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

• Published in: Nature communications 2020-06, Vol.11 (1), p.2742-2742, Article 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: Article
• Language: English
• 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
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-16550-9

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.