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

Zhu, Hongtao, Liu, Xueqing, Ding, Yuan, Tan, Kezhe, Ni, Wen, Ouyang, Weili, Tang, Jianfeng, Ding, Xiaojun, Zhao, Jianfeng, Hao, Yingcai, Teng, Zenghui, Deng, Xiaoming, Ding, Zhaoping·2022·Stem Cell Research & Therapy
DOI 10.1186/s13287-021-02675-1PMC PMC8802508
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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 (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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  • Vitamin C, IL-6, TGFβ and bone morphogenetic proteins regulate cellular reprogramming by affecting DNA methylation levels, thereby adjusting the expression of certain microRNAs or facilitating the mesenchymal-to-epithelial transition (MET).

    “In addition to cell intrinsic transcription factors for cellular reprogramming, modulators such as vitamin C [62][63][64][65] , IL-6 [66][67][68] , TGFβ 69 and bone morphogenetic proteins 70 have been shown to regulate cellular reprogramming by affecting DNA methylation levels, thereby adjusting the expression of certain microRNAs or facilitating the mesenchymal-to-epithelial transition (MET).”

    From Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming (2023) · cites this paper as [67]

    The Discussion section (‘Cellular dedifferentiation as a pre-regenerative intermediate’; page not provided) reports that IL-6/STAT3 signaling induces cardiomyocyte dedifferentiation, supporting the IL-6 reprogramming component. It does not link that effect to DNA methylation, altered microRNA expression, or mesenchymal-to-epithelial transition; instead, the Background describes JAK/STAT and other signaling pathways. (LLM, conf=0.87)

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Metadata

Authors
Zhu, H., Liu, X., Ding, Y., Tan, K., Ni, W., Ouyang, W., Tang, J., Ding, X., Zhao, J., Hao, Y., Teng, Z., Deng, X., & Ding, Z.
Venue
Stem Cell Research & Therapy
Publisher
Springer Science and Business Media LLC
Published
2022-01-31
Volume
13
Issue
1
ISSN
1757-6512
DOI
10.1186/s13287-021-02675-1
PMC
PMC8802508
Cited by
19
References
3
Language
en
Licence
Funders
  • National Natural Science Foundation of China (81570244)
  • Jiangsu Provincial Commission of Health and Family Planning (M2020077)
  • Science and Technology Planning Social Development Project of Zhenjiang City (SH2018407)
  • Personal Promotion Foundation of Danyang City (----)
  • Universitätsklinikum Düsseldorf. Anstalt öffentlichen Rechts

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