NKX2.2 regulates endocrine commitment via metabolic regulation of NEUROG3 progenitors [scRNA-seq]

ABSTRACT: In mice and humans, the four major populations of adult pancreatic islet cells are derived from a common Neurogenin3 (NEUROG3)-expressing endocrine progenitor population. In mice, the homeobox transcription factor NKX2.2 is essential for islet cell differentiation and function, although the molecular mechanisms underlying its functions are not completely understood. NKX2.2 is also expressed in the developing human pancreas and individuals carrying homozygous null mutations in NKX2.2 present with neonatal diabetes and have undetectable serum levels of insulin at birth, suggesting a conserved developmental function. To investigate the molecular mechanism of NKX2.2-mediated regulation in early pancreas development, I have generated human embryonic stem cell (hESC) lines carrying a deletion of NKX2.2. Upon differentiation through an established stem cell (sc)-derived isletprotocol, the NKX2.2KO line displays a dramatic decrease in insulin-producing β-cells and the few hormone producing cells that are generated are polyhormonal. Cells that express insulin are distinctly lacking expression of NKX6.1, which has been shown to be necessary for β-cell identity and function. Sustained NEUROG3 expression suggests that NKX2.2 is required for proper exit from the endocrine progenitor stage – a phenotype that is also distinct from what was observed in the Nkx2.2 mutant mice. Global metabolic flux analysis suggests that the NKX2.2KO cells have metabolic defects that impair the appropriate formation of NEUROG3-expressing endocrine progenitor cells. Further, the dysregulated levels of metabolic intermediates

ORGANISM(S): Homo sapiens

PROVIDER: GSE308822 | GEO | 2026/09/23

REPOSITORIES: GEO