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Gastroenterology. 2009 May;136(5):1750-60.e13. doi: 10.1053/j.gastro.2009.01.047. Epub 2009 Jan 27.

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

Author information

1
Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium.

Abstract

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.

PMID:
19208356
DOI:
10.1053/j.gastro.2009.01.047
[Indexed for MEDLINE]

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