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Human umbilical cord-derived mesenchymal stem cells alleviate insulin resistance in diet-induced obese mice via an interaction with splenocytes
BACKGROUND: Previous research has demonstrated that the spleen plays an important role in mesenchymal stem cell (MSC)-mediated alleviation of acute inflammation, as MSC infusion increases the spleen-derived anti-inflammatory cytokine interleukin 10 (IL-10) levels. However, studies on splenic involve...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8935757/ https://www.ncbi.nlm.nih.gov/pubmed/35313972 http://dx.doi.org/10.1186/s13287-022-02791-6 |
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author | Xue, Jing Gao, Jieqing Gu, Yulin Wang, Aihong Yu, Songyan Li, Bing Yin, Yaqi Wang, Jie Su, Wanlu Zhang, Haixia Ren, Weizheng Gu, Weijun Lv, Zhaohui Mu, Yiming Cheng, Yu |
author_facet | Xue, Jing Gao, Jieqing Gu, Yulin Wang, Aihong Yu, Songyan Li, Bing Yin, Yaqi Wang, Jie Su, Wanlu Zhang, Haixia Ren, Weizheng Gu, Weijun Lv, Zhaohui Mu, Yiming Cheng, Yu |
author_sort | Xue, Jing |
collection | PubMed |
description | BACKGROUND: Previous research has demonstrated that the spleen plays an important role in mesenchymal stem cell (MSC)-mediated alleviation of acute inflammation, as MSC infusion increases the spleen-derived anti-inflammatory cytokine interleukin 10 (IL-10) levels. However, studies on splenic involvement in MSC-induced protection against chronic inflammatory diseases are limited. Obesity is characterized by chronic low-grade inflammation, a key driver of insulin resistance. This study aims to evaluate the effects of MSCs on obesity-related insulin resistance and explore the underlying mechanism, particularly regarding splenic involvement. METHODS: We induced obesity in mice by feeding them high-fat diets for 20 weeks. Human umbilical cord-derived MSCs (UC-MSCs) were systemically infused into the obese mice once per week for 6 weeks. Systemic glucose metabolic homeostasis and insulin sensitivity in epididymal adipose tissue (EAT) were evaluated. Then, we conducted in vivo blockade of IL-10 during UC-MSC infusion by intraperitoneally administrating an IL-10-neutralizing antibody twice per week. We also investigated the therapeutic effects of UC-MSCs on obese mice after removal of the spleen by splenectomy. RESULTS: UC-MSC infusions improved systemic metabolic homeostasis and alleviated insulin resistance in EAT but elicited no change in weight. Despite rare engraftment of UC-MSCs in EAT, UC-MSC infusions attenuated insulin resistance in EAT by polarizing macrophages into the M2 phenotype, coupled with elevated serum IL-10 levels. In vivo blockade of IL-10 blunted the effects of UC-MSCs on obese mice. Furthermore, UC-MSCs overwhelmingly homed to the spleen, and the ability of UC-MSCs to elevate serum IL-10 levels and alleviate insulin resistance was impaired in the absence of the spleen. Further in vivo and in vitro studies revealed that UC-MSCs promoted the capacity of regulatory T cells (Treg cells) to produce IL-10 in the spleen. CONCLUSIONS: Our results demonstrated that UC-MSCs elevated serum IL-10 levels and subsequently promoted macrophage polarization, leading to alleviation of insulin resistance in EAT. The underlying mechanism was that UC-MSCs improved the capacity of Treg cells to produce IL-10 in the spleen. Our findings indicated that the spleen played a critical role in amplifying MSC-mediated immunomodulatory effects, which may contribute to maximizing MSC efficacy in clinical applications in the future. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13287-022-02791-6. |
format | Online Article Text |
id | pubmed-8935757 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-89357572022-03-23 Human umbilical cord-derived mesenchymal stem cells alleviate insulin resistance in diet-induced obese mice via an interaction with splenocytes Xue, Jing Gao, Jieqing Gu, Yulin Wang, Aihong Yu, Songyan Li, Bing Yin, Yaqi Wang, Jie Su, Wanlu Zhang, Haixia Ren, Weizheng Gu, Weijun Lv, Zhaohui Mu, Yiming Cheng, Yu Stem Cell Res Ther Research BACKGROUND: Previous research has demonstrated that the spleen plays an important role in mesenchymal stem cell (MSC)-mediated alleviation of acute inflammation, as MSC infusion increases the spleen-derived anti-inflammatory cytokine interleukin 10 (IL-10) levels. However, studies on splenic involvement in MSC-induced protection against chronic inflammatory diseases are limited. Obesity is characterized by chronic low-grade inflammation, a key driver of insulin resistance. This study aims to evaluate the effects of MSCs on obesity-related insulin resistance and explore the underlying mechanism, particularly regarding splenic involvement. METHODS: We induced obesity in mice by feeding them high-fat diets for 20 weeks. Human umbilical cord-derived MSCs (UC-MSCs) were systemically infused into the obese mice once per week for 6 weeks. Systemic glucose metabolic homeostasis and insulin sensitivity in epididymal adipose tissue (EAT) were evaluated. Then, we conducted in vivo blockade of IL-10 during UC-MSC infusion by intraperitoneally administrating an IL-10-neutralizing antibody twice per week. We also investigated the therapeutic effects of UC-MSCs on obese mice after removal of the spleen by splenectomy. RESULTS: UC-MSC infusions improved systemic metabolic homeostasis and alleviated insulin resistance in EAT but elicited no change in weight. Despite rare engraftment of UC-MSCs in EAT, UC-MSC infusions attenuated insulin resistance in EAT by polarizing macrophages into the M2 phenotype, coupled with elevated serum IL-10 levels. In vivo blockade of IL-10 blunted the effects of UC-MSCs on obese mice. Furthermore, UC-MSCs overwhelmingly homed to the spleen, and the ability of UC-MSCs to elevate serum IL-10 levels and alleviate insulin resistance was impaired in the absence of the spleen. Further in vivo and in vitro studies revealed that UC-MSCs promoted the capacity of regulatory T cells (Treg cells) to produce IL-10 in the spleen. CONCLUSIONS: Our results demonstrated that UC-MSCs elevated serum IL-10 levels and subsequently promoted macrophage polarization, leading to alleviation of insulin resistance in EAT. The underlying mechanism was that UC-MSCs improved the capacity of Treg cells to produce IL-10 in the spleen. Our findings indicated that the spleen played a critical role in amplifying MSC-mediated immunomodulatory effects, which may contribute to maximizing MSC efficacy in clinical applications in the future. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13287-022-02791-6. BioMed Central 2022-03-21 /pmc/articles/PMC8935757/ /pubmed/35313972 http://dx.doi.org/10.1186/s13287-022-02791-6 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 Xue, Jing Gao, Jieqing Gu, Yulin Wang, Aihong Yu, Songyan Li, Bing Yin, Yaqi Wang, Jie Su, Wanlu Zhang, Haixia Ren, Weizheng Gu, Weijun Lv, Zhaohui Mu, Yiming Cheng, Yu Human umbilical cord-derived mesenchymal stem cells alleviate insulin resistance in diet-induced obese mice via an interaction with splenocytes |
title | Human umbilical cord-derived mesenchymal stem cells alleviate insulin resistance in diet-induced obese mice via an interaction with splenocytes |
title_full | Human umbilical cord-derived mesenchymal stem cells alleviate insulin resistance in diet-induced obese mice via an interaction with splenocytes |
title_fullStr | Human umbilical cord-derived mesenchymal stem cells alleviate insulin resistance in diet-induced obese mice via an interaction with splenocytes |
title_full_unstemmed | Human umbilical cord-derived mesenchymal stem cells alleviate insulin resistance in diet-induced obese mice via an interaction with splenocytes |
title_short | Human umbilical cord-derived mesenchymal stem cells alleviate insulin resistance in diet-induced obese mice via an interaction with splenocytes |
title_sort | human umbilical cord-derived mesenchymal stem cells alleviate insulin resistance in diet-induced obese mice via an interaction with splenocytes |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8935757/ https://www.ncbi.nlm.nih.gov/pubmed/35313972 http://dx.doi.org/10.1186/s13287-022-02791-6 |
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