Loss of the transcription factor MAFB limits β-cell derivation from human PSCs

Next generation sequencing studies have highlighted discrepancies in β-cells which exist between mice and men. Numerous reports have identified MAF BZIP Transcription Factor B (MAFB) to be present in human β-cells postnatally, while its expression is restricted to embryonic and neo-natal β-cells in...

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Bibliographic Details
Published in:	Nature communications Vol. 11; no. 1; p. 2742
Main Authors:	Russell, Ronan, Carnese, Phichitpol P., Hennings, Thomas G., Walker, Emily M., Russ, Holger A., Liu, Jennifer S., Giacometti, Simone, Stein, Roland, Hebrok, Matthias
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 02-06-2020 Nature Publishing Group Nature Portfolio
Subjects:	13/100 13/31 14 38 38/91 59 631/136 631/337/4041 631/532/1360 631/80 Animals Beta cells Cell Differentiation Cell fate CRISPR CRISPR-Cas Systems Differentiation (biology) Female Gene Editing Gene Expression Regulation, Developmental Gene Knockdown Techniques Genetic modification Genome editing Glucagon Glucagon - metabolism Glucagon-Secreting Cells - metabolism Humanities and Social Sciences Humans Insulin Insulin - metabolism Insulin-Secreting Cells - metabolism Islets of Langerhans - metabolism MafB Transcription Factor - genetics MafB Transcription Factor - metabolism Male Mice multidisciplinary Next-generation sequencing Pancreatic Stellate Cells - metabolism Polypeptides Science Science (multidisciplinary) Somatostatin Specifications Stem Cells Transcription factors Transcriptome
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Summary:	Next generation sequencing studies have highlighted discrepancies in β-cells which exist between mice and men. Numerous reports have identified MAF BZIP Transcription Factor B (MAFB) to be present in human β-cells postnatally, while its expression is restricted to embryonic and neo-natal β-cells in mice. Using CRISPR/Cas9-mediated gene editing, coupled with endocrine cell differentiation strategies, we dissect the contribution of MAFB to β-cell development and function specifically in humans. Here we report that MAFB knockout hPSCs have normal pancreatic differentiation capacity up to the progenitor stage, but favor somatostatin- and pancreatic polypeptide–positive cells at the expense of insulin- and glucagon-producing cells during endocrine cell development. Our results describe a requirement for MAFB late in the human pancreatic developmental program and identify it as a distinguishing transcription factor within islet cell subtype specification. We propose that hPSCs represent a powerful tool to model human pancreatic endocrine development and associated disease pathophysiology. The MAF bZIP transcription factor B (MAFB) is present in postnatal human beta cells but its role is unclear. Here, the authors show that MAFB regulates endocrine pancreatic cell fate specification.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-020-16550-9