Pancreas is a combined endocrine and exocrine gland that ...

Pancreas is a combined endocrine and exocrine gland that develops from an outgrowth of the primitive foregut and is closely associated with the upper duodenum. During development, cells of exocrine and endocrine pancreas are both derived from the pancreatic duct epithelium. The endocrine pancreas is composed of the islets of Langerhans that are built of several endocrine cell types: alpha cells (secrete glucagon), beta cells (secrete insulin and amylin), gamma cells (also known as PP or F cells, secrete pancreatic polypeptide), delta cells (secrete somatostatin), and epsilon cells (secrete ghrelin). Alpha, beta and delta cells are the most numerous. In humans, the islets of Langerhans possess the so-called double basement membrane, as both islet cells and islet blood vessels have basal lamina. The vascular-specific basement membrane and the parenchymal basement membrane are distinct from each other and create a microenvironmental niche optimal for beta cell function (Otonkoski et al. 2008). The endocrine pancreas comprises less than 5% of the pancreas mass, with islets of Langerhans dispersed within the exocrine pancreas tissue. For overview, please refer to Liggitt and Dintzis; "Pancreas"; Comparative Anatomy and Histology; a Mouse, Rat, and Human Atlas; edited by Treuting, Dintzis, and Montine, Elsevier Inc., 2018, 241-250. For review, please refer to Tritschler et al. 2017.

Single cell analysis of trunk bipotent pancreatic progenitors derived from human embryonic stem cells reveals that cell confinement is a prerequisite for endocrine specification (Mamidi et al. 2018). Trunk bipotent pancreatic progenitors give rise to ductal and endocrine lineages (reviewed in Shih et al. 2013; Jennings et al. 2015). Single cell analysis shows that cell spreading, which is associated with extracellular matrix (ECM)-integrin alpha 5 (ITGA5) signaling through the F-actin-YAP1-NOTCH mechanosignaling axis, drives trunk progenitors towards the ductal fate, while confinement, which disrupts ECM-ITGA5 signaling, thereby silencing the YAP1-NOTCH axis, drives them towards the endocrine fate (Mamidi et al. 2018).

Neurogenin-3 (NEUROG3, also known as NGN3) is the essential pro-endocrine transcription factor, that promotes endocrine specification of trunk progenitors (Apelqvist et al. 1999; Gradwohl et al. 2000; McGrath et al. 2015; Krentz et al. 2017).

The developmental lineage of pancreatic endocrine mid progenitor cells describes the sequential transition from bipotent trunk progenitors through early endocrine stages to a committed mid-progenitor state capable of generating all pancreatic endocrine lineages. The lineage originates from pancreatic bipotent trunk progenitors, which are characterized by the expression of FOXA2, NKX6-1, PDX1, SOX9, and YAP1 (Jennings et al. 2013, Mamidi et al. 2018). A critical event in the commitment to the endocrine fate is the downregulation of YAP1, which acts as a repressor of pancreatic endocrinogenesis (Mamidi et al. 2018). As bipotent trunk progenitors of pancreas transition into early endocrine progenitors (also categorized as stages EP1 and EP2), they initiate the expression of NEUROG3, although initial mRNA levels remain low (Mamidi et al. 2018; Ma et al. 2023). As differentiation advances, early endocrine progenitors progress to become mid endocrine progenitors (also known as EP3 or endocrine precursors) (Yu et al. 2021; Ma et al. 2023). This transition is marked by a significant increase in NEUROG3 expression and a concomitant attenuation of progenitor state markers, specifically SOX9, ONECUT1, FOXA2, and PDX1 (Yu et al. 2021; Ma et al. 2023; Traba et al. 2025). The progression along this lineage is tightly regulated by mechanosignalling and extracellular factors. Positive regulation is provided by extracellular matrix proteins laminin and collagen, which promote endocrine commitment by inhibiting cell spreading. Negative regulation is attributed to extracellular matrix proteins fibronectin (FN1) and vitronectin (VTN), which inhibit endocrine commitment through integrin alpha5beta1 (ITGA5:ITGB1) signaling (Mamidi et al. 2018). Additionally, Epidermal Growth Factor (EGF) inhibits endocrine differentiation, as blocking EGFR signaling has been shown to increase NEUROG3 expression (Juksar et al. 2025). The pancreatic endocrine mid progenitor (EP3) represents a more advanced precursor state that retains the multipotency required to give rise to all five endocrine cell types found in the islets of Langerhans: alpha, beta, delta, gamma (PP), and epsilon cells (Yu et al. 2021; Ma et al. 2023).