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:10.1186/s13287-021-02675-1

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

Stem Cell Res Ther. 2022 Jan 31;13(1):44. doi: 10.1186/s13287-021-02675-1.

Authors

Hongtao Zhu^#¹, Xueqing Liu^#¹, Yuan Ding^#², Kezhe Tan³, Wen Ni³, Weili Ouyang¹, Jianfeng Tang¹, Xiaojun Ding¹, Jianfeng Zhao¹, Yingcai Hao¹, Zenghui Teng⁴, Xiaoming Deng⁵, Zhaoping Ding⁶

Affiliations

¹ Department of Cardiology, The People's Hospital of Danyang, Affiliated Danyang Hospital of Nantong University, West Xinmin Rd. 2, Danyang, 212300, China.
² Department of Clinical Laboratory, Danyang Hospital for Chinese Traditional Medicine, Danyang, 212300, China.
³ Department of Anesthesiology and Critical Care, Changhai Hospital, Navy Medical University, Changhai Road 168, Shanghai, 200433, China.
⁴ Institute of Neuro and Sensory Physiology, Heinrich-Heine University of Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany.
⁵ Department of Anesthesiology and Critical Care, Changhai Hospital, Navy Medical University, Changhai Road 168, Shanghai, 200433, China. dengphd@163.com.
⁶ Institute of Molecular Cardiology, Heinrich-Heine University of Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany. ding@uni-duesseldorf.de.

^# Contributed equally.

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 (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.

Keywords: Cardiac regeneration; Dedifferentiation; Interleukin-6 (IL-6); Pericardial adipose stromal cells; STAT3; WT1.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adipose Tissue*
Animals
Interleukin-6* / genetics
Interleukin-6* / metabolism
Mice
Myocytes, Cardiac / metabolism
Pericardium / metabolism
Stromal Cells

Substances

Interleukin-6