Journal
STEM CELL RESEARCH & THERAPY
Volume 13, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s13287-021-02675-1
Keywords
Pericardial adipose stromal cells; Interleukin-6 (IL-6); Dedifferentiation; WT1; STAT3; Cardiac regeneration
Funding
- Projekt DEAL
- National Natural Science Foundation of China [81570244]
- Jiangsu Commission of Health [M2020077, LR2021056]
- Social Development Foundation, S&T Department of Zhenjiang City [SH2018047]
- Personnel Promotion Foundation of Danyang City
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This study reveals the role of IL-6 in cardiac dedifferentiation and regeneration, providing an innovative strategy for stem cell therapy in ischemic heart disease.
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 (ADSC(gfp+)). Bulk RNA-seq revealed upregulation of cardiac-related genes and trophic factors in ADSC(gfp+) subset, of which IL-6 was most abundant as compared to non-WT1 ADSC (ADSC(gfp-)). Injection of ADSC(gfp+) subset into the infarcted hearts yielded striking structural repair and functional improvement in comparison to ADSC(gfp-) subset. Notably, ADSC(gfp+) 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.
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