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Updated: Jun 21, 2026
Generation of Scaffold-free, Three-dimensional Insulin Expressing Pancreatoids from Mouse Pancreatic Progenitors In Vitro
Published on: June 2, 2018
Expression of MafA in pancreatic progenitors is detrimental for pancreatic development
Wataru Nishimura1, Susan Bonner-Weir, Arun Sharma
1Section of Islet Transplantation & Cell Biology, Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA.
Abstract:
The transcription factor MafA regulates glucose-responsive expression of insulin. MafA-deficient mice have a normal proportion of insulin+ cells at birth but develop diabetes gradually with age, suggesting that MafA is required for maturation and not specification of pancreatic beta-cells. However, several studies show that ectopic expression of MafA may have a role in specification as it induces insulin+ cells in chicken gut epithelium, reprograms adult murine acinar cells into insulin+ cells in combination with Ngn3 and Pdx1, and triggers the lens differentiation. Hence, we examined whether MafA can induce specification of beta-cells during pancreatic development. When the MafA transgene is expressed in Pdx1+ pancreatic progenitors, both pancreatic mass and proliferation of progenitors are reduced, at least partially due to induction of cyclin kinase inhibitors p27 and p57. Expression of MafA in Pdx1+ cells until E12.5 was sufficient to cause these effects and to disproportionately inhibit the formation of endocrine cells in the remnant pancreas. Thus, in mice, MafA expression in Pdx1+ pancreatic progenitors is not sufficient to specify insulin+ cells but in fact deters pancreatic development and the differentiation of endocrine cells. These findings imply that MafA should be used to enhance maturation, rather than specification, of beta-cells from stem/progenitor cells.
Insights
The transcription factor MafA is crucial for pancreatic beta-cell maturation, not specification. Overexpression in developing pancreatic progenitors hinders development and endocrine cell differentiation, suggesting MafA enhances beta-cell maturation from stem cells.
Area of Science:
- Developmental Biology
- Endocrinology
- Stem Cell Biology
Background:
- MafA (Mafa) is a transcription factor regulating insulin expression in pancreatic beta-cells.
- MafA deficiency leads to age-dependent diabetes, suggesting a role in beta-cell maturation rather than initial specification.
- Ectopic MafA expression has shown potential in inducing insulin-producing cells in other tissues.
Purpose of the Study:
- To investigate the role of MafA in the specification of beta-cells during embryonic pancreatic development.
- To determine if MafA can induce beta-cell specification in Pdx1-expressing pancreatic progenitors.
Main Methods:
- Transgenic mouse models expressing MafA in Pdx1+ pancreatic progenitors.
- Analysis of pancreatic development, progenitor proliferation, and endocrine cell differentiation.
- Assessment of cell cycle inhibitor expression (p27, p57).
Main Results:
- MafA expression in Pdx1+ progenitors reduced pancreatic mass and progenitor proliferation.
- MafA induction of p27 and p57 contributed to decreased proliferation.
- MafA expression inhibited endocrine cell formation, demonstrating it deters pancreatic development and differentiation.
Conclusions:
- MafA is not sufficient to specify insulin+ cells during mouse pancreatic development.
- MafA expression in early pancreatic progenitors negatively impacts pancreatic growth and endocrine cell differentiation.
- MafA's function is best suited for enhancing beta-cell maturation, not specification, from stem/progenitor cells.
