Type 2 diabetes alters quiescent pancreatic stellate cells to tumor-prone state
Yutaro Hara, Hiroki Mizukami, Takahiro Yamada, Shuji Shimoyama, Keisuke Yamazaki, Takanori Sasaki, Zhenchao Wang, Hanae Kushibiki, Masaki Ryuzaki, Saori Ogasawara, Hiroaki Tamba, Akiko Itaya, Norihisa Kimura, Keinosuke Ishido, Shinya Ueno, Kenichi Hakamada
Yutaro Hara, Hiroki Mizukami, Takahiro Yamada, Shuji Shimoyama, Keisuke Yamazaki, Takanori Sasaki, Zhenchao Wang, Hanae Kushibiki, Masaki Ryuzaki, Saori Ogasawara, Hiroaki Tamba, Akiko Itaya, Norihisa Kimura, Keinosuke Ishido, Shinya Ueno, Kenichi Hakamada
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Research Article Endocrinology Gastroenterology

Type 2 diabetes alters quiescent pancreatic stellate cells to tumor-prone state

Abstract

Pancreatic stellate cells (PSCs) are the origin of cancer-associated fibroblasts. Type 2 diabetes mellitus (T2D) may promote pancreatic ductal adenocarcinoma (PDAC), eliciting changes in the quiescent PSC (qPSC) population from the precancerous stage. However, the details are unknown. We evaluated the subpopulations of qPSCs and the impact of T2D. PSCs isolated from 8-week-old C57BL/6J mice and diabetic db/db mice were analyzed by single-cell RNA-seq. Sorted qPSCs and PDAC cells were transplanted into allogenic mice. The isolated qPSCs were broadly classified into mesothelial cell and pancreatic fibroblast (Paf) populations by single-cell RNA-seq. Pafs were subclassified into inflammatory Pafs, myofibroblastic Pafs (myPafs) and a small population named tumor immunity- and angiogenesis-promoting Pafs (tapPafs), expressing Cxcl13. In the subcutaneous transplantation model, the tumors transplanted with myPafs were significantly larger than the tumors transplanted with tapPafs. An increase in myPafs and a decrease in tapPafs were observed from the precancerous stage in human T2D, indicating the effects of tumor progression. This study revealed the subpopulation changes in qPSCs in T2D. A therapy that increases the number of tapPafs could be a therapeutic option for patients with PDAC and T2D and even those in a precancerous stage of T2D.

Authors

Yutaro Hara, Hiroki Mizukami, Takahiro Yamada, Shuji Shimoyama, Keisuke Yamazaki, Takanori Sasaki, Zhenchao Wang, Hanae Kushibiki, Masaki Ryuzaki, Saori Ogasawara, Hiroaki Tamba, Akiko Itaya, Norihisa Kimura, Keinosuke Ishido, Shinya Ueno, Kenichi Hakamada

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Figure 4

Impact of T2D on Paf subpopulations.

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Impact of T2D on Paf subpopulations. (A) UMAP-visualized subpopulations ...
(A) UMAP-visualized subpopulations of Pafs based on scRNA-seq transcriptomes pooled from WT (n = 2) and db/db mice (n = 2). (B) Pie chart showing the prevalence of different Paf cell types in WT and db/db mice. (C) Comparison of gene expression in myPafs between WT and db/db mice. (D) Representative immunocytofluorescence images showing the coexpression of α-SMA and PDGFRα or CXCL13 and SCA1 (green arrows) in Pafs from WT (n = 8) and db/db mice (n = 8) (original magnification, ×20). (E) Representative immunofluorescence images showing α-SMA–positive and vWF-negative Pafs (white arrow), α-SMA– and vWF-positive vessels (arrowheads), and CXCL13-positive Pafs (yellow arrows) in samples from WT and db/db mice (original magnification, ×20 and ×40 [insets]). Statistical analysis was performed by Mann-Whitney U test. Pafs, pancreatic fibroblasts; iPafs, inflammatory Pafs; myPafs, myofibroblastic Pafs; tapPafs, tumor immunity- and angiogenesis-promoting Pafs. *P < 0.01. Scale bars: 50 μm (D and E) and 25 μm (E, insets).