Differentiation of pancreatic endocrine progenitors reversibly blocked by premature induction of MafA

• Published in: Developmental biology Vol. 385; no. 1; pp. 2 - 12
• Main Authors: Hu He, KaiHui, Juhl, Kirstine, Karadimos, Michael, El Khattabi, Ilham, Fitzpatrick, Connor, Bonner-Weir, Susan, Sharma, Arun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-01-2014
• Subjects: Animals; Basic Helix-Loop-Helix Transcription Factors - genetics; Cell Differentiation - genetics; Differentiation of endocrine progenitors; Endocrine Cells - cytology; Endocrine Cells - metabolism; Gene Expression Regulation, Developmental; Insulin - biosynthesis; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - metabolism; Maf Transcription Factors, Large - biosynthesis; Maf Transcription Factors, Large - genetics; Maf Transcription Factors, Large - metabolism; MafB Transcription Factor - biosynthesis; MafB Transcription Factor - genetics; MafB Transcription Factor - metabolism; Mice; Mice, Transgenic; Nerve Tissue Proteins - genetics; Pancreas - cytology; Pancreas - metabolism; Stem Cells - metabolism; Transcription factor MafA; β-Cell maturation; Transcription factor MafA; Differentiation of endocrine progenitors; β-Cell maturation
• DOI: 10.1016/j.ydbio.2013.10.024
• EISSN: 1095-564X
• ISSN: 0012-1606

Specification and maturation of insulin+ cells accompanies a transition in expression of Maf family of transcription factors. In development, MafA is expressed after specification of insulin+ cells that are expressing another Maf factor, MafB; after birth, these insulin+ MafA+ cells stop MafB expression and gain glucose responsiveness. Current differentiation protocols for deriving insulin-producing β-cells from stem cells result in β-cells lacking both MafA expression and glucose-stimulated insulin secretion. So driving expression of MafA, a β-cell maturation factor in endocrine precursors could potentially generate glucose-responsive MafA+ β cells. Using inducible transgenic mice, we characterized the final stages of β-cell differentiation and maturation with MafA pause/release experiments. We found that forcing MafA transgene expression, out of its normal developmental context, in Ngn3+ endocrine progenitors blocked endocrine differentiation and prevented the formation of hormone+ cells. However, this arrest was reversible such that with stopping the transgene expression, the cells resumed their differentiation to hormone+ cells, including α-cells, indicating that the block likely occurred after progenitors had committed to a specific hormonal fate. Interestingly, this delayed resumption of endocrine differentiation resulted in a greater proportion of immature insulin+MafB+ cells at P5, demonstrating that during maturation the inhibition of MafB in β-cell transitioning from insulin+MafB+ to insulin+MafB− stage is regulated by cell-autonomous mechanisms. These results demonstrate the importance of proper context of initiating MafA expression on the endocrine differentiation and suggest that generating mature Insulin+MafA+ β-cells will require the induction of MafA in a narrow temporal window to achieve normal endocrine differentiation.
•Enforced expression of MafA in endocrine progenitors inhibits their differentiation.•MafA blocks differentiation after progenitors commit to a specific hormonal fate.•Stopping MafA expression relieves the block and cells resume their differentiation.•Cell‐autonomous mechanisms regulate the loss of MafB in maturing insulin+ cells.