZengBMCCell Communication and Signaling1478-811X2025-07-0123112110.1186/s12964-025-02350-5Knockout of thyroid hormone receptor alpha a (thraa) enhances cardiac regeneration in zebrafish through metabolic and hypoxic regulationMan Yee Cheung0Chunmei Jiang1Imtiaz Ul Hassan2Hui Wang3Donghao Guo4Daniel Wuyang Dio5Huan Yan6Jianmin Sun7Xufeng Qi8Dongqing Cai9Wei Ge10Sheue-yann Cheng11Wai-Yee Chan12Hui Zhao13Key Laboratory for Regenerative Medicine, School of Biomedical Sciences, Faculty of Medicine, Ministry of Education, The Chinese University of Hong KongKey Laboratory for Regenerative Medicine, School of Biomedical Sciences, Faculty of Medicine, Ministry of Education, The Chinese University of Hong KongKey Laboratory for Regenerative Medicine, School of Biomedical Sciences, Faculty of Medicine, Ministry of Education, The Chinese University of Hong KongTranslational and Functional Genomics Branch, National Human Genome Research InstituteDivision of Cardiology, Renji Hospital, School of Medicine, Shanghai Jiao Tong UniversityKey Laboratory for Regenerative Medicine, School of Biomedical Sciences, Faculty of Medicine, Ministry of Education, The Chinese University of Hong KongKey Laboratory for Regenerative Medicine, School of Biomedical Sciences, Faculty of Medicine, Ministry of Education, The Chinese University of Hong KongDepartment of Pathogen Biology and Immunology, School of Basic Medical Sciences, Ningxia Medical UniversityKey Laboratory of Regenerative Medicine of Ministry of Education, Department of Developmental & Regenerative Biology, Jinan UniversityKey Laboratory of Regenerative Medicine of Ministry of Education, Department of Developmental & Regenerative Biology, Jinan UniversityDepartment of Biomedical Sciences and Centre of Reproduction, Development and Aging (CRDA), Faculty of Health Sciences, University of MacauLaboratory of Molecular Biology, National Cancer Institute, National Institutes of HealthKey Laboratory for Regenerative Medicine, School of Biomedical Sciences, Faculty of Medicine, Ministry of Education, The Chinese University of Hong KongKey Laboratory for Regenerative Medicine, School of Biomedical Sciences, Faculty of Medicine, Ministry of Education, The Chinese University of Hong KongAbstract Background Thyroid hormone (TH) signaling drives cardiomyocyte (CM) maturation in endothermic animals. Elevated TH levels, coupled with increased basal metabolism, promote CM cell cycle exit and polyploidization, thus limiting heart regenerative potential. However, a comprehensive understanding of TH and its receptors, thyroid hormone receptors (TRs), orchestrating with other regulatory processes for heart regeneration, such as the hypoxia signaling pathway and post-injury metabolic switches, remains elusive. Results Here, we investigated the molecular mechanisms of TH signaling in heart regeneration using a time-course sequencing experiment. We assessed heart regeneration capacity in thyroid hormone receptor alpha a (thraa) mutant zebrafish, which carry an 8-bp insertion that leads to truncation of the Thraa protein and impaired TH signaling. The thraa + 8 bp mutant zebrafish exhibited an enhanced heart regenerative response. Our study showed that, in thraa +/– mutants, a transiently augmented inflammatory response and an extended CM proliferative window are associated with metabolic switches across different phases. Moreover, we found that thraa transcriptionally regulates hypoxia-inducible factor 3 subunit alpha (hif3a), and its knockout in zebrafish impairs heart regeneration. Conclusions In conclusion, our study highlights the role of TH signaling via thraa in modulating zebrafish heart regeneration through metabolic regulation, inflammation, cardiac tissue regeneration, and its interplay with hif3a.https://doi.org/10.1186/s12964-025-02350-5Thyroid hormoneMetabolismHypoxiaHeart regenerationInflammationCardiomyocytes |
| spellingShingle | Man Yee Cheung Chunmei Jiang Imtiaz Ul Hassan Hui Wang Donghao Guo Daniel Wuyang Dio Huan Yan Jianmin Sun Xufeng Qi Dongqing Cai Wei Ge Sheue-yann Cheng Wai-Yee Chan Hui Zhao Knockout of thyroid hormone receptor alpha a (thraa) enhances cardiac regeneration in zebrafish through metabolic and hypoxic regulation Cell Communication and Signaling Thyroid hormone Metabolism Hypoxia Heart regeneration Inflammation Cardiomyocytes |
| title | Knockout of thyroid hormone receptor alpha a (thraa) enhances cardiac regeneration in zebrafish through metabolic and hypoxic regulation |
| title_full | Knockout of thyroid hormone receptor alpha a (thraa) enhances cardiac regeneration in zebrafish through metabolic and hypoxic regulation |
| title_fullStr | Knockout of thyroid hormone receptor alpha a (thraa) enhances cardiac regeneration in zebrafish through metabolic and hypoxic regulation |
| title_full_unstemmed | Knockout of thyroid hormone receptor alpha a (thraa) enhances cardiac regeneration in zebrafish through metabolic and hypoxic regulation |
| title_short | Knockout of thyroid hormone receptor alpha a (thraa) enhances cardiac regeneration in zebrafish through metabolic and hypoxic regulation |
| title_sort | knockout of thyroid hormone receptor alpha a thraa enhances cardiac regeneration in zebrafish through metabolic and hypoxic regulation |
| topic | Thyroid hormone Metabolism Hypoxia Heart regeneration Inflammation Cardiomyocytes |
| url | https://doi.org/10.1186/s12964-025-02350-5 |
| work_keys_str_mv | AT manyeecheung knockoutofthyroidhormonereceptoralphaathraaenhancescardiacregenerationinzebrafishthroughmetabolicandhypoxicregulation AT chunmeijiang knockoutofthyroidhormonereceptoralphaathraaenhancescardiacregenerationinzebrafishthroughmetabolicandhypoxicregulation AT imtiazulhassan knockoutofthyroidhormonereceptoralphaathraaenhancescardiacregenerationinzebrafishthroughmetabolicandhypoxicregulation AT huiwang knockoutofthyroidhormonereceptoralphaathraaenhancescardiacregenerationinzebrafishthroughmetabolicandhypoxicregulation AT donghaoguo knockoutofthyroidhormonereceptoralphaathraaenhancescardiacregenerationinzebrafishthroughmetabolicandhypoxicregulation AT danielwuyangdio knockoutofthyroidhormonereceptoralphaathraaenhancescardiacregenerationinzebrafishthroughmetabolicandhypoxicregulation AT huanyan knockoutofthyroidhormonereceptoralphaathraaenhancescardiacregenerationinzebrafishthroughmetabolicandhypoxicregulation AT jianminsun knockoutofthyroidhormonereceptoralphaathraaenhancescardiacregenerationinzebrafishthroughmetabolicandhypoxicregulation AT xufengqi knockoutofthyroidhormonereceptoralphaathraaenhancescardiacregenerationinzebrafishthroughmetabolicandhypoxicregulation AT dongqingcai knockoutofthyroidhormonereceptoralphaathraaenhancescardiacregenerationinzebrafishthroughmetabolicandhypoxicregulation AT weige knockoutofthyroidhormonereceptoralphaathraaenhancescardiacregenerationinzebrafishthroughmetabolicandhypoxicregulation AT sheueyanncheng knockoutofthyroidhormonereceptoralphaathraaenhancescardiacregenerationinzebrafishthroughmetabolicandhypoxicregulation AT waiyeechan knockoutofthyroidhormonereceptoralphaathraaenhancescardiacregenerationinzebrafishthroughmetabolicandhypoxicregulation AT huizhao knockoutofthyroidhormonereceptoralphaathraaenhancescardiacregenerationinzebrafishthroughmetabolicandhypoxicregulation |