Validating expression of beta cell maturation-associated genes in human pancreas development

Abstract

The identification of genes associated with human pancreatic beta cell maturation could stimulate a better understanding of normal human islet development and function, be informative for improving stem cell-derived islet (SC-islet) differentiation, and facilitate the sorting of more mature beta cells from a pool of differentiated cells. While several candidate factors to mark beta cell maturation have been identified, much of the data supporting these markers come from animal models or differentiated SC-islets. One such marker is Urocortin-3 (UCN3). In this study, we provide evidence that UCN3 is expressed in human fetal islets well before the acquisition of functional maturation. When SC-islets expressing significant levels of UCN3 were generated, the cells did not exhibit glucose-stimulated insulin secretion, indicating that UCN3 expression is not correlated with functional maturation in these cells. We utilized our tissue bank and SC-islet resources to test an array of other candidate maturation-associated genes, and identified CHGB, G6PC2, FAM159B, GLUT1, IAPP and ENTPD3 as markers with expression patterns that correlate developmentally with the onset of functional maturation in human beta cells. We also find that human beta cell expression of ERO1LB, HDAC9, KLF9, and ZNT8 does not change between fetal and adult stages.

Glucose Transporters Are Key Components of the Human Glucostat

“…This SC-islets model provides a readily available source of insulin-producing cells for experimental interrogation, providing a practical way to study the contribution of GLUT1 and GLUT2 to insulin secretion and glucose homeostasis. On the other hand, SC-islets exhibit suboptimal insulin secretion in response to extracellular glucose when compared with adult β-cells, suggesting that they may correspond to a partially mature fetal developmental stage ( 55 , 56 ). Moreover, SC-islets differ from adult islets in both endocrine cell composition and overall architecture, which could impair intercellular interactions and affect overall islet function ( 52 , 57 , 58 ).…”

Cell identity dynamics and insight into insulin secretagogues when employing stem cell-derived islets for disease modeling

“…Cells that express multiple endocrine hormones concurrently, such as insulin and glucagon, are recognized as an immature cell type in the developing pancreas ( Tremmel et al, 2023 ). Cp+/GCG + cells, namely bi-hormonal cells, were frequently reported in previous studies ( Hogrebe et al, 2020 ; Mahaddalkar et al, 2020 ; Balboa et al, 2022 ; Tremmel et al, 2023 ), including in single-cell sequencing analysis among the final products of SC-islets differentiation ( Shiraki and Kume, 2020 ; Wiedenmann et al, 2021 ; van Gurp et al, 2022 ; de la O et al, 2023 ). Somatostatin inhibits the secretion of both insulin and glucagon from the pancreas ( Carril Pardo et al, 2022 ).…”

A Novel Variant Of Regenerating Iα Gene (REG) In Type II Diabetics Among Pakistani Targeted Population

“…1,2 It has been hypothesized that insulin-secreting cells multiply and encourage the production of a variety of progenitor stem cells. Numerous genes and associated transcription factors, including the proteins that can be derived from Reg islets such as, "NeuroD1, Sox 9, Netrin 1, and Neurogenin-3", 3 participate in insulin production. Members of the REG gene family found in humans, have been linked to the neogenesis and regeneration of cells.…”