Adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model

Abstract Cancer-associated fibroblasts (CAFs) are the key components of the densely proliferated stroma in pancreatic ductal adenocarcinoma (PDAC) and contribute to tumor progression and drug resistance. CAFs comprise heterogeneous subpopulations playing unique and vital roles. However, the commonly...

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Autores principales:	Yoshihiro Miyazaki, Tatsuya Oda, Yuki Inagaki, Hiroko Kushige, Yutaka Saito, Nobuhito Mori, Yuzo Takayama, Yutaro Kumagai, Toutai Mitsuyama, Yasuyuki S. Kida
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4dd4de5030214100981257e70a7cbe46
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spelling	oai:doaj.org-article:4dd4de5030214100981257e70a7cbe462021-12-02T13:20:12ZAdipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model10.1038/s41598-021-84058-32045-2322https://doaj.org/article/4dd4de5030214100981257e70a7cbe462021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84058-3https://doaj.org/toc/2045-2322Abstract Cancer-associated fibroblasts (CAFs) are the key components of the densely proliferated stroma in pancreatic ductal adenocarcinoma (PDAC) and contribute to tumor progression and drug resistance. CAFs comprise heterogeneous subpopulations playing unique and vital roles. However, the commonly used mouse models have not been able to fully reproduce the histological and functional characteristics of clinical human CAF. Here, we generated a human cell-derived stroma-rich CDX (Sr-CDX) model, to reproduce the clinical tumor microenvironment. By co-transplanting human adipose-derived mesenchymal stem cells (AD-MSCs) and a human PDAC cell line (Capan-1) into mice, the Sr-CDX model recapitulated the characteristics of clinical pancreatic cancer, such as accelerated tumor growth, abundant stromal proliferation, chemoresistance, and dense stroma formed from the heterogeneous CAFs. Global RNA sequencing, single-cell based RNA sequencing, and histological analysis of CAFs in the Sr-CDX model revealed that the CAFs of the Sr-CDX mice were derived from the transplanted AD-MSCs and composed of heterogeneous subpopulations of CAF, including known and unknown subtypes. These lines of evidences suggest that our new tumor-bearing mouse model has the potential to address an open question in CAF research, that is the mechanism of CAF differentiation.Yoshihiro MiyazakiTatsuya OdaYuki InagakiHiroko KushigeYutaka SaitoNobuhito MoriYuzo TakayamaYutaro KumagaiToutai MitsuyamaYasuyuki S. KidaNature 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 Yoshihiro Miyazaki Tatsuya Oda Yuki Inagaki Hiroko Kushige Yutaka Saito Nobuhito Mori Yuzo Takayama Yutaro Kumagai Toutai Mitsuyama Yasuyuki S. Kida Adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model
description	Abstract Cancer-associated fibroblasts (CAFs) are the key components of the densely proliferated stroma in pancreatic ductal adenocarcinoma (PDAC) and contribute to tumor progression and drug resistance. CAFs comprise heterogeneous subpopulations playing unique and vital roles. However, the commonly used mouse models have not been able to fully reproduce the histological and functional characteristics of clinical human CAF. Here, we generated a human cell-derived stroma-rich CDX (Sr-CDX) model, to reproduce the clinical tumor microenvironment. By co-transplanting human adipose-derived mesenchymal stem cells (AD-MSCs) and a human PDAC cell line (Capan-1) into mice, the Sr-CDX model recapitulated the characteristics of clinical pancreatic cancer, such as accelerated tumor growth, abundant stromal proliferation, chemoresistance, and dense stroma formed from the heterogeneous CAFs. Global RNA sequencing, single-cell based RNA sequencing, and histological analysis of CAFs in the Sr-CDX model revealed that the CAFs of the Sr-CDX mice were derived from the transplanted AD-MSCs and composed of heterogeneous subpopulations of CAF, including known and unknown subtypes. These lines of evidences suggest that our new tumor-bearing mouse model has the potential to address an open question in CAF research, that is the mechanism of CAF differentiation.
format	article
author	Yoshihiro Miyazaki Tatsuya Oda Yuki Inagaki Hiroko Kushige Yutaka Saito Nobuhito Mori Yuzo Takayama Yutaro Kumagai Toutai Mitsuyama Yasuyuki S. Kida
author_facet	Yoshihiro Miyazaki Tatsuya Oda Yuki Inagaki Hiroko Kushige Yutaka Saito Nobuhito Mori Yuzo Takayama Yutaro Kumagai Toutai Mitsuyama Yasuyuki S. Kida
author_sort	Yoshihiro Miyazaki
title	Adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model
title_short	Adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model
title_full	Adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model
title_fullStr	Adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model
title_full_unstemmed	Adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model
title_sort	adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/4dd4de5030214100981257e70a7cbe46
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Adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model

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