Abstract
It has been suggested that new beta cells can arise from specific populations of adult pancreatic progenitors or facultative stem cells. However, their existence remains controversial, and the conditions under which they would contribute to new beta-cell formation are not clear. Here, we use a suite of mouse models enabling dual-recombinase-mediated genetic tracing to simultaneously fate map insulin-positive and insulin-negative cells in the adult pancreas. We find that the insulin-negative cells, of both endocrine and exocrine origin, do not generate new beta cells in the adult pancreas during homeostasis, pregnancy or injury, including partial pancreatectomy, pancreatic duct ligation or beta-cell ablation with streptozotocin. However, non-beta cells can give rise to insulin-positive cells after extreme genetic ablation of beta cells, consistent with transdifferentiation. Together, our data indicate that pancreatic endocrine and exocrine progenitor cells do not contribute to new beta-cell formation in the adult mouse pancreas under physiological conditions.
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Data availability
Newly generated mouse lines will be deposited in a commercial animal repository and will be available, together with data that support the plots and findings within this paper, from the corresponding author upon reasonable request. Source data are provided with this paper.
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Acknowledgements
We thank Shanghai Biomodel Organism for mouse generation and H. Zeng for reporter mice. This study was supported by the National key Research & Development Program of China (2019YFA0802000, 2019YFA0110403, 2018YFA0108100, 2017YFC1001303, 2020YFA0803202, 2019YFA0802803 and 2018YFA0107900), Strategic Priority Research Program of the Chinese Academy of Sciences (CAS; XDB19000000 and XDA16010507), National Science Foundation of China (31730112, 82088101, 32050087, 91849202, 31625019, 31922032, 81872241 and 31900625), Key Project of Frontier Sciences of CAS (QYZDB-SSW-SMC003), Shanghai Science and Technology Commission (19JC1415700, 20QC1401000, 19YF1455300 and 19ZR1479800), Collaborative Innovation Program of Shanghai Municipal Health Commission (2020CXJQ01), China Postdoctoral Science Foundation, National Postdoctoral Program for Innovative Talents (BX20190343, 2019M660100, 2020TQ0336 and 2020M681409), the Pearl River Talent Recruitment Program of Guangdong Province (2017ZT07S347), Royal Society-Newton Advanced Fellowship, AstraZeneca, Boehringer-Ingelheim, Sanofi-SIBS Fellowship, SIBS President Fund and the support from the Xplorer Prize.
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H.Z. and B.Z. designed the study, performed experiments and analysed the data. X.H., Z. Liu, W.P., L.H. and Z. Lv bred the mice, performed experiments or provided valuable comments. Q.Z. provided valuable comments and suggestions, and edited the manuscript. Y.L. and K.O.L. contributed to interpreting the data and writing the manuscript. B.Z. supervised the study, analysed the data and wrote the manuscript.
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Peer review information Nature Metabolism thanks the anonymous reviewers for their contribution to the peer review of this work. Primary Handling Editor: Christoph Schmitt.
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Extended data
Extended Data Fig. 1 Generation and characterization of Ins2-Dre mouse allele.
a, A Schematic diagram illustrating knock-in strategy for Ins2-Dre by homologous recombination using CRISPR/Cas9. b, A Schematic diagram illustrating the strategy for labeling pancreatic β cells by Ins2-Dre using interleaved reporter 1 (IR1). c, A Schematic diagram illustrating the experimental strategy. 4 weeks old mice (both male and female mice were used) were euthanized for analysis (n = 5). d, Whole-mount bright-field and fluorescent images of pancreas from Ins2-Dre;IR1. e, Immunostaining for tdT, zsGreen, and Ins on pancreatic slides collected from Ins2-Dre;IR1. Arrows indicate tdT+Ins+ β cells. Scale bars, yellow, 1 mm; white, 100 μm. Each image is representative of 5 individual biological samples.
Extended Data Fig. 2 Ins2-Dre;R26-iCre;IR1 efficiently labels most of cells in pancreas.
(a-b) Immunostaining for tdT and zsGreen on slides collected from Ins2-Dre;R26-iCre;IR1 mice at 7 weeks old after Dox treatment (both male and female mice were used, n = 5). Boxed regions in (a) are magnified in (b). Scale bars, yellow, 1mm; white, 100 μm. Each image is representative of 5 individual biological samples.
Extended Data Fig. 3 R26-iCre efficiently labels most of cell lineages in pancreatic endocrine glands.
(a-c) Immunostaining for tdT, zsGreen, Glucagon (GCG, a), Somatostatin (Stt, b) and Pancreatic Polypeptide (PP, c) on slides collected from Ins2-Dre;R26-iCre;IR1 mice at 7 weeks old after Dox treatment (both male and female mice were used, n = 5). Arrows indicate zsGreen+ cell lineages. Right panel is the quantification of the percentage of indicated non-β cell lineages expressing zsGreen. Data are mean ± SEM, n = 5. Scale bars, 100 μm. Each image is representative of 5 individual biological samples.
Extended Data Fig. 4 R26-iCre efficiently labels most of cell lineages in pancreatic exocrine gland.
(a-f) Immunostaining for tdT, zsGreen and E-cadherin (E-cad), or Amylase (Amy), Cytokeratin 19 (CK19), Vascular endothelial cadherin (VE-cad), Lymphatic vessel endothelial hyaluronan receptor 1 (Lyve1) and Platelet derived growth factor receptor a (Pdgfra) on slides collected from Ins2-Dre;R26-iCre;IR1 mice at 7 weeks old after Dox treatment (both male and female mice were used, n = 5). Right panel is the quantification of the percentage of indicated non-β cell lineages expressing zsGreen. Data are mean ± SEM, n = 5 (Dox group). Scale bars, 100 μm. Each image is representative of 5 individual biological samples.
Extended Data Fig. 5 Non-β cells contribute to β cells in embryonic stage.
a, Immunostaining for tdT, zsGreen, and Ins on pancreatic sections of Ins-Dre;R26-iCre;IR1 mice without Dox treatment at E14.5 (both male and female mice were used, n = 5). b, A schematic figure showing experimental strategy of Dox injection and analysis. c, Immunostaining for tdT, zsGreen, and Ins on pancreatic sections of Ins-Dre;R26-iCre;IR1 mice at E16.0 (top) and P21 (bottom) treated with Dox at E14.5 (both male and female mice were used, E16.0 group, n = 5; P21 group, n = 5). White arrows indicate tdT+Ins+ β cells. Yellow arrowheads indicate zsGreen+Ins+ β cells. d, Quantification of the percentage of zsGreen+ β cells from indicated mice. Numbers of investigated mice were as follows: E14.5>E16.0 group, n = 5; E14.5>P21 group, n = 5, Data are mean ± SEM, P=1.12 × 10–4, *P<0.05 (unpaired, two-sided, Student’s t-test). e, Illustration showing contribution of non-β cells to β cells in embryonic stage. f, A schematic figure showing experimental strategy of Dox injection and analysis (both male and female mice were used, n = 5). g, Whole-mount bright-field and fluorescent images of pancreas from Ins-Dre;R26-iCre;IR1 mice with Dox treatment. h, Immunostaining for tdT, zsGreen, and Ins on pancreatic sections of Ins-Dre;R26-iCre;IR1 mice at P21 with Dox treatment at P7. Arrows indicate tdT+Ins+ β cells. Arrowheads indicate zsGreen+Ins– non-β cells. i, Quantification of the percentage of β cells expressing tdT or zsGreen from indicated mice. Data are mean ± SEM, n=5 (P7>P21 group). (j) Illustration showing no contribution of non-β cells to β cells in postnatal stage. Scale bars, yellow, 1 mm; white, 100 μm. Each image is representative of 5 individual samples.
Extended Data Fig. 6 β cells proliferate after partial pancreatectomy and during pregnancy.
a, A schematic diagram illustrating the experimental strategy for Dox induction, partial pancreatectomy (PPX) and analysis. 6 weeks old mice (both male and female mice were used) were treated with Dox for 1 week. After washout for 2 weeks and PPX injury for 2 and 4 weeks, mice were euthanized (PPX group: n = 5; Sham group: n = 5). b, Immunostaining for tdT, ZsGreen and Ins on pancreatic sections collected after PPX 2 weeks. Arrows indicate tdT+Ins+ β cells. Arrowheads indicate zsGreen+Ins– non-β cells. c, Immunostaining on pancreatic sections for tdT, ZsGreen and EdU collected after PPX 2 weeks. Arrows indicate EdU+tdT+ cells. EdU was injected 12 hours before sacrifice. Right panel shows quantification of the percentage of tdT+ cells with incorporated EdU. Numbers of investigated mice were as follows: PPX group, n = 5; Sham group, n = 5, Data are mean ± SEM, P=1.22×10–5, *P<0.05 (unpaired, two-sided, Student’s t-test). d, Immunostaining for tdT, ZsGreen and Ins on pancreatic sections collected after PPX 4 weeks. Arrows indicate tdT+Ins+ β cells. Arrowheads indicate zsGreen+Ins– non-β cells. e, A schematic diagram illustrating experimental strategy of Dox induction, pregnancy and analysis. 6 weeks old mice (only female mice were used) were treated with Dox for 1 week. After washout for 2 weeks and Pregnancy for 15.5 d, mice were euthanized (Pregnancy group: n = 5; Sham group: n = 5). f, Immunostaining for tdT, ZsGreen and EdU on pancreatic sections collected after pregnancy. Arrows indicate EdU+tdT+ cells. EdU was injected 12 hours before sacrifice. Right panel shows quantification of the percentage of tdT+ cells with incorporated EdU. Numbers of investigated mice were as follows: Pregnancy group, n = 5; Sham group, n = 5, Data are mean ± SEM, P=3.38×10–6, *P<0.05 (unpaired, two-sided, Student’s t-test). Scale bars, 100 μm. Each image is representative of 5 individual samples.
Extended Data Fig. 7 β cells are not generated from non-β cells after pancreatic ductal ligation.
a, A schematic diagram illustrating experimental strategy of Dox induction, pancreatic ductal ligation (PDL) and analysis. 6 weeks old mice (both male and female mice were used) were treated with Dox for 1 week. After washout for 2 weeks and PDL injury for 2 and 4 weeks, mice were euthanized (PDL group: n = 5; Sham group: n = 5). b, Immunostaining for tdT, ZsGreen and Ins on pancreatic tail (left) and head (right) sections collected after PDL 2 weeks. Arrows indicate tdT+Ins+ β cells. Arrowheads indicate zsGreen+Ins– non-β cells. c, Immunostaining for tdT, ZsGreen and EdU collected after PDL. Arrowheads indicate EdU+tdT+ cells. EdU was injected 12 hours before sacrifice. Right panel shows quantification of the percentage of tdT+ cells with incorporated EdU. Numbers of investigated mice were as follows: PDL group, n = 5; Sham group, n = 5, Data are mean ± SEM, n.s., not significant (unpaired, two-sided, Student’s t-test). d, Immunostaining for tdT, ZsGreen and Ins on pancreatic tail (left) and head (right) sections collected after PDL 4 weeks. Arrows indicate tdT+Ins+ β cells. Arrowheads indicate zsGreen+Ins– non-β cells. Scale bars, 100 μm. Each image is representative of 5 individual samples.
Extended Data Fig. 8 Generation and characterization of IR1-DTR.
a, A schematic diagram illustrating knock-in strategy for generation of IR1-DTR by homologous recombination using CRISPR/Cas9. b, Strategy for labeling pancreatic β cells by Ins2-Dre;IR1-DTR mouse line. c, Immunostaining for tdT, zsGreen and Ins on pancreatic slides collected from 8 weeks old Ins2-Dre;IR1-DTR (both male and female mice were used, n = 5). d, Immunostaining for tdT, zsGreen, and DTR on pancreatic slides collected from 8 weeks old Ins2-Dre;IR1-DTR. e, A schematic figure showing experimental strategy of DT injection and analysis. 7–8 weeks old mice (both male and female mice were used) were treated with DT for 2 times. After 3 days, mice were euthanized (DT group: n = 5; no DT group: n = 5). f, Whole-mount bright-field and fluorescent images of pancreas from Ins2-Dre;IR1-DTR mice. g, Immunostaining for tdT, zsGreen, and Ins on pancreatic sections of Ins2-Dre;IR1-DTR mice. h, Immunostaining for tdT, zsGreen, and DTR on pancreatic sections of Ins2-Dre;IR1-DTR mice. Scale bars, yellow, 1 mm; white, 100 μm. Each image is representative of 5 individual biological samples.
Extended Data Fig. 9 Ins2-DreER specifically and efficiently labels β cells in the adult pancreas.
Immunostaining for tdT and Insulin on consecutive sections (section 1–23) of pancreatic islets of 8 weeks old Ins2-DreER;H11-rox-tdT mice treated with Tam (both male and female mice were used, n = 5). Scale bars, 100 μm. This data is representative of 5 individual biological samples.
Extended Data Fig. 10 Analysis of β cells after injuries by inducible Ins2-DreER;H11-rox-tdT system.
a, A schematic diagram illustrating the experimental design to test for β cell neogenesis during pregnancy in the inducible system. 6 weeks old mice (only female mice were used) were treated with Tamoxifen for 3 times. After washout for 2 weeks and Pregnancy for 15.5 days, mice were euthanized (Pregnancy group, n = 5; Sham group, n = 5). b, Immunostaining for tdT and Ins on pancreatic slides collected from Ins2-DreER;H11-rox-tdT during pregnancy (Preg15.5). c, Quantification of β cells expressing tdT in the indicated mice. Numbers of investigated mice were as follows: Pregnancy group, n = 5; Sham group, n = 5, Data are mean ± SEM, n.s., not significant (unpaired, two-sided, Student’s t-test). d, A schematic diagram illustrating the experimental design to test for β cell neogenesis after pancreatic ductal ligation (PDL). 6 weeks old mice (both male and female mice were used) were treated with Tamoxifen for 3 times. After washout for 2 weeks and PDL injury for 2 weeks, mice were euthanized (PDL group, n = 5; Sham group, n = 5). e, Immunostaining for tdT and Ins on pancreatic slides collected from Ins2-DreER;H11-rox-tdT after PDL. f, Quantification of β cells expressing tdT in the indicated mice. Numbers of investigated mice were as follows: PDL group, n = 5; Sham group, n = 5, Data are mean ± SEM, n.s., not significant (unpaired, two-sided, Student’s t-test). g, A schematic diagram illustrating the experimental design to test for β cell neogenesis after streptozocin (STZ)-induced injury. 6 weeks old mice (both male and female mice were used) were treated with Tamoxifen for 3 times. After washout for 2 weeks and STZ injury for 2 weeks, mice were euthanized (STZ group, n = 5; Sham group, n = 5). h, Immunostaining for tdT and Ins on pancreatic slides collected from Ins2-DreER;H11-rox-tdT after streptozocin (STZ)-induced injury. (i) Quantification of β cells expressing tdT in the indicated mice. Numbers of investigated mice were as follows: STZ group, n = 5; Sham group, n = 5, Data are mean ± SEM, n.s., not significant (unpaired, two-sided, Student’s t-test). Scale bars, yellow, 1 mm; white, 100 μm. Each image is representative of 5 individual biological samples.
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Zhao, H., Huang, X., Liu, Z. et al. Pre-existing beta cells but not progenitors contribute to new beta cells in the adult pancreas. Nat Metab 3, 352–365 (2021). https://doi.org/10.1038/s42255-021-00364-0
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DOI: https://doi.org/10.1038/s42255-021-00364-0
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