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

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 perica...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8802508/
https://www.ncbi.nlm.nih.gov/pubmed/35101092
http://dx.doi.org/10.1186/s13287-021-02675-1
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author 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
author_facet 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
author_sort Zhu, Hongtao
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13287-021-02675-1.
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spelling pubmed-88025082022-02-02 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 Stem Cell Res Ther Research 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13287-021-02675-1. BioMed Central 2022-01-31 /pmc/articles/PMC8802508/ /pubmed/35101092 http://dx.doi.org/10.1186/s13287-021-02675-1 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
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
IL-6 coaxes cellular dedifferentiation as a pro-regenerative intermediate that contributes to pericardial ADSC-induced cardiac repair
title IL-6 coaxes cellular dedifferentiation as a pro-regenerative intermediate that contributes to pericardial ADSC-induced cardiac repair
title_full IL-6 coaxes cellular dedifferentiation as a pro-regenerative intermediate that contributes to pericardial ADSC-induced cardiac repair
title_fullStr IL-6 coaxes cellular dedifferentiation as a pro-regenerative intermediate that contributes to pericardial ADSC-induced cardiac repair
title_full_unstemmed IL-6 coaxes cellular dedifferentiation as a pro-regenerative intermediate that contributes to pericardial ADSC-induced cardiac repair
title_short IL-6 coaxes cellular dedifferentiation as a pro-regenerative intermediate that contributes to pericardial ADSC-induced cardiac repair
title_sort il-6 coaxes cellular dedifferentiation as a pro-regenerative intermediate that contributes to pericardial adsc-induced cardiac repair
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8802508/
https://www.ncbi.nlm.nih.gov/pubmed/35101092
http://dx.doi.org/10.1186/s13287-021-02675-1
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