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Towards consistent generation of pancreatic lineage progenitors from human pluripotent stem cells.


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Authors

Rostovskaya, Maria 
Bredenkamp, Nicholas 

Abstract

Human pluripotent stem cells can in principle be used as a source of any differentiated cell type for disease modelling, drug screening, toxicology testing or cell replacement therapy. Type I diabetes is considered a major target for stem cell applications due to the shortage of primary human beta cells. Several protocols have been reported for generating pancreatic progenitors by in vitro differentiation of human pluripotent stem cells. Here we first assessed one of these protocols on a panel of pluripotent stem cell lines for capacity to engender glucose sensitive insulin-producing cells after engraftment in immunocompromised mice. We observed variable outcomes with only one cell line showing a low level of glucose response. We, therefore, undertook a systematic comparison of different methods for inducing definitive endoderm and subsequently pancreatic differentiation. Of several protocols tested, we identified a combined approach that robustly generated pancreatic progenitors in vitro from both embryo-derived and induced pluripotent stem cells. These findings suggest that, although there are intrinsic differences in lineage specification propensity between pluripotent stem cell lines, optimal differentiation procedures may consistently direct a substantial fraction of cells into pancreatic specification.

Description

Keywords

differentiation, embryonic stem cells, pancreatic progenitors, Animals, Cell Differentiation, Cell Line, Cell Lineage, Cell- and Tissue-Based Therapy, Diabetes Mellitus, Type 1, Embryonic Stem Cells, Endoderm, Hepatocyte Nuclear Factor 3-beta, Homeodomain Proteins, Humans, Induced Pluripotent Stem Cells, Mice, Pancreas, Pluripotent Stem Cells, SOX9 Transcription Factor, Trans-Activators

Journal Title

Philos Trans R Soc Lond B Biol Sci

Conference Name

Journal ISSN

0962-8436
1471-2970

Volume Title

370

Publisher

The Royal Society
Sponsorship
Medical Research Council (G1001028)
Medical Research Council (MC_PC_12009)
MRC (G1100526)
European Commission (241883)
Wellcome Trust (097922/Z/11/B)
This research was supported by European Commission Grant agreement 241883, “BetaCellTherapy”, and by the United Kingdom Medical Research Council.