N-Cadherin promotes cardiac regeneration by potentiating pro-mitotic β-Catenin signaling in cardiomyocytes
Abstract Adult human hearts exhibit limited regenerative capacity. Post-injury cardiomyocyte (CM) loss can lead to myocardial dysfunction and failure. Although neonatal mammalian hearts can regenerate, the underlying molecular mechanisms remain elusive. Herein, comparative transcriptome analyses ide...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56216-y |
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| author | Yi-Wei Tsai Yi-Shuan Tseng Yu-Shuo Wu Wei-Lun Song Min-Yi You Yun-Chia Hsu Wen-Pin Chen Wei-Han Huang Jia-Ci Chng Chai-Ling Lim Ke-Hsuan Wei Shih-Lei Ben Lai Wen-Chih Lee Kai-Chien Yang |
| author_facet | Yi-Wei Tsai Yi-Shuan Tseng Yu-Shuo Wu Wei-Lun Song Min-Yi You Yun-Chia Hsu Wen-Pin Chen Wei-Han Huang Jia-Ci Chng Chai-Ling Lim Ke-Hsuan Wei Shih-Lei Ben Lai Wen-Chih Lee Kai-Chien Yang |
| author_sort | Yi-Wei Tsai |
| collection | DOAJ |
| description | Abstract Adult human hearts exhibit limited regenerative capacity. Post-injury cardiomyocyte (CM) loss can lead to myocardial dysfunction and failure. Although neonatal mammalian hearts can regenerate, the underlying molecular mechanisms remain elusive. Herein, comparative transcriptome analyses identify adherens junction protein N-Cadherin as a crucial regulator of CM proliferation/renewal. Its expression correlates positively with mitotic genes and shows an age-dependent reduction. N-Cadherin is upregulated in the neonatal mouse heart following injury, coinciding with increased CM mitotic activities. N-Cadherin knockdown reduces, whereas overexpression increases, the proliferation activity of neonatal mouse CMs and human induced pluripotent stem cell-derived CMs. Mechanistically, N-Cadherin binds and stabilizes pro-mitotic transcription regulator β-Catenin, driving CM self-renewal. Targeted N-Cadherin deletion in CMs impedes cardiac regeneration in neonatal mice, leading to excessive scarring. N-Cadherin overexpression, by contrast, promotes regeneration in adult mouse hearts following ischemic injury. N-Cadherin targeting presents a promising avenue for promoting cardiac regeneration and restoring function in injured adult human hearts. |
| format | Article |
| id | doaj-art-750ed86c979742dba0a7cf1d4b0447f6 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-750ed86c979742dba0a7cf1d4b0447f62025-01-26T12:40:56ZengNature PortfolioNature Communications2041-17232025-01-0116111910.1038/s41467-025-56216-yN-Cadherin promotes cardiac regeneration by potentiating pro-mitotic β-Catenin signaling in cardiomyocytesYi-Wei Tsai0Yi-Shuan Tseng1Yu-Shuo Wu2Wei-Lun Song3Min-Yi You4Yun-Chia Hsu5Wen-Pin Chen6Wei-Han Huang7Jia-Ci Chng8Chai-Ling Lim9Ke-Hsuan Wei10Shih-Lei Ben Lai11Wen-Chih Lee12Kai-Chien Yang13Department and Graduate Institute of Pharmacology, National Taiwan University College of MedicineDepartment and Graduate Institute of Pharmacology, National Taiwan University College of MedicineDepartment and Graduate Institute of Pharmacology, National Taiwan University College of MedicineDepartment and Graduate Institute of Pharmacology, National Taiwan University College of MedicineDepartment and Graduate Institute of Pharmacology, National Taiwan University College of MedicineDepartment and Graduate Institute of Pharmacology, National Taiwan University College of MedicineDepartment and Graduate Institute of Pharmacology, National Taiwan University College of MedicineDepartment and Graduate Institute of Pharmacology, National Taiwan University College of MedicineInstitute of Biomedical Sciences, Academia SinicaInstitute of Biomedical Sciences, Academia SinicaTaiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung UniversityInstitute of Biomedical Sciences, Academia SinicaDepartment and Graduate Institute of Pharmacology, National Taiwan University College of MedicineDepartment and Graduate Institute of Pharmacology, National Taiwan University College of MedicineAbstract Adult human hearts exhibit limited regenerative capacity. Post-injury cardiomyocyte (CM) loss can lead to myocardial dysfunction and failure. Although neonatal mammalian hearts can regenerate, the underlying molecular mechanisms remain elusive. Herein, comparative transcriptome analyses identify adherens junction protein N-Cadherin as a crucial regulator of CM proliferation/renewal. Its expression correlates positively with mitotic genes and shows an age-dependent reduction. N-Cadherin is upregulated in the neonatal mouse heart following injury, coinciding with increased CM mitotic activities. N-Cadherin knockdown reduces, whereas overexpression increases, the proliferation activity of neonatal mouse CMs and human induced pluripotent stem cell-derived CMs. Mechanistically, N-Cadherin binds and stabilizes pro-mitotic transcription regulator β-Catenin, driving CM self-renewal. Targeted N-Cadherin deletion in CMs impedes cardiac regeneration in neonatal mice, leading to excessive scarring. N-Cadherin overexpression, by contrast, promotes regeneration in adult mouse hearts following ischemic injury. N-Cadherin targeting presents a promising avenue for promoting cardiac regeneration and restoring function in injured adult human hearts.https://doi.org/10.1038/s41467-025-56216-y |
| spellingShingle | Yi-Wei Tsai Yi-Shuan Tseng Yu-Shuo Wu Wei-Lun Song Min-Yi You Yun-Chia Hsu Wen-Pin Chen Wei-Han Huang Jia-Ci Chng Chai-Ling Lim Ke-Hsuan Wei Shih-Lei Ben Lai Wen-Chih Lee Kai-Chien Yang N-Cadherin promotes cardiac regeneration by potentiating pro-mitotic β-Catenin signaling in cardiomyocytes Nature Communications |
| title | N-Cadherin promotes cardiac regeneration by potentiating pro-mitotic β-Catenin signaling in cardiomyocytes |
| title_full | N-Cadherin promotes cardiac regeneration by potentiating pro-mitotic β-Catenin signaling in cardiomyocytes |
| title_fullStr | N-Cadherin promotes cardiac regeneration by potentiating pro-mitotic β-Catenin signaling in cardiomyocytes |
| title_full_unstemmed | N-Cadherin promotes cardiac regeneration by potentiating pro-mitotic β-Catenin signaling in cardiomyocytes |
| title_short | N-Cadherin promotes cardiac regeneration by potentiating pro-mitotic β-Catenin signaling in cardiomyocytes |
| title_sort | n cadherin promotes cardiac regeneration by potentiating pro mitotic β catenin signaling in cardiomyocytes |
| url | https://doi.org/10.1038/s41467-025-56216-y |
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