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23.10.2023 | Article

Novel time-resolved reporter mouse reveals spatial and transcriptional heterogeneity during alpha cell differentiation

verfasst von: Miwa Himuro, Yuka Wakabayashi, Tomomi Taguchi, Takehiro Katahira, Luka Suzuki, Hitoshi Iida, Takeshi Ogihara, Yuya Nishida, Shugo Sasaki, Francis C. Lynn, Yuichi Hiraoka, Shigeru Oshima, Ryuichi Okamoto, Yoshio Fujitani, Hirotaka Watada, Takeshi Miyatsuka

Erschienen in: Diabetologia | Ausgabe 1/2024

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Abstract

Aims/hypothesis

Glucagon-expressing pancreatic alpha cells have attracted much attention for their plasticity to transdifferentiate into insulin-producing beta cells; however, it remains unclear precisely when, and from where, alpha cells emerge and what regulates alpha cell fate. We therefore explored the spatial and transcriptional heterogeneity of alpha cell differentiation using a novel time-resolved reporter system.

Methods

We established the mouse model, ‘Gcg-Timer’, in which newly generated alpha cells can be distinguished from more-differentiated cells by their fluorescence. Fluorescence imaging and transcriptome analysis were performed with Gcg-Timer mice during the embryonic and postnatal stages.

Results

Fluorescence imaging and flow cytometry demonstrated that green fluorescence-dominant cells were present in Gcg-Timer mice at the embryonic and neonatal stages but not after 1 week of age, suggesting that alpha cell neogenesis occurs during embryogenesis and early neonatal stages under physiological conditions. Transcriptome analysis of Gcg-Timer embryos revealed that the mRNAs related to angiogenesis were enriched in newly generated alpha cells. Histological analysis revealed that some alpha cells arise close to the pancreatic ducts, whereas the others arise away from the ducts and adjacent to the blood vessels. Notably, when the glucagon signal was suppressed by genetic ablation or by chemicals, such as neutralising glucagon antibody, green-dominant cells emerged again in adult mice.

Conclusions/interpretation

Novel time-resolved analysis with Gcg-Timer reporter mice uncovered spatiotemporal features of alpha cell neogenesis that will enhance our understanding of cellular identity and plasticity within the islets.

Data availability

Raw and processed RNA sequencing data for this study has been deposited in the Gene Expression Omnibus under accession number GSE229090.

Graphical Abstract

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Titel: Novel time-resolved reporter mouse reveals spatial and transcriptional heterogeneity during alpha cell differentiation
verfasst von: Miwa Himuro
Yuka Wakabayashi
Tomomi Taguchi
Takehiro Katahira
Luka Suzuki
Hitoshi Iida
Takeshi Ogihara
Yuya Nishida
Shugo Sasaki
Francis C. Lynn
Yuichi Hiraoka
Shigeru Oshima
Ryuichi Okamoto
Yoshio Fujitani
Hirotaka Watada
Takeshi Miyatsuka
Publikationsdatum: 23.10.2023
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 1/2024
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-023-06028-w

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Novel time-resolved reporter mouse reveals spatial and transcriptional heterogeneity during alpha cell differentiation