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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.

SUBMITTER: Gribben C

PROVIDER: S-EPMC8577827 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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

Gribben Christopher C Lambert Christopher C Messal Hendrik A HA Hubber Ella-Louise EL Rackham Chloe C Evans Ian I Heimberg Harry H Jones Peter P Sancho Rocio R Behrens Axel A

Cell stem cell 20210902 11

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-expresse ...[more]

PMID: 34478642

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Project description:In vivo beta-cell neogenesis may be one way to treat diabetes. We aimed to investigate the effect of glucagon-like peptide-1 (GLP-1) on beta-cell neogenesis in type 2 diabetes mellitus (T2DM). Male C57BL/6J mice, 6 wk old, were randomly divided into three groups: Control, T2DM, and T2DM + Lira. T2DM was induced using high-fat diet and intraperitoneal injection of streptozotocin (40 mg/kg/d for 3 d). At 8 wk after streptozotocin injection, T2DM + Lira group was injected intraperitoneally with GLP-1 analog liraglutide (0.8 mg/kg/d) for 4 wk. Apparently for the first time, we report the appearance of a primitive bud connected to pancreas in all adult mice from each group. The primitive bud was characterized by scattered single monohormonal cells expressing insulin, GLP-1, somatostatin, or pancreatic polypeptide, and four-hormonal cells, but no acinar cells and ductal epithelial cells. Monohormonal cells in it were small, newborn, immature cells that rapidly proliferated and expressed cell markers indicative of immaturity. In parallel, Ngn3+ endocrine progenitors and Nestin+ cells existed in the primitive bud. Liraglutide facilitated neogenesis and rapid growth of acinar cells, pancreatic ducts, and blood vessels in the primitive bud. Meanwhile, scattered hormonal cells aggregated into cell clusters and grew into larger islets; polyhormonal cells differentiated into monohormonal cells. Extensive growth of exocrine and endocrine glands resulted in the neogenesis of immature pancreatic lobes in adult mice of T2DM + Lira group. Contrary to predominant acinar cells in mature pancreatic lobes, there were still a substantial number of mesenchymal cells around acinar cells in immature pancreatic lobes, which resulted in the loose appearance. Our results suggest that adult mice preserve the capacity of pancreatic neogenesis from the primitive bud, which liraglutide facilitates in adult T2DM mice. To our knowledge, this is the first time such a phenomenon has been reported.

Dataset Information

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

Publications

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

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