Shift of EMT gradient in 3D spheroid MSCs for activation of mesenchymal niche function

Abstract Despite the wide use of mesenchymal stromal cells (MSCs) for paracrine support in clinical trials, their variable and heterogeneous supporting activity pose major challenges. While three-dimensional (3D) MSC cultures are emerging as alternative approaches, key changes in cellular characteri...

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Autores principales:	Sohee Jeon, Ho-Sun Lee, Ga-Young Lee, Gyeongsin Park, Tae-Min Kim, Jihye Shin, Cheolju Lee, Il-Hoan Oh
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/05c7820835e242239d012f3c5b2ec563
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spelling	oai:doaj.org-article:05c7820835e242239d012f3c5b2ec5632021-12-02T16:06:23ZShift of EMT gradient in 3D spheroid MSCs for activation of mesenchymal niche function10.1038/s41598-017-07049-32045-2322https://doaj.org/article/05c7820835e242239d012f3c5b2ec5632017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-07049-3https://doaj.org/toc/2045-2322Abstract Despite the wide use of mesenchymal stromal cells (MSCs) for paracrine support in clinical trials, their variable and heterogeneous supporting activity pose major challenges. While three-dimensional (3D) MSC cultures are emerging as alternative approaches, key changes in cellular characteristics during 3D-spheroid formation remain unclear. Here, we show that MSCs in 3D spheroids undergo further progression towards the epithelial-mesenchymal transition (EMT), driven by upregulation of EMT-promoting microRNAs and suppression of EMT-inhibitory miRNAs. The shift of EMT in MSCs is associated with widespread histone modifications mimicking the epigenetic reprogramming towards enhanced chromatin dynamics and stem cell-like properties, but without changes in their surface phenotype. Notably, these molecular shifts towards EMT in 3D MSCs caused enhanced stem cell niche activity, resulting in higher stimulation of hematopoietic progenitor self-renewal and cancer stem cell metastasis. Moreover, miRNA-mediated induction of EMT in 2D MSCs were sufficient to mimic the enhanced niche activity of 3D spheroid MSCs. Thus, the molecular hierarchy in the EMT gradient among phenotypically indistinguishable MSCs revealed the previously unrecognized functional parameters in MSCs, and the EMT-enhanced “naïve” mesenchymal state represents an ‘activated mesenchymal niche’ in 3D spheroid MSCs.Sohee JeonHo-Sun LeeGa-Young LeeGyeongsin ParkTae-Min KimJihye ShinCheolju LeeIl-Hoan OhNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Sohee Jeon Ho-Sun Lee Ga-Young Lee Gyeongsin Park Tae-Min Kim Jihye Shin Cheolju Lee Il-Hoan Oh Shift of EMT gradient in 3D spheroid MSCs for activation of mesenchymal niche function
description	Abstract Despite the wide use of mesenchymal stromal cells (MSCs) for paracrine support in clinical trials, their variable and heterogeneous supporting activity pose major challenges. While three-dimensional (3D) MSC cultures are emerging as alternative approaches, key changes in cellular characteristics during 3D-spheroid formation remain unclear. Here, we show that MSCs in 3D spheroids undergo further progression towards the epithelial-mesenchymal transition (EMT), driven by upregulation of EMT-promoting microRNAs and suppression of EMT-inhibitory miRNAs. The shift of EMT in MSCs is associated with widespread histone modifications mimicking the epigenetic reprogramming towards enhanced chromatin dynamics and stem cell-like properties, but without changes in their surface phenotype. Notably, these molecular shifts towards EMT in 3D MSCs caused enhanced stem cell niche activity, resulting in higher stimulation of hematopoietic progenitor self-renewal and cancer stem cell metastasis. Moreover, miRNA-mediated induction of EMT in 2D MSCs were sufficient to mimic the enhanced niche activity of 3D spheroid MSCs. Thus, the molecular hierarchy in the EMT gradient among phenotypically indistinguishable MSCs revealed the previously unrecognized functional parameters in MSCs, and the EMT-enhanced “naïve” mesenchymal state represents an ‘activated mesenchymal niche’ in 3D spheroid MSCs.
format	article
author	Sohee Jeon Ho-Sun Lee Ga-Young Lee Gyeongsin Park Tae-Min Kim Jihye Shin Cheolju Lee Il-Hoan Oh
author_facet	Sohee Jeon Ho-Sun Lee Ga-Young Lee Gyeongsin Park Tae-Min Kim Jihye Shin Cheolju Lee Il-Hoan Oh
author_sort	Sohee Jeon
title	Shift of EMT gradient in 3D spheroid MSCs for activation of mesenchymal niche function
title_short	Shift of EMT gradient in 3D spheroid MSCs for activation of mesenchymal niche function
title_full	Shift of EMT gradient in 3D spheroid MSCs for activation of mesenchymal niche function
title_fullStr	Shift of EMT gradient in 3D spheroid MSCs for activation of mesenchymal niche function
title_full_unstemmed	Shift of EMT gradient in 3D spheroid MSCs for activation of mesenchymal niche function
title_sort	shift of emt gradient in 3d spheroid mscs for activation of mesenchymal niche function
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/05c7820835e242239d012f3c5b2ec563
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Shift of EMT gradient in 3D spheroid MSCs for activation of mesenchymal niche function

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