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Adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model
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 mou...
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| Published in: | Scientific reports 2021-02, Vol.11 (1), p.4690-4690, Article 4690 |
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| creator | Miyazaki, Yoshihiro Oda, Tatsuya Inagaki, Yuki Kushige, Hiroko Saito, Yutaka Mori, Nobuhito Takayama, Yuzo Kumagai, Yutaro Mitsuyama, Toutai Kida, Yasuyuki S. |
| description | 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. |
| doi_str_mv | 10.1038/s41598-021-84058-3 |
| format | article |
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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.</description><identifier>ISSN: 2045-2322</identifier><identifier>EISSN: 2045-2322</identifier><identifier>DOI: 10.1038/s41598-021-84058-3</identifier><identifier>PMID: 33633222</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>631/532/2074 ; 631/67/1504 ; 631/67/327 ; 631/67/70 ; 692/4028/67/1504 ; 692/4028/67/327 ; 692/4028/67/70 ; 692/699/1503/1712 ; 692/699/1503/1712/1713 ; Adenocarcinoma ; Adipose Tissue - cytology ; Animal models ; Animals ; Cancer ; Carcinoma, Pancreatic Ductal - pathology ; Cell Differentiation ; Chemoresistance ; Drug resistance ; Fibroblasts ; Fibroblasts - cytology ; Heterografts ; Humanities and Social Sciences ; Humans ; Mesenchymal stem cells ; Mesenchymal Stem Cells - cytology ; Mice ; multidisciplinary ; Pancreatic cancer ; Pancreatic Neoplasms ; Pancreatic Neoplasms - pathology ; Ribonucleic acid ; RNA ; Science ; Science (multidisciplinary) ; Stem cell transplantation ; Stem cells ; Stroma ; Stromal Cells - cytology ; Subpopulations ; Tumor microenvironment ; Tumors ; Xenografts</subject><ispartof>Scientific reports, 2021-02, Vol.11 (1), p.4690-4690, Article 4690</ispartof><rights>The Author(s) 2021</rights><rights>The Author(s) 2021. 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Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c650t-27dbc7a82d0d70ef5d29b584c381c3c0958f4311205bc07491c84197ce4de0b13</citedby><cites>FETCH-LOGICAL-c650t-27dbc7a82d0d70ef5d29b584c381c3c0958f4311205bc07491c84197ce4de0b13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/2493254812/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/2493254812?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,37013,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33633222$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Miyazaki, Yoshihiro</creatorcontrib><creatorcontrib>Oda, Tatsuya</creatorcontrib><creatorcontrib>Inagaki, Yuki</creatorcontrib><creatorcontrib>Kushige, Hiroko</creatorcontrib><creatorcontrib>Saito, Yutaka</creatorcontrib><creatorcontrib>Mori, Nobuhito</creatorcontrib><creatorcontrib>Takayama, Yuzo</creatorcontrib><creatorcontrib>Kumagai, Yutaro</creatorcontrib><creatorcontrib>Mitsuyama, Toutai</creatorcontrib><creatorcontrib>Kida, Yasuyuki S.</creatorcontrib><title>Adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model</title><title>Scientific reports</title><addtitle>Sci Rep</addtitle><addtitle>Sci Rep</addtitle><description>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. 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Scientific reports</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Miyazaki, Yoshihiro</au><au>Oda, Tatsuya</au><au>Inagaki, Yuki</au><au>Kushige, Hiroko</au><au>Saito, Yutaka</au><au>Mori, Nobuhito</au><au>Takayama, Yuzo</au><au>Kumagai, Yutaro</au><au>Mitsuyama, Toutai</au><au>Kida, Yasuyuki S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model</atitle><jtitle>Scientific reports</jtitle><stitle>Sci Rep</stitle><addtitle>Sci Rep</addtitle><date>2021-02-25</date><risdate>2021</risdate><volume>11</volume><issue>1</issue><spage>4690</spage><epage>4690</epage><pages>4690-4690</pages><artnum>4690</artnum><issn>2045-2322</issn><eissn>2045-2322</eissn><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.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>33633222</pmid><doi>10.1038/s41598-021-84058-3</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 631/532/2074 631/67/1504 631/67/327 631/67/70 692/4028/67/1504 692/4028/67/327 692/4028/67/70 692/699/1503/1712 692/699/1503/1712/1713 Adenocarcinoma Adipose Tissue - cytology Animal models Animals Cancer Carcinoma, Pancreatic Ductal - pathology Cell Differentiation Chemoresistance Drug resistance Fibroblasts Fibroblasts - cytology Heterografts Humanities and Social Sciences Humans Mesenchymal stem cells Mesenchymal Stem Cells - cytology Mice multidisciplinary Pancreatic cancer Pancreatic Neoplasms Pancreatic Neoplasms - pathology Ribonucleic acid RNA Science Science (multidisciplinary) Stem cell transplantation Stem cells Stroma Stromal Cells - cytology Subpopulations Tumor microenvironment Tumors Xenografts |
| title | Adipose-derived mesenchymal stem cells differentiate into heterogeneous cancer-associated fibroblasts in a stroma-rich xenograft model |
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