Ductal Ngn3-expressing progenitors contribute to adult β cell neogenesis in the pancreas

Christopher Gribben; Christopher Lambert; Hendrik A. Messal; Ella-louise Hubber; Chloe Rackham; Ian Evans; Harry Heimberg; Peter Jones; Rocio Sancho; Axel Behrens

doi:10.1016/j.stem.2021.08.003

Ductal Ngn3-expressing progenitors contribute to adult β cell neogenesis in the pancreas

Christopher Gribben, Christopher Lambert, Hendrik A. Messal, Ella-louise Hubber, Chloe Rackham, Ian Evans, Harry Heimberg, Peter Jones, Rocio Sancho, Axel Behrens

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Abstract

Ductal cells have been proposed as a source of adult β cell neogenesis, but this has remained controversial. By combining lineage tracing, 3D imaging, and single-cell RNA sequencing (scRNA-seq) approaches, we show that ductal cells contribute to the β cell population over time. Lineage tracing using the Neurogenin3 (Ngn3)-CreERT line identified ductal cells expressing the endocrine master transcription factor Ngn3 that were positive for the δ cell marker somatostatin and occasionally co-expressed insulin. The number of hormone-expressing ductal cells was increased in Akita+/− diabetic mice, and ngn3 heterozygosity accelerated diabetes onset. scRNA-seq of Ngn3 lineage-traced islet cells indicated that duct-derived somatostatin-expressing cells, some of which retained expression of ductal markers, gave rise to β cells. This study identified Ngn3-expressing ductal cells as a source of adult β cell neogenesis in homeostasis and diabetes, suggesting that this mechanism, in addition to β cell proliferation, maintains the adult islet β cell population.

Original language	English
Pages (from-to)	2000-2008.e4
Journal	Cell Stem Cell
Volume	28
Issue number	11
Early online date	2 Sept 2021
DOIs	https://doi.org/10.1016/j.stem.2021.08.003
Publication status	Published - 4 Nov 2021

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title = "Ductal Ngn3-expressing progenitors contribute to adult β cell neogenesis in the pancreas",

abstract = "Ductal cells have been proposed as a source of adult β cell neogenesis, but this has remained controversial. By combining lineage tracing, 3D imaging, and single-cell RNA sequencing (scRNA-seq) approaches, we show that ductal cells contribute to the β cell population over time. Lineage tracing using the Neurogenin3 (Ngn3)-CreERT line identified ductal cells expressing the endocrine master transcription factor Ngn3 that were positive for the δ cell marker somatostatin and occasionally co-expressed insulin. The number of hormone-expressing ductal cells was increased in Akita+/− diabetic mice, and ngn3 heterozygosity accelerated diabetes onset. scRNA-seq of Ngn3 lineage-traced islet cells indicated that duct-derived somatostatin-expressing cells, some of which retained expression of ductal markers, gave rise to β cells. This study identified Ngn3-expressing ductal cells as a source of adult β cell neogenesis in homeostasis and diabetes, suggesting that this mechanism, in addition to β cell proliferation, maintains the adult islet β cell population.",

author = "Christopher Gribben and Christopher Lambert and Messal, {Hendrik A.} and Ella-louise Hubber and Chloe Rackham and Ian Evans and Harry Heimberg and Peter Jones and Rocio Sancho and Axel Behrens",

note = "Funding Information: We thank Dr. J. Ferrer for the Hnf1b-CreERT mouse line. This work was supported by the Francis Crick Institute , which receives its core funding from Cancer Research UK ( FC001039 ), the UK Medical Research Council ( FC001039 ), and the Wellcome Trust ( FC001039 ); by King{\textquoteright}s College London ; by a UK Medical Research Council grant ( MR/S000011/1 to R.S.); and by a Wellcome Seed Award in Science ( 207529/Z/17/Z to R.S.). C.L. is supported by the MRC-KCL Doctoral Training Partnership in Biomedical Sciences ( MR/N013700/1 ). Funding Information: We thank Dr. J. Ferrer for the Hnf1b-CreERT mouse line. This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001039), the UK Medical Research Council (FC001039), and the Wellcome Trust (FC001039); by King's College London; by a UK Medical Research Council grant (MR/S000011/1 to R.S.); and by a Wellcome Seed Award in Science (207529/Z/17/Z to R.S.). C.L. is supported by the MRC-KCL Doctoral Training Partnership in Biomedical Sciences (MR/N013700/1). C.G. C.L. R.S. and A.B. conceived the study, analyzed data, and wrote the paper. C.G. performed lineage tracing, C.G. and C.L. performed immunofluorescence, C.L. performed the single-cell analysis, I.E. assisted with the in vivo experiments, H.A.M. developed and performed the FLASH imaging, C.R. and E.-L.H. performed islet isolation for RNA-seq, and H.H. and P.J. assisted with study design and interpretation. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Authors",

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AU - Lambert, Christopher

AU - Messal, Hendrik A.

AU - Hubber, Ella-louise

AU - Rackham, Chloe

AU - Evans, Ian

AU - Heimberg, Harry

AU - Jones, Peter

AU - Sancho, Rocio

AU - Behrens, Axel

N1 - Funding Information: We thank Dr. J. Ferrer for the Hnf1b-CreERT mouse line. This work was supported by the Francis Crick Institute , which receives its core funding from Cancer Research UK ( FC001039 ), the UK Medical Research Council ( FC001039 ), and the Wellcome Trust ( FC001039 ); by King’s College London ; by a UK Medical Research Council grant ( MR/S000011/1 to R.S.); and by a Wellcome Seed Award in Science ( 207529/Z/17/Z to R.S.). C.L. is supported by the MRC-KCL Doctoral Training Partnership in Biomedical Sciences ( MR/N013700/1 ). Funding Information: We thank Dr. J. Ferrer for the Hnf1b-CreERT mouse line. This work was supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001039), the UK Medical Research Council (FC001039), and the Wellcome Trust (FC001039); by King's College London; by a UK Medical Research Council grant (MR/S000011/1 to R.S.); and by a Wellcome Seed Award in Science (207529/Z/17/Z to R.S.). C.L. is supported by the MRC-KCL Doctoral Training Partnership in Biomedical Sciences (MR/N013700/1). C.G. C.L. R.S. and A.B. conceived the study, analyzed data, and wrote the paper. C.G. performed lineage tracing, C.G. and C.L. performed immunofluorescence, C.L. performed the single-cell analysis, I.E. assisted with the in vivo experiments, H.A.M. developed and performed the FLASH imaging, C.R. and E.-L.H. performed islet isolation for RNA-seq, and H.H. and P.J. assisted with study design and interpretation. The authors declare no competing interests. Publisher Copyright: © 2021 The Authors

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N2 - Ductal cells have been proposed as a source of adult β cell neogenesis, but this has remained controversial. By combining lineage tracing, 3D imaging, and single-cell RNA sequencing (scRNA-seq) approaches, we show that ductal cells contribute to the β cell population over time. Lineage tracing using the Neurogenin3 (Ngn3)-CreERT line identified ductal cells expressing the endocrine master transcription factor Ngn3 that were positive for the δ cell marker somatostatin and occasionally co-expressed insulin. The number of hormone-expressing ductal cells was increased in Akita+/− diabetic mice, and ngn3 heterozygosity accelerated diabetes onset. scRNA-seq of Ngn3 lineage-traced islet cells indicated that duct-derived somatostatin-expressing cells, some of which retained expression of ductal markers, gave rise to β cells. This study identified Ngn3-expressing ductal cells as a source of adult β cell neogenesis in homeostasis and diabetes, suggesting that this mechanism, in addition to β cell proliferation, maintains the adult islet β cell population.

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Ductal Ngn3-expressing progenitors contribute to adult β cell neogenesis in the pancreas

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