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| Status |
Public on Jan 29, 2022 |
| Title |
MYCL-mediated in vivo reprogramming expands pancreatic insulin-producing cells to reverse diabetes - RNA-Seq |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
β cell proliferation rates decline with age and adult β cells have limited self-duplicating activity for regeneration, which predisposes to diabetes. Here we show that, among MYC family members, Mycl was expressed preferentially in proliferating immature endocrine cells. Genetic ablation of Mycl caused a modest reduction in cell proliferation of pancreatic endocrine cells in neonatal mice. By contrast, systemic expression of Mycl in mice stimulated proliferation in pancreatic islet cells and resulted in expansion of pancreatic islets without forming tumors in other organs. Single-cell RNA sequencing and genetic tracing experiments revealed that the expression of Mycl provoked transcription signatures associated with immature proliferating endocrine cells and stimulated self-duplication in adult hormone-expressing cells. The expanded hormone-expressing cells ceased proliferation but persisted after withdrawal of Mycl expression. Remarkably, a subset of the expanded α cells gave rise to insulin-producing cells after the withdrawal. Moreover, transient Mycl expression in vivo was sufficient to normalize increased blood glucose levels in diabetic mice evoked by chemical ablation of β cells. In vitro expression of Mycl similarly provoked active replication without inducing apoptosis in adult hormone-expressing islet cells, even those from aged mice. Furthermore, the expanded islet cells functioned in diabetic mice after transplantation. Finally, we show that MYCL stimulated self-duplication of human adult cadaveric islet cells. Collectively, these results demonstrate that sole induction of Mycl expands adult β cells both in vivo and in vitro. Moreover, islet cell-specific reprogramming via transient Mycl transduction elicits endogenous expansion of insulin-producing cells in adult pancreas through both self-duplication of β cells and transdifferentiation ofα cells into insulin-producing cells, which may provide a regenerative strategy of β cells.
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| Overall design |
For RNAseq in mouse liver, we transduced c-Myc or Mycl in 4-week-old adult mice for 48 hrs by intraperitoneal injection of Dox (0.2 ml; 2.0mg/mL). For the control, liver were harvested from no treatment Mycl inducible mice at 4wks(WT).
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| Contributor(s) |
Yamamoto T, Yamada Y |
| Citation missing |
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| Submission date |
Jun 23, 2021 |
| Last update date |
Jan 29, 2022 |
| Contact name |
Yasuhiro Yamada |
| E-mail(s) |
yyamada@m.u-tokyo.ac.jp
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| Organization name |
University of Tokyo
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| Department |
Department of Molecular Pathology
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| Street address |
7-3-1 Hongo, Bunkyo-ku
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| City |
Tokyo |
| ZIP/Postal code |
113-0033 |
| Country |
Japan |
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| Platforms (1) |
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| Samples (9)
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| Relations |
| BioProject |
PRJNA740240 |
| SRA |
SRP325243 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE178726_processed_file.xlsx |
1.2 Mb |
(ftp)(http) |
XLSX |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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