Stem Cell Research & Therapy (Jan 2022)

IL-6 coaxes cellular dedifferentiation as a pro-regenerative intermediate that contributes to pericardial ADSC-induced cardiac repair

  • 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

DOI
https://doi.org/10.1186/s13287-021-02675-1
Journal volume & issue
Vol. 13, no. 1
pp. 1 – 18

Abstract

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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.

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