Author:
Banga Anannya,Akinci Ersin,Greder Lucas V.,Dutton James R.,Slack Jonathan M. W.
Abstract
In embryonic development, the pancreas and liver share developmental history up to the stage of bud formation. Therefore, we postulated that direct reprogramming of liver to pancreatic cells can occur when suitable transcription factors are overexpressed. Using a polycistronic vector we misexpressPdx1,Ngn3, andMafAin the livers of NOD-SCID mice rendered diabetic by treatment with streptozotocin (STZ). The diabetes is relieved long term. Many ectopic duct-like structures appear that express a variety of β-cell markers, including dense core granules visible by electron microscopy (EM). Use of a vector also expressing GFP shows that the ducts persist long after the viral gene expression has ceased, indicating that this is a true irreversible cell reprogramming event. We have recovered the insulin+cells by cell sorting and shown that they display glucose-sensitive insulin secretion. The early formed insulin+cells can be seen to coexpress SOX9 and are also labeled in mice lineage labeled forSox9expression. SOX9+cells are normally found associated with small bile ducts in the periportal region, indicating that the duct-like structures arise from this source. This work confirms that developmentally related cells can be reprogrammed by suitable transcription factors and also suggests a unique therapy for diabetes.
Publisher
Proceedings of the National Academy of Sciences
Cited by
129 articles.
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