Academic Journal
Excessive branched-chain amino acid accumulation restricts mesenchymal stem cell-based therapy efficacy in myocardial infarction
| العنوان: | Excessive branched-chain amino acid accumulation restricts mesenchymal stem cell-based therapy efficacy in myocardial infarction |
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| المؤلفون: | Fuyang Zhang, Guangyu Hu, Xiyao Chen, Ling Zhang, Lanyan Guo, Congye Li, Hang Zhao, Zhe Cui, Xiong Guo, Fangfang Sun, Dandan Song, Wenjun Yan, Yunlong Xia, Shan Wang, Miaomiao Fan, Ling Tao |
| المصدر: | Signal Transduction and Targeted Therapy, Vol 7, Iss 1, Pp 1-18 (2022) |
| بيانات النشر: | Nature Publishing Group, 2022. |
| سنة النشر: | 2022 |
| المجموعة: | LCC:Medicine LCC:Biology (General) |
| مصطلحات موضوعية: | Medicine, Biology (General), QH301-705.5 |
| الوصف: | Abstract Mesenchymal stem cells (MSCs) delivered into the post-ischemic heart milieu have a low survival and retention rate, thus restricting the cardioreparative efficacy of MSC-based therapy. Chronic ischemia results in metabolic reprogramming in the heart, but little is known about how these metabolic changes influence implanted MSCs. Here, we found that excessive branched-chain amino acid (BCAA) accumulation, a metabolic signature seen in the post-ischemic heart, was disadvantageous to the retention and cardioprotection of intramyocardially injected MSCs. Discovery-driven experiments revealed that BCAA at pathological levels sensitized MSCs to stress-induced cell death and premature senescence via accelerating the loss of histone 3 lysine 9 trimethylation (H3K9me3). A novel mTORC1/DUX4/KDM4E axis was identified as the cause of BCAA-induced H3K9me3 loss and adverse phenotype acquisition. Enhancing BCAA catabolic capability in MSCs via genetic/pharmacological approaches greatly improved their adaptation to the high BCAA milieu and strengthened their cardioprotective efficacy. We conclude that aberrant BCAA accumulation is detrimental to implanted MSCs via a previously unknown metabolite-signaling-epigenetic mechanism, emphasizing that the metabolic changes of the post-ischemic heart crucially influence the fate of implanted MSCs and their therapeutic benefits. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2059-3635 |
| Relation: | https://doaj.org/toc/2059-3635 |
| DOI: | 10.1038/s41392-022-00971-7 |
| URL الوصول: | https://doaj.org/article/cb67349c15aa454aaa1984cb877ee820 |
| رقم الانضمام: | edsdoj.b67349c15aa454aaa1984cb877ee820 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 20593635 |
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| DOI: | 10.1038/s41392-022-00971-7 |