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Hypoxia-preconditioned mesenchymal stem cells attenuate bleomycin-induced pulmonary fibrosis

INTRODUCTION: Idiopathic pulmonary fibrosis is a progressive diffuse parenchymal lung disorder of unknown etiology. Mesenchymal stem cell (MSC)-based therapy is a novel approach with great therapeutic potential for the treatment of lung diseases. Despite demonstration of MSC grafting, the population...

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Autores principales: Lan, Ying-Wei, Choo, Kong-Bung, Chen, Chuan-Mu, Hung, Tsai-Hsien, Chen, Young-Bin, Hsieh, Chung-Hsing, Kuo, Han-Pin, Chong, Kowit-Yu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487587/
https://www.ncbi.nlm.nih.gov/pubmed/25986930
http://dx.doi.org/10.1186/s13287-015-0081-6
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author Lan, Ying-Wei
Choo, Kong-Bung
Chen, Chuan-Mu
Hung, Tsai-Hsien
Chen, Young-Bin
Hsieh, Chung-Hsing
Kuo, Han-Pin
Chong, Kowit-Yu
author_facet Lan, Ying-Wei
Choo, Kong-Bung
Chen, Chuan-Mu
Hung, Tsai-Hsien
Chen, Young-Bin
Hsieh, Chung-Hsing
Kuo, Han-Pin
Chong, Kowit-Yu
author_sort Lan, Ying-Wei
collection PubMed
description INTRODUCTION: Idiopathic pulmonary fibrosis is a progressive diffuse parenchymal lung disorder of unknown etiology. Mesenchymal stem cell (MSC)-based therapy is a novel approach with great therapeutic potential for the treatment of lung diseases. Despite demonstration of MSC grafting, the populations of engrafted MSCs have been shown to decrease dramatically 24 hours post-transplantation due to exposure to harsh microenvironments. Hypoxia is known to induce expression of cytoprotective genes and also secretion of anti-inflammatory, anti-apoptotic and anti-fibrotic factors. Hypoxic preconditioning is thought to enhance the therapeutic potency and duration of survival of engrafted MSCs. In this work, we aimed to prolong the duration of survival of engrafted MSCs and to enhance the effectiveness of idiopathic pulmonary fibrosis transplantation therapy by the use of hypoxia-preconditioned MSCs. METHODS: Hypoxic preconditioning was achieved in MSCs under an optimal hypoxic environment. The expression levels of cytoprotective factors and their biological effects on damaged alveolar epithelial cells or transforming growth factor-beta 1-treated fibroblast cells were studied in co-culture experiments in vitro. Furthermore, hypoxia-preconditioned MSCs (HP-MSCs) were intratracheally instilled into bleomycin-induced pulmonary fibrosis mice at day 3, and lung functions, cellular, molecular and pathological changes were assessed at 7 and 21 days after bleomycin administration. RESULTS: The expression of genes for pro-survival, anti-apoptotic, anti-oxidant and growth factors was upregulated in MSCs under hypoxic conditions. In transforming growth factor-beta 1-treated MRC-5 fibroblast cells, hypoxia-preconditioned MSCs attenuated extracellular matrix production through paracrine effects. The pulmonary respiratory functions significantly improved for up to 18 days of hypoxia-preconditioned MSC treatment. Expression of inflammatory factors and fibrotic factor were all downregulated in the lung tissues of the hypoxia-preconditioned MSC-treated mice. Histopathologic examination observed a significant amelioration of the lung fibrosis. Several LacZ-labeled MSCs were observed within the lungs in the hypoxia-preconditioned MSC treatment groups at day 21, but no signals were detected in the normoxic MSC group. Our data further demonstrated that upregulation of hepatocyte growth factor possibly played an important role in mediating the therapeutic effects of transplanted hypoxia-preconditioned MSCs. CONCLUSION: Transplantation of hypoxia-preconditioned MSCs exerted better therapeutic effects in bleomycin-induced pulmonary fibrotic mice and enhanced the survival rate of engrafted MSCs, partially due to the upregulation of hepatocyte growth factor.
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spelling pubmed-44875872015-07-02 Hypoxia-preconditioned mesenchymal stem cells attenuate bleomycin-induced pulmonary fibrosis Lan, Ying-Wei Choo, Kong-Bung Chen, Chuan-Mu Hung, Tsai-Hsien Chen, Young-Bin Hsieh, Chung-Hsing Kuo, Han-Pin Chong, Kowit-Yu Stem Cell Res Ther Research INTRODUCTION: Idiopathic pulmonary fibrosis is a progressive diffuse parenchymal lung disorder of unknown etiology. Mesenchymal stem cell (MSC)-based therapy is a novel approach with great therapeutic potential for the treatment of lung diseases. Despite demonstration of MSC grafting, the populations of engrafted MSCs have been shown to decrease dramatically 24 hours post-transplantation due to exposure to harsh microenvironments. Hypoxia is known to induce expression of cytoprotective genes and also secretion of anti-inflammatory, anti-apoptotic and anti-fibrotic factors. Hypoxic preconditioning is thought to enhance the therapeutic potency and duration of survival of engrafted MSCs. In this work, we aimed to prolong the duration of survival of engrafted MSCs and to enhance the effectiveness of idiopathic pulmonary fibrosis transplantation therapy by the use of hypoxia-preconditioned MSCs. METHODS: Hypoxic preconditioning was achieved in MSCs under an optimal hypoxic environment. The expression levels of cytoprotective factors and their biological effects on damaged alveolar epithelial cells or transforming growth factor-beta 1-treated fibroblast cells were studied in co-culture experiments in vitro. Furthermore, hypoxia-preconditioned MSCs (HP-MSCs) were intratracheally instilled into bleomycin-induced pulmonary fibrosis mice at day 3, and lung functions, cellular, molecular and pathological changes were assessed at 7 and 21 days after bleomycin administration. RESULTS: The expression of genes for pro-survival, anti-apoptotic, anti-oxidant and growth factors was upregulated in MSCs under hypoxic conditions. In transforming growth factor-beta 1-treated MRC-5 fibroblast cells, hypoxia-preconditioned MSCs attenuated extracellular matrix production through paracrine effects. The pulmonary respiratory functions significantly improved for up to 18 days of hypoxia-preconditioned MSC treatment. Expression of inflammatory factors and fibrotic factor were all downregulated in the lung tissues of the hypoxia-preconditioned MSC-treated mice. Histopathologic examination observed a significant amelioration of the lung fibrosis. Several LacZ-labeled MSCs were observed within the lungs in the hypoxia-preconditioned MSC treatment groups at day 21, but no signals were detected in the normoxic MSC group. Our data further demonstrated that upregulation of hepatocyte growth factor possibly played an important role in mediating the therapeutic effects of transplanted hypoxia-preconditioned MSCs. CONCLUSION: Transplantation of hypoxia-preconditioned MSCs exerted better therapeutic effects in bleomycin-induced pulmonary fibrotic mice and enhanced the survival rate of engrafted MSCs, partially due to the upregulation of hepatocyte growth factor. BioMed Central 2015-05-20 /pmc/articles/PMC4487587/ /pubmed/25986930 http://dx.doi.org/10.1186/s13287-015-0081-6 Text en © Lan et al. 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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
Lan, Ying-Wei
Choo, Kong-Bung
Chen, Chuan-Mu
Hung, Tsai-Hsien
Chen, Young-Bin
Hsieh, Chung-Hsing
Kuo, Han-Pin
Chong, Kowit-Yu
Hypoxia-preconditioned mesenchymal stem cells attenuate bleomycin-induced pulmonary fibrosis
title Hypoxia-preconditioned mesenchymal stem cells attenuate bleomycin-induced pulmonary fibrosis
title_full Hypoxia-preconditioned mesenchymal stem cells attenuate bleomycin-induced pulmonary fibrosis
title_fullStr Hypoxia-preconditioned mesenchymal stem cells attenuate bleomycin-induced pulmonary fibrosis
title_full_unstemmed Hypoxia-preconditioned mesenchymal stem cells attenuate bleomycin-induced pulmonary fibrosis
title_short Hypoxia-preconditioned mesenchymal stem cells attenuate bleomycin-induced pulmonary fibrosis
title_sort hypoxia-preconditioned mesenchymal stem cells attenuate bleomycin-induced pulmonary fibrosis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4487587/
https://www.ncbi.nlm.nih.gov/pubmed/25986930
http://dx.doi.org/10.1186/s13287-015-0081-6
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