| Autor: |
Hongtao Zhu, Xueqing Liu, Yuan Ding, Kezhe Tan, Wen Ni, Weili Ouyang, Jianfeng Tang, Xiaojun Ding, Jianfeng Zhao, Yingcai Hao, Zenghui Teng, Xiaoming Deng, Zhaoping Ding |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Stem Cell Research & Therapy, Vol 13, Iss 1, Pp 1-18 (2022) |
| Druh dokumentu: |
article |
| ISSN: |
1757-6512 |
| DOI: |
10.1186/s13287-021-02675-1 |
| Popis: |
Abstract Background Cellular dedifferentiation is a regenerative prerequisite that warrants cell cycle reentry and appropriate mitotic division during de novo formation of cardiomyocytes. In the light of our previous finding that expression of injury-responsive element, Wilms Tumor factor 1 (WT1), in pericardial adipose stromal cells (ADSC) conferred a compelling reparative activity with concomitant IL-6 upregulation, we then aim to unravel the mechanistic network that governs the process of regenerative dedifferentiation after ADSC-based therapy. Methods and results WT1-expressing ADSC (eGFP:WT1) were irreversibly labeled in transgenic mice (WT1-iCre/Gt(ROSA)26Sor-eGFP) primed with myocardial infarction. EGFP:WT1 cells were enzymatically isolated from the pericardial adipose tissue and cytometrically purified (ADSCgfp+). Bulk RNA-seq revealed upregulation of cardiac-related genes and trophic factors in ADSCgfp+ subset, of which IL-6 was most abundant as compared to non-WT1 ADSC (ADSCgfp−). Injection of ADSCgfp+ subset into the infarcted hearts yielded striking structural repair and functional improvement in comparison to ADSCgfp− subset. Notably, ADSCgfp+ injection triggered significant quantity of dedifferentiated cardiomyocytes recognized as round-sharp, marginalization of sarcomeric proteins, expression of molecular signature of non-myogenic genes (Vimentin, RunX1), and proliferative markers (Ki-67, Aurora B and pH3). In the cultured neonatal cardiomyocytes, spontaneous dedifferentiation was accelerated by adding tissue extracts from the ADSC-treated hearts, which was neutralized by IL-6 antibody. Genetical lack of IL-6 in ADSC dampened cardiac dedifferentiation and reparative activity. Conclusions Taken collectively, our results revealed a previous unappreciated effect of IL-6 on cardiac dedifferentiation and regeneration. The finding, therefore, fulfills the promise of stem cell therapy and may represent an innovative strategy in the treatment of ischemic heart disease. |
| Databáze: |
Directory of Open Access Journals |
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