As pancreatic bipotent trunk progenitors derived from hum...

As pancreatic bipotent trunk progenitors derived from human embryonic stem cells (hESCs) are grown in culture, confined cells in the central region of cell aggregates, which are representative of pancreatic endocrine progenitors, maintain high PDX1 and NKX6-1 (NKX6.1) protein expression, while spread-out cells at the periphery of cell aggregates, which are committing to the ductal lineage, downregulate PDX1 and NKX6-1 expression (Mamidi et al. 2018). The expression of SOX9, FOXA2 and ONECUT1 (HNF6) is maintained in central and peripheral populations (Mamidi et al. 2018). While pancreatic bipotent trunk progenitors are YAP1 positive and express high levels of PDX1, ductal cells derived from them maintain YAP1 expression and downregulate PDX1, while endocrine progenitors begin to express NEUROG3 (NGN3), but stop expressing YAP1 (Mamidi et al. 2018). YAP1 plays an evolutionarily conserved role as a repressor of pancreatic endocrinogenesis, maintaining pancreatic bipotent trunk progenitors and inhibiting their commitment to the endocrine lineage (Mamidi et al. 2018). Extracellular matrix (ECM) proteins laminin and collagen inhibit cell spreading and promote endocrine commitment of pancreatic bipotent trunk progenitors while fibronectin (FN1) and vitronectin (VTN), through ITGA5:ITGB1 (integrin alpha5beta1) signaling, promote spreading and inhibit endocrine commitment (Mamidi et al. 2018). A single cell RNA-seq (scRNA-seq) study of developing human fetal pancreas confirms that NEUROG3, NKX6-1, ONECUT1, and SOX9 are differentially expressed at the mRNA level in early endocrine progenitors, with levels of NEUROG3 and NKX6-1 mRNAs being low compared to mid endocrine progenitors, which would correspond to endocrine precursors (Ma et al. 2023). ID3 is also identified as an RNA marker of early pancreatic endocrine progenitors in this study (Ma et al. 2023). PDX1 and FOXA2 are not identified as RNA markers of early pancreatic endocrine progenitors in this study, although FOXA2 transcriptional targets are upregulated (Ma et al. 2023).

For a more detailed description of pancreatic bipotent progenitors, please refer to the cell development step “Primary multipotent pancreatic progenitor cell produces trunk bipotent pancreatic progenitor cell”.

Markers of human early pancreatic endocrine progenitors are shown in the table below. Only markers reported in at least two studies have been included.

While the study by Yu et al. 2021 does not identify FOXA2, NEUROG3, NKX6-1, ONECUT1, PDX1, and SOX9 as differentially expressed marker genes of early pancreatic progenitors, it list NEUROG3 as a gene upregulated, and ONECUT1 and SOX9 as genes downregulated during differentiation of both mouse and human pancreatic endocrine progenitors.