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Gain of CXCR7 function with mesenchymal stem cell therapy ameliorates experimental arthritis via enhancing tissue regeneration and immunomodulation

BACKGROUND: The major barriers to mesenchymal stem cell (MSC) therapy in rheumatoid arthritis (RA) are a low extent of tissue regeneration and insufficient immunomodulation after cell transplantation. In addition, the role of C-X-C chemokine receptor type 7 (CXCR7) and its mechanism of action in MSC...

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Autores principales: Wei, Sung-Tai, Huang, Yen-Chih, Chiang, Jung-Ying, Lin, Chia-Ching, Lin, Yu-Jung, Shyu, Woei-Cherng, Chen, Hui-Chen, Hsieh, Chia-Hung
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164772/
https://www.ncbi.nlm.nih.gov/pubmed/34051857
http://dx.doi.org/10.1186/s13287-021-02402-w
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author Wei, Sung-Tai
Huang, Yen-Chih
Chiang, Jung-Ying
Lin, Chia-Ching
Lin, Yu-Jung
Shyu, Woei-Cherng
Chen, Hui-Chen
Hsieh, Chia-Hung
author_facet Wei, Sung-Tai
Huang, Yen-Chih
Chiang, Jung-Ying
Lin, Chia-Ching
Lin, Yu-Jung
Shyu, Woei-Cherng
Chen, Hui-Chen
Hsieh, Chia-Hung
author_sort Wei, Sung-Tai
collection PubMed
description BACKGROUND: The major barriers to mesenchymal stem cell (MSC) therapy in rheumatoid arthritis (RA) are a low extent of tissue regeneration and insufficient immunomodulation after cell transplantation. In addition, the role of C-X-C chemokine receptor type 7 (CXCR7) and its mechanism of action in MSC-mediated osteogenic or chondrogenic differentiation and immunomodulation are unclear. METHODS: Gain of CXCR7 function on human MSCs was carried out by lentiviral vector-mediated CXCR7 overexpression or CXCR7 agonist, TC14012. These cells were determined the role and potential mechanisms for CXCR7-regulated MSC differentiation and immunomodulation using cellular and molecular assays. The therapeutic benefits in RA were investigated in rats with collagen-induced arthritis (CIA). RESULTS: CXCR7 was upregulated in MSCs during the induction of osteogenic or chondrogenic differentiation. Blockage of CXCR7 function inhibited osteogenic or chondrogenic differentiation of MSCs whereas gain of CXCR7 function had the opposite effects. Besides, MSCs with CXCR7 gain-of-function facilitated macrophage apoptosis and regulatory T cell differentiation in a co-culture system. Gain of CXCR7 function also promoted the production of anti-inflammatory soluble factors. A gene expression profiling assay and signaling reporter assays revealed that CXCR7 could regulate several candidate genes related to the PPAR, WNT, Hedgehog or Notch pathways, and their signaling activities, which are known to control cell differentiation and immunomodulation. Finally, MSCs with CXCR7 gain-of-function significantly reduced the articular index scores, ankle circumference, radiographic scores, histologic scores, and inflammation in rats with CIA compared with control MSCs. CONCLUSIONS: CXCR7 promotes the osteogenic and chondrogenic differentiation of MSCs and MSC-mediated immunomodulation by regulating several signaling pathways and anti-inflammatory soluble factors. MSCs with CXCR7 gain-of-function significantly ameliorate arthritic symptoms in a CIA model. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13287-021-02402-w.
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spelling pubmed-81647722021-06-01 Gain of CXCR7 function with mesenchymal stem cell therapy ameliorates experimental arthritis via enhancing tissue regeneration and immunomodulation Wei, Sung-Tai Huang, Yen-Chih Chiang, Jung-Ying Lin, Chia-Ching Lin, Yu-Jung Shyu, Woei-Cherng Chen, Hui-Chen Hsieh, Chia-Hung Stem Cell Res Ther Research BACKGROUND: The major barriers to mesenchymal stem cell (MSC) therapy in rheumatoid arthritis (RA) are a low extent of tissue regeneration and insufficient immunomodulation after cell transplantation. In addition, the role of C-X-C chemokine receptor type 7 (CXCR7) and its mechanism of action in MSC-mediated osteogenic or chondrogenic differentiation and immunomodulation are unclear. METHODS: Gain of CXCR7 function on human MSCs was carried out by lentiviral vector-mediated CXCR7 overexpression or CXCR7 agonist, TC14012. These cells were determined the role and potential mechanisms for CXCR7-regulated MSC differentiation and immunomodulation using cellular and molecular assays. The therapeutic benefits in RA were investigated in rats with collagen-induced arthritis (CIA). RESULTS: CXCR7 was upregulated in MSCs during the induction of osteogenic or chondrogenic differentiation. Blockage of CXCR7 function inhibited osteogenic or chondrogenic differentiation of MSCs whereas gain of CXCR7 function had the opposite effects. Besides, MSCs with CXCR7 gain-of-function facilitated macrophage apoptosis and regulatory T cell differentiation in a co-culture system. Gain of CXCR7 function also promoted the production of anti-inflammatory soluble factors. A gene expression profiling assay and signaling reporter assays revealed that CXCR7 could regulate several candidate genes related to the PPAR, WNT, Hedgehog or Notch pathways, and their signaling activities, which are known to control cell differentiation and immunomodulation. Finally, MSCs with CXCR7 gain-of-function significantly reduced the articular index scores, ankle circumference, radiographic scores, histologic scores, and inflammation in rats with CIA compared with control MSCs. CONCLUSIONS: CXCR7 promotes the osteogenic and chondrogenic differentiation of MSCs and MSC-mediated immunomodulation by regulating several signaling pathways and anti-inflammatory soluble factors. MSCs with CXCR7 gain-of-function significantly ameliorate arthritic symptoms in a CIA model. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13287-021-02402-w. BioMed Central 2021-05-29 /pmc/articles/PMC8164772/ /pubmed/34051857 http://dx.doi.org/10.1186/s13287-021-02402-w Text en © The Author(s) 2021 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
Wei, Sung-Tai
Huang, Yen-Chih
Chiang, Jung-Ying
Lin, Chia-Ching
Lin, Yu-Jung
Shyu, Woei-Cherng
Chen, Hui-Chen
Hsieh, Chia-Hung
Gain of CXCR7 function with mesenchymal stem cell therapy ameliorates experimental arthritis via enhancing tissue regeneration and immunomodulation
title Gain of CXCR7 function with mesenchymal stem cell therapy ameliorates experimental arthritis via enhancing tissue regeneration and immunomodulation
title_full Gain of CXCR7 function with mesenchymal stem cell therapy ameliorates experimental arthritis via enhancing tissue regeneration and immunomodulation
title_fullStr Gain of CXCR7 function with mesenchymal stem cell therapy ameliorates experimental arthritis via enhancing tissue regeneration and immunomodulation
title_full_unstemmed Gain of CXCR7 function with mesenchymal stem cell therapy ameliorates experimental arthritis via enhancing tissue regeneration and immunomodulation
title_short Gain of CXCR7 function with mesenchymal stem cell therapy ameliorates experimental arthritis via enhancing tissue regeneration and immunomodulation
title_sort gain of cxcr7 function with mesenchymal stem cell therapy ameliorates experimental arthritis via enhancing tissue regeneration and immunomodulation
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8164772/
https://www.ncbi.nlm.nih.gov/pubmed/34051857
http://dx.doi.org/10.1186/s13287-021-02402-w
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