Identification of hepatic fibrosis inhibitors through morphometry analysis of a hepatic multicellular spheroids model

Abstract A chronic, local inflammatory milieu can cause tissue fibrosis that results in epithelial-to-mesenchymal transition (EMT), endothelial-to-mesenchymal transition (EndMT), increased abundance of fibroblasts, and further acceleration of fibrosis. In this study, we aimed to identify potential m...

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Autores principales:	Yeonhwa Song, Sanghwa Kim, Jinyeong Heo, David Shum, Su-Yeon Lee, Minji Lee, A-Ram Kim, Haeng Ran Seo
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/60f1bcc2f01e4486943eb23c58717e36
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spelling	oai:doaj.org-article:60f1bcc2f01e4486943eb23c58717e362021-12-02T15:00:25ZIdentification of hepatic fibrosis inhibitors through morphometry analysis of a hepatic multicellular spheroids model10.1038/s41598-021-90263-x2045-2322https://doaj.org/article/60f1bcc2f01e4486943eb23c58717e362021-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-90263-xhttps://doaj.org/toc/2045-2322Abstract A chronic, local inflammatory milieu can cause tissue fibrosis that results in epithelial-to-mesenchymal transition (EMT), endothelial-to-mesenchymal transition (EndMT), increased abundance of fibroblasts, and further acceleration of fibrosis. In this study, we aimed to identify potential mechanisms and inhibitors of fibrosis using 3D model-based phenotypic screening. We established liver fibrosis models using multicellular tumor spheroids (MCTSs) composed of hepatocellular carcinoma (HCC) and stromal cells such as fibroblasts (WI38), hepatic stellate cells (LX2), and endothelial cells (HUVEC) seeded at constant ratios. Through high-throughput screening of FDA-approved drugs, we identified retinoic acid and forskolin as candidates to attenuate the compactness of MCTSs as well as inhibit the expression of ECM-related proteins. Additionally, retinoic acid and forskolin induced reprogramming of fibroblast and cancer stem cells in the HCC microenvironment. Of interest, retinoic acid and forskolin had anti-fibrosis effects by decreasing expression of α-SMA and F-actin in LX2 cells and HUVEC cells. Moreover, when sorafenib was added along with retinoic acid and forskolin, apoptosis was increased, suggesting that anti-fibrosis drugs may improve tissue penetration to support the efficacy of anti-cancer drugs. Collectively, these findings support the potential utility of morphometric analyses of hepatic multicellular spheroid models in the development of new drugs with novel mechanisms for the treatment of hepatic fibrosis and HCCs.Yeonhwa SongSanghwa KimJinyeong HeoDavid ShumSu-Yeon LeeMinji LeeA-Ram KimHaeng Ran SeoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Yeonhwa Song Sanghwa Kim Jinyeong Heo David Shum Su-Yeon Lee Minji Lee A-Ram Kim Haeng Ran Seo Identification of hepatic fibrosis inhibitors through morphometry analysis of a hepatic multicellular spheroids model
description	Abstract A chronic, local inflammatory milieu can cause tissue fibrosis that results in epithelial-to-mesenchymal transition (EMT), endothelial-to-mesenchymal transition (EndMT), increased abundance of fibroblasts, and further acceleration of fibrosis. In this study, we aimed to identify potential mechanisms and inhibitors of fibrosis using 3D model-based phenotypic screening. We established liver fibrosis models using multicellular tumor spheroids (MCTSs) composed of hepatocellular carcinoma (HCC) and stromal cells such as fibroblasts (WI38), hepatic stellate cells (LX2), and endothelial cells (HUVEC) seeded at constant ratios. Through high-throughput screening of FDA-approved drugs, we identified retinoic acid and forskolin as candidates to attenuate the compactness of MCTSs as well as inhibit the expression of ECM-related proteins. Additionally, retinoic acid and forskolin induced reprogramming of fibroblast and cancer stem cells in the HCC microenvironment. Of interest, retinoic acid and forskolin had anti-fibrosis effects by decreasing expression of α-SMA and F-actin in LX2 cells and HUVEC cells. Moreover, when sorafenib was added along with retinoic acid and forskolin, apoptosis was increased, suggesting that anti-fibrosis drugs may improve tissue penetration to support the efficacy of anti-cancer drugs. Collectively, these findings support the potential utility of morphometric analyses of hepatic multicellular spheroid models in the development of new drugs with novel mechanisms for the treatment of hepatic fibrosis and HCCs.
format	article
author	Yeonhwa Song Sanghwa Kim Jinyeong Heo David Shum Su-Yeon Lee Minji Lee A-Ram Kim Haeng Ran Seo
author_facet	Yeonhwa Song Sanghwa Kim Jinyeong Heo David Shum Su-Yeon Lee Minji Lee A-Ram Kim Haeng Ran Seo
author_sort	Yeonhwa Song
title	Identification of hepatic fibrosis inhibitors through morphometry analysis of a hepatic multicellular spheroids model
title_short	Identification of hepatic fibrosis inhibitors through morphometry analysis of a hepatic multicellular spheroids model
title_full	Identification of hepatic fibrosis inhibitors through morphometry analysis of a hepatic multicellular spheroids model
title_fullStr	Identification of hepatic fibrosis inhibitors through morphometry analysis of a hepatic multicellular spheroids model
title_full_unstemmed	Identification of hepatic fibrosis inhibitors through morphometry analysis of a hepatic multicellular spheroids model
title_sort	identification of hepatic fibrosis inhibitors through morphometry analysis of a hepatic multicellular spheroids model
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/60f1bcc2f01e4486943eb23c58717e36
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Identification of hepatic fibrosis inhibitors through morphometry analysis of a hepatic multicellular spheroids model

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