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

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posted on 08.12.2021, 11:12 authored by Christopher Gribben, Christopher Lambert, Hendrik A Messal, Ella-Louise Hubber, Chloe Rackham, Ian Evans, Harry Heimberg, Peter Jones, Rocio Sancho, Axel Behrens
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.

Funding

Crick (Grant ID: 10039, Grant title: Behrens FC001039)

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