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
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Publicado: Nature Portfolio 2021
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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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