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Mesenchymal Stem Cells Modulate Albumin-Induced Renal Tubular Inflammation and Fibrosis
Bone marrow-derived mesenchymal stem cells (BM-MSCs) have recently shown promise as a therapeutic tool in various types of chronic kidney disease (CKD) models. However, the mechanism of action is incompletely understood. As renal prognosis in CKD is largely determined by the degree of renal tubular...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3960109/ https://www.ncbi.nlm.nih.gov/pubmed/24646687 http://dx.doi.org/10.1371/journal.pone.0090883 |
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author | Wu, Hao Jia Yiu, Wai Han Li, Rui Xi Wong, Dickson W. L. Leung, Joseph C. K. Chan, Loretta Y. Y. Zhang, Yuelin Lian, Qizhou Lin, Miao Tse, Hung Fat Lai, Kar Neng Tang, Sydney C. W. |
author_facet | Wu, Hao Jia Yiu, Wai Han Li, Rui Xi Wong, Dickson W. L. Leung, Joseph C. K. Chan, Loretta Y. Y. Zhang, Yuelin Lian, Qizhou Lin, Miao Tse, Hung Fat Lai, Kar Neng Tang, Sydney C. W. |
author_sort | Wu, Hao Jia |
collection | PubMed |
description | Bone marrow-derived mesenchymal stem cells (BM-MSCs) have recently shown promise as a therapeutic tool in various types of chronic kidney disease (CKD) models. However, the mechanism of action is incompletely understood. As renal prognosis in CKD is largely determined by the degree of renal tubular injury that correlates with residual proteinuria, we hypothesized that BM-MSCs may exert modulatory effects on renal tubular inflammation and epithelial-to-mesenchymal transition (EMT) under a protein-overloaded milieu. Using a co-culture model of human proximal tubular epithelial cells (PTECs) and BM-MSCs, we showed that concomitant stimulation of BM-MSCs by albumin excess was a prerequisite for them to attenuate albumin-induced IL-6, IL-8, TNF-α, CCL-2, CCL-5 overexpression in PTECs, which was partly mediated via deactivation of tubular NF-κB signaling. In addition, albumin induced tubular EMT, as shown by E-cadherin loss and α-SMA, FN and collagen IV overexpression, was also prevented by BM-MSC co-culture. Albumin-overloaded BM-MSCs per se retained their tri-lineage differentiation capacity and overexpressed hepatocyte growth factor (HGF) and TNFα-stimulating gene (TSG)-6 via P38 and NF-κB signaling. Albumin-induced tubular CCL-2, CCL-5 and TNF-α overexpression were suppressed by recombinant HGF treatment, while the upregulation of α-SMA, FN and collagen IV was attenuated by recombinant TSG-6. Neutralizing HGF and TSG-6 abolished the anti-inflammatory and anti-EMT effects of BM-MSC co-culture in albumin-induced PTECs, respectively. In vivo, albumin-overloaded mice treated with mouse BM-MSCs had markedly reduced BUN, tubular CCL-2 and CCL-5 expression, α-SMA and collagen IV accumulation independent of changes in proteinuria. These data suggest anti-inflammatory and anti-fibrotic roles of BM-MSCs on renal tubular cells under a protein overloaded condition, probably mediated via the paracrine action of HGF and TSG-6. |
format | Online Article Text |
id | pubmed-3960109 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-39601092014-03-24 Mesenchymal Stem Cells Modulate Albumin-Induced Renal Tubular Inflammation and Fibrosis Wu, Hao Jia Yiu, Wai Han Li, Rui Xi Wong, Dickson W. L. Leung, Joseph C. K. Chan, Loretta Y. Y. Zhang, Yuelin Lian, Qizhou Lin, Miao Tse, Hung Fat Lai, Kar Neng Tang, Sydney C. W. PLoS One Research Article Bone marrow-derived mesenchymal stem cells (BM-MSCs) have recently shown promise as a therapeutic tool in various types of chronic kidney disease (CKD) models. However, the mechanism of action is incompletely understood. As renal prognosis in CKD is largely determined by the degree of renal tubular injury that correlates with residual proteinuria, we hypothesized that BM-MSCs may exert modulatory effects on renal tubular inflammation and epithelial-to-mesenchymal transition (EMT) under a protein-overloaded milieu. Using a co-culture model of human proximal tubular epithelial cells (PTECs) and BM-MSCs, we showed that concomitant stimulation of BM-MSCs by albumin excess was a prerequisite for them to attenuate albumin-induced IL-6, IL-8, TNF-α, CCL-2, CCL-5 overexpression in PTECs, which was partly mediated via deactivation of tubular NF-κB signaling. In addition, albumin induced tubular EMT, as shown by E-cadherin loss and α-SMA, FN and collagen IV overexpression, was also prevented by BM-MSC co-culture. Albumin-overloaded BM-MSCs per se retained their tri-lineage differentiation capacity and overexpressed hepatocyte growth factor (HGF) and TNFα-stimulating gene (TSG)-6 via P38 and NF-κB signaling. Albumin-induced tubular CCL-2, CCL-5 and TNF-α overexpression were suppressed by recombinant HGF treatment, while the upregulation of α-SMA, FN and collagen IV was attenuated by recombinant TSG-6. Neutralizing HGF and TSG-6 abolished the anti-inflammatory and anti-EMT effects of BM-MSC co-culture in albumin-induced PTECs, respectively. In vivo, albumin-overloaded mice treated with mouse BM-MSCs had markedly reduced BUN, tubular CCL-2 and CCL-5 expression, α-SMA and collagen IV accumulation independent of changes in proteinuria. These data suggest anti-inflammatory and anti-fibrotic roles of BM-MSCs on renal tubular cells under a protein overloaded condition, probably mediated via the paracrine action of HGF and TSG-6. Public Library of Science 2014-03-19 /pmc/articles/PMC3960109/ /pubmed/24646687 http://dx.doi.org/10.1371/journal.pone.0090883 Text en © 2014 Wu et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Wu, Hao Jia Yiu, Wai Han Li, Rui Xi Wong, Dickson W. L. Leung, Joseph C. K. Chan, Loretta Y. Y. Zhang, Yuelin Lian, Qizhou Lin, Miao Tse, Hung Fat Lai, Kar Neng Tang, Sydney C. W. Mesenchymal Stem Cells Modulate Albumin-Induced Renal Tubular Inflammation and Fibrosis |
title | Mesenchymal Stem Cells Modulate Albumin-Induced Renal Tubular Inflammation and Fibrosis |
title_full | Mesenchymal Stem Cells Modulate Albumin-Induced Renal Tubular Inflammation and Fibrosis |
title_fullStr | Mesenchymal Stem Cells Modulate Albumin-Induced Renal Tubular Inflammation and Fibrosis |
title_full_unstemmed | Mesenchymal Stem Cells Modulate Albumin-Induced Renal Tubular Inflammation and Fibrosis |
title_short | Mesenchymal Stem Cells Modulate Albumin-Induced Renal Tubular Inflammation and Fibrosis |
title_sort | mesenchymal stem cells modulate albumin-induced renal tubular inflammation and fibrosis |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3960109/ https://www.ncbi.nlm.nih.gov/pubmed/24646687 http://dx.doi.org/10.1371/journal.pone.0090883 |
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