Endocrine Pancreas Development and Dysfunction Through the Lens of Single-Cell RNA-Sequencing

Abstract

A chronic inability to maintain blood glucose homeostasis leads to diabetes, which can damage multiple organs. The pancreatic islets regulate blood glucose levels through the coordinated action of islet cell-secreted hormones, with the insulin released by β-cells playing a crucial role in this process. Diabetes is caused by insufficient insulin secretion due to β-cell loss, or a pancreatic dysfunction. The restoration of a functional β-cell mass might, therefore, offer a cure. To this end, major efforts are underway to generate human β-cells de novo, in vitro, or in vivo. The efficient generation of functional β-cells requires a comprehensive knowledge of pancreas development, including the mechanisms driving cell fate decisions or endocrine cell maturation. Rapid progress in single-cell RNA sequencing (scRNA-Seq) technologies has brought a new dimension to pancreas development research. These methods can capture the transcriptomes of thousands of individual cells, including rare cell types, subtypes, and transient states. With such massive datasets, it is possible to infer the developmental trajectories of cell transitions and gene regulatory pathways. Here, we summarize recent advances in our understanding of endocrine pancreas development and function from scRNA-Seq studies on developing and adult pancreas and human endocrine differentiation models. We also discuss recent scRNA-Seq findings for the pathological pancreas in diabetes, and their implications for better treatment.

Characterization of cell-fate decision landscapes by estimating transcription factor dynamics

“…5C), the dynamic profiles showed that Sox9 was active early on, confirming its role in inducing Neurog3 in the progenitor cord 65 . Additionally, we found Meis2 with an increasing profile towards the end of the β-trajectories; previous studies reported it to be enriched in the second wave of murine fetal α cells 66 , but its specific role in β-cell differentiation remains known. We observed two dynamic waves regarding the human-specific factors (Fig.…”

“…Additionally, we found Meis2 with an increasing profile towards the end of the -trajectories; previous 66 , but its specific role in -cell differentiation remains known. We observed two dynamic waves regarding the human-specific factors (Fig.…”

Heterogeneity of Islet Cells during Embryogenesis and Differentiation

“…The Notch and canonical Wnt pathways are known to block EP specification [52][53][54][55]. Thus, Amotl2 might regulate EP specification upstream of Neurog3 [56]. AMOTL2 knockdown in human ES cell-derived CP cells increases glucagon and decreases insulin expression at the endocrine cell stage [46].…”

Using single‐cell multi‐omics screening of human fetal pancreas to identify novel players in human beta cell development

“… 11 , 13 More detailed information on the use of scRNAseq to provide wider information on pancreas development may be found in a recent review. 32 …”

“…In addition, these studies have provided information on pseudo‐time ordering, which has led to improved understanding of the order in which genes are expressed during pancreatic cell lineage specification 11,13 . More detailed information on the use of scRNAseq to provide wider information on pancreas development may be found in a recent review 32 …”