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MRTF-A controls myofibroblastic differentiation of human multipotent stromal cells and their tumour-supporting function in xenograft models
Tumour growth and metastatic colonization is strongly influenced by the tumour stroma, including cancer-associated fibroblasts (CAF). Multipotent mesenchymal stromal cells (MSC) are a possible source of CAF following myofibroblastic differentiation, and we have previously shown that MSC support tumo...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692381/ https://www.ncbi.nlm.nih.gov/pubmed/31409840 http://dx.doi.org/10.1038/s41598-019-48142-z |
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author | Werner, Sara Lützkendorf, Jana Müller, Thomas Müller, Lutz P. Posern, Guido |
author_facet | Werner, Sara Lützkendorf, Jana Müller, Thomas Müller, Lutz P. Posern, Guido |
author_sort | Werner, Sara |
collection | PubMed |
description | Tumour growth and metastatic colonization is strongly influenced by the tumour stroma, including cancer-associated fibroblasts (CAF). Multipotent mesenchymal stromal cells (MSC) are a possible source of CAF following myofibroblastic differentiation, and we have previously shown that MSC support tumour growth. Triggered by tumour cell-derived factors like transforming growth factor β1 (TGF-β1), myofibroblastic MSC differentiation is associated with the increased expression of markers including alpha smooth muscle actin (α-SMA). Here we show that myocardin-related transcription factor A (MRTF-A) plays an important role in myofibroblastic differentiation of primary human MSC in vitro and their tumour-supporting function in vivo. Recombinant TGF-β1 or tumour cell conditioned medium (TCM) elevated α-SMA, calponin 1 and collagen 1 A1 (COL1A1) amount on mRNA and protein level in MSC. This correlated with increased MRTF-A activity during MSC differentiation. MRTF-A knockdown by siRNA or shRNA impaired TGF-β1 and TCM induction of α-SMA and calponin 1, but not of COL1A1. Mixed xenograft experiments using HCT8 colorectal carcinoma cells and primary MSC of different donors revealed a significant reduction in tumour weight and volume upon MRTF-A knockdown in MSC. Our study suggests that MRTF-A is involved in the functional differentiation of MSC towards a tumour-promoting CAF phenotype in vivo. |
format | Online Article Text |
id | pubmed-6692381 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-66923812019-08-19 MRTF-A controls myofibroblastic differentiation of human multipotent stromal cells and their tumour-supporting function in xenograft models Werner, Sara Lützkendorf, Jana Müller, Thomas Müller, Lutz P. Posern, Guido Sci Rep Article Tumour growth and metastatic colonization is strongly influenced by the tumour stroma, including cancer-associated fibroblasts (CAF). Multipotent mesenchymal stromal cells (MSC) are a possible source of CAF following myofibroblastic differentiation, and we have previously shown that MSC support tumour growth. Triggered by tumour cell-derived factors like transforming growth factor β1 (TGF-β1), myofibroblastic MSC differentiation is associated with the increased expression of markers including alpha smooth muscle actin (α-SMA). Here we show that myocardin-related transcription factor A (MRTF-A) plays an important role in myofibroblastic differentiation of primary human MSC in vitro and their tumour-supporting function in vivo. Recombinant TGF-β1 or tumour cell conditioned medium (TCM) elevated α-SMA, calponin 1 and collagen 1 A1 (COL1A1) amount on mRNA and protein level in MSC. This correlated with increased MRTF-A activity during MSC differentiation. MRTF-A knockdown by siRNA or shRNA impaired TGF-β1 and TCM induction of α-SMA and calponin 1, but not of COL1A1. Mixed xenograft experiments using HCT8 colorectal carcinoma cells and primary MSC of different donors revealed a significant reduction in tumour weight and volume upon MRTF-A knockdown in MSC. Our study suggests that MRTF-A is involved in the functional differentiation of MSC towards a tumour-promoting CAF phenotype in vivo. Nature Publishing Group UK 2019-08-13 /pmc/articles/PMC6692381/ /pubmed/31409840 http://dx.doi.org/10.1038/s41598-019-48142-z Text en © The Author(s) 2019 Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Werner, Sara Lützkendorf, Jana Müller, Thomas Müller, Lutz P. Posern, Guido MRTF-A controls myofibroblastic differentiation of human multipotent stromal cells and their tumour-supporting function in xenograft models |
title | MRTF-A controls myofibroblastic differentiation of human multipotent stromal cells and their tumour-supporting function in xenograft models |
title_full | MRTF-A controls myofibroblastic differentiation of human multipotent stromal cells and their tumour-supporting function in xenograft models |
title_fullStr | MRTF-A controls myofibroblastic differentiation of human multipotent stromal cells and their tumour-supporting function in xenograft models |
title_full_unstemmed | MRTF-A controls myofibroblastic differentiation of human multipotent stromal cells and their tumour-supporting function in xenograft models |
title_short | MRTF-A controls myofibroblastic differentiation of human multipotent stromal cells and their tumour-supporting function in xenograft models |
title_sort | mrtf-a controls myofibroblastic differentiation of human multipotent stromal cells and their tumour-supporting function in xenograft models |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6692381/ https://www.ncbi.nlm.nih.gov/pubmed/31409840 http://dx.doi.org/10.1038/s41598-019-48142-z |
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