Notch signaling as gatekeeper of rat acinar-to-beta-cell conversion in vitro

Luc Baeyens, Stefan Bonné, Tomas Bos, Ilse Rooman, Cindy Peleman, Tony Lahoutte, Michael German, Harry Heimberg, Luc Bouwens

Onderzoeksoutput: Articlepeer review

79 Citaten (Scopus)

Samenvatting

BACKGROUND & AIMS: Exocrine acinar cells in the pancreas are highly differentiated cells that retain a remarkable degree of plasticity. After isolation and an initial phase of dedifferentiation in vitro, rodent acinar cells can convert to endocrine beta-cells when cultured in the presence of appropriate factors. The mechanisms regulating this phenotypic conversion are largely unknown.

METHODS: Using rat acinar cell cultures, we studied the role of Notch signaling in a model of acinar-to-beta-cell conversion.

RESULTS: We report a novel lectin-based cell labeling method to demonstrate the acinar origin of newly formed insulin-expressing beta-cells. This method allows for specific tracing of the acinar cells. We demonstrate that growth factor-induced conversion of adult acinar cells to beta-cells is negatively regulated by Notch1 signaling. Activated Notch1 signaling prevents the reexpression of the proendocrine transcription factor Neurogenin-3, the key regulator of endocrine development in the embryonic pancreas. Interfering with Notch1 signaling allows modulating the acinar cell susceptibility to the differentiation-inducing factors. Its inhibition significantly improves beta-cell neoformation with approximately 30% of acinar cells that convert to beta-cells. The newly formed beta-cells mature when transplanted ectopically and are capable of restoring normal blood glycemia in diabetic recipients.

CONCLUSIONS: We report for the first time an efficient way to reprogram one third of the acinar cells to beta-cells by adult cell type conversion. This could find application in cell replacement therapy of type 1 diabetes, provided that it can be translated from rodent to human models.

Originele taal-2English
Pagina's (van-tot)1750-1760
Aantal pagina's11
TijdschriftGASTROENTEROLOGY
Volume136
Nummer van het tijdschrift5
DOI's
StatusPublished - 2009

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