In vivo reprogramming of Sox9 + cells in the liver to insulin-secreting ducts
Open Access
- 4 September 2012
- journal article
- research article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 109 (38), 15336-15341
- https://doi.org/10.1073/pnas.1201701109
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 misexpress Pdx1, Ngn3, and MafA in 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 for Sox9 expression. 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.Keywords
This publication has 44 references indexed in Scilit:
- Reprogramming of pancreatic exocrine cells towards a beta (β) cell character using Pdx1, Ngn3 and MafABiochemical Journal, 2012
- Embryonic Ductal Plate Cells Give Rise to Cholangiocytes, Periportal Hepatocytes, and Adult Liver Progenitor CellsGastroenterology, 2011
- Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes by Defined FactorsCell, 2010
- Deconstructing Pancreas Development to Reconstruct Human Islets from Pluripotent Stem CellsCell Stem Cell, 2010
- Direct conversion of fibroblasts to functional neurons by defined factorsNature, 2010
- Insulin crystallization depends on zinc transporter ZnT8 expression, but is not required for normal glucose homeostasis in miceProceedings of the National Academy of Sciences of the United States of America, 2009
- Intrahepatic Bile Ducts Develop According to a New Mode of Tubulogenesis Regulated by the Transcription Factor SOX9Gastroenterology, 2009
- Neurogenin3 Is Sufficient for Transdetermination of Hepatic Progenitor Cells into Neo-Islets In Vivo but Not Transdifferentiation of HepatocytesDevelopmental Cell, 2009
- Generation of germline-competent induced pluripotent stem cellsNature, 2007
- Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined FactorsCell, 2006