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Overexpression of apelin in Wharton’ jelly mesenchymal stem cell reverses insulin resistance and promotes pancreatic β cell proliferation in type 2 diabetic rats

BACKGROUND: Apelin plays a key beneficial role in energy metabolism by increasing glucose uptake and insulin sensitivity; however, apelin has a short half-life because it is rapidly cleared from the circulation limiting its therapeutic benefit. The aim of this study is to create a new approach to tr...

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Autores principales: Gao, Lian Ru, Zhang, Ning Kun, Zhang, Yan, Chen, Yu, Wang, Li, Zhu, Ying, Tang, Hai Hong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286553/
https://www.ncbi.nlm.nih.gov/pubmed/30526660
http://dx.doi.org/10.1186/s13287-018-1084-x
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author Gao, Lian Ru
Zhang, Ning Kun
Zhang, Yan
Chen, Yu
Wang, Li
Zhu, Ying
Tang, Hai Hong
author_facet Gao, Lian Ru
Zhang, Ning Kun
Zhang, Yan
Chen, Yu
Wang, Li
Zhu, Ying
Tang, Hai Hong
author_sort Gao, Lian Ru
collection PubMed
description BACKGROUND: Apelin plays a key beneficial role in energy metabolism by increasing glucose uptake and insulin sensitivity; however, apelin has a short half-life because it is rapidly cleared from the circulation limiting its therapeutic benefit. The aim of this study is to create a new approach to treat type 2 diabetes by inducing prolonged expression of apelin in Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs). METHODS: A type 2 diabetic rat model was given a high-fat diet combined with low-dose streptozotocin (STZ) injection. The human WJ-MSCs were isolated and subsequently transduced with apelin-expressing lentiviral particles (WJMSCs-apelin), and expression was verified by flow cytometry, Western blot, ELISA, and RT-PCR analysis. Type 2 diabetic rats were infused with either WJMSCs-apelin (2 × 10(6) cells) or an equivalent dose of saline through the tail vein injection 7 days after STZ injection. The therapeutic effects of each infusion group were evaluated by monitoring plasma glucose levels and performing glucose tolerance tests (OGTTs), insulin tolerance tests (IPITTs), confocal microscopy, and immunocytochemical analysis for quantitating islet beta cells. Plasma inflammatory cytokines IL-6 and TNF-α and anti-inflammatory factors adiponectin were measured as well. RESULTS: Type 2 diabetic rats infused with WJ-MSCs-apelin significantly decreased levels of blood glucose (from 26.03 ± 2.83 to 15.85 ± 2.13 mmol/L on 7 days P < 0.001, and to 9.41 ± 2.05 on 14 days, P < 0.001). Infusion of WJMSCs-apelin not only improved significantly insulin sensitivity and glucose disposal, but also promoted endogenous pancreatic ß cell proliferation (9.6-fold increase compared to the control group). Furthermore, infusion of the WJMSCs-apelin consistently increased insulin and C-peptide levels in the plasma, and the above effects persisted up to 42 days. The inflammatory cytokines IL-6 and TNF-α were significantly decreased, whereas anti-inflammatory factor adiponectin was significantly increased after WJ-MSC-apelin infusion. CONCLUSION: In this study, we report a novel approach to treat type 2 diabetic rats that combines apelin gene therapy with WJ-MSC cell therapy, which could provide a promising therapeutic option for management of type 2 diabetes clinically.
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spelling pubmed-62865532018-12-14 Overexpression of apelin in Wharton’ jelly mesenchymal stem cell reverses insulin resistance and promotes pancreatic β cell proliferation in type 2 diabetic rats Gao, Lian Ru Zhang, Ning Kun Zhang, Yan Chen, Yu Wang, Li Zhu, Ying Tang, Hai Hong Stem Cell Res Ther Research BACKGROUND: Apelin plays a key beneficial role in energy metabolism by increasing glucose uptake and insulin sensitivity; however, apelin has a short half-life because it is rapidly cleared from the circulation limiting its therapeutic benefit. The aim of this study is to create a new approach to treat type 2 diabetes by inducing prolonged expression of apelin in Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs). METHODS: A type 2 diabetic rat model was given a high-fat diet combined with low-dose streptozotocin (STZ) injection. The human WJ-MSCs were isolated and subsequently transduced with apelin-expressing lentiviral particles (WJMSCs-apelin), and expression was verified by flow cytometry, Western blot, ELISA, and RT-PCR analysis. Type 2 diabetic rats were infused with either WJMSCs-apelin (2 × 10(6) cells) or an equivalent dose of saline through the tail vein injection 7 days after STZ injection. The therapeutic effects of each infusion group were evaluated by monitoring plasma glucose levels and performing glucose tolerance tests (OGTTs), insulin tolerance tests (IPITTs), confocal microscopy, and immunocytochemical analysis for quantitating islet beta cells. Plasma inflammatory cytokines IL-6 and TNF-α and anti-inflammatory factors adiponectin were measured as well. RESULTS: Type 2 diabetic rats infused with WJ-MSCs-apelin significantly decreased levels of blood glucose (from 26.03 ± 2.83 to 15.85 ± 2.13 mmol/L on 7 days P < 0.001, and to 9.41 ± 2.05 on 14 days, P < 0.001). Infusion of WJMSCs-apelin not only improved significantly insulin sensitivity and glucose disposal, but also promoted endogenous pancreatic ß cell proliferation (9.6-fold increase compared to the control group). Furthermore, infusion of the WJMSCs-apelin consistently increased insulin and C-peptide levels in the plasma, and the above effects persisted up to 42 days. The inflammatory cytokines IL-6 and TNF-α were significantly decreased, whereas anti-inflammatory factor adiponectin was significantly increased after WJ-MSC-apelin infusion. CONCLUSION: In this study, we report a novel approach to treat type 2 diabetic rats that combines apelin gene therapy with WJ-MSC cell therapy, which could provide a promising therapeutic option for management of type 2 diabetes clinically. BioMed Central 2018-12-07 /pmc/articles/PMC6286553/ /pubmed/30526660 http://dx.doi.org/10.1186/s13287-018-1084-x Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Gao, Lian Ru
Zhang, Ning Kun
Zhang, Yan
Chen, Yu
Wang, Li
Zhu, Ying
Tang, Hai Hong
Overexpression of apelin in Wharton’ jelly mesenchymal stem cell reverses insulin resistance and promotes pancreatic β cell proliferation in type 2 diabetic rats
title Overexpression of apelin in Wharton’ jelly mesenchymal stem cell reverses insulin resistance and promotes pancreatic β cell proliferation in type 2 diabetic rats
title_full Overexpression of apelin in Wharton’ jelly mesenchymal stem cell reverses insulin resistance and promotes pancreatic β cell proliferation in type 2 diabetic rats
title_fullStr Overexpression of apelin in Wharton’ jelly mesenchymal stem cell reverses insulin resistance and promotes pancreatic β cell proliferation in type 2 diabetic rats
title_full_unstemmed Overexpression of apelin in Wharton’ jelly mesenchymal stem cell reverses insulin resistance and promotes pancreatic β cell proliferation in type 2 diabetic rats
title_short Overexpression of apelin in Wharton’ jelly mesenchymal stem cell reverses insulin resistance and promotes pancreatic β cell proliferation in type 2 diabetic rats
title_sort overexpression of apelin in wharton’ jelly mesenchymal stem cell reverses insulin resistance and promotes pancreatic β cell proliferation in type 2 diabetic rats
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6286553/
https://www.ncbi.nlm.nih.gov/pubmed/30526660
http://dx.doi.org/10.1186/s13287-018-1084-x
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