Diabetes Metab J.  2023 Mar;47(2):173-184. 10.4093/dmj.2022.0324.

Heterogeneity of Islet Cells during Embryogenesis and Differentiation

• Sasaki S
• Miyatsuka T

• KMID: 2540514
• DOI: http://doi.org/10.4093/dmj.2022.0324

Abstract

Diabetes is caused by insufficient insulin secretion due to β-cell dysfunction and/or β-cell loss. Therefore, the restoration of functional β-cells by the induction of β-cell differentiation from embryonic stem (ES) and induced-pluripotent stem (iPS) cells, or from somatic non-β-cells, may be a promising curative therapy. To establish an efficient and feasible method for generating functional insulin-producing cells, comprehensive knowledge of pancreas development and β-cell differentiation, including the mechanisms driving cell fate decisions and endocrine cell maturation is crucial. Recent advances in single-cell RNA sequencing (scRNA-seq) technologies have opened a new era in pancreas development and diabetes research, leading to clarification of the detailed transcriptomes of individual insulin-producing cells. Such extensive high-resolution data enables the inference of developmental trajectories during cell transitions and gene regulatory networks. Additionally, advancements in stem cell research have not only enabled their immediate clinical application, but also has made it possible to observe the genetic dynamics of human cell development and maturation in a dish. In this review, we provide an overview of the heterogeneity of islet cells during embryogenesis and differentiation as demonstrated by scRNA-seq studies on the developing and adult pancreata, with implications for the future application of regenerative medicine for diabetes.

Keyword

Cell differentiation; Diabetes mellitus; Embryonic development; Endocrine cells; Regenerative medicine; Single-cell gene expression analysis; Stem cell research

Figure

• 

  Fig. 1. Heterogeneous properties of pancreatic cells during development. Cell-type transitions during pancreas development in mice that have been clarified by single-cell transcriptome analyses are shown. Cell-specific markers are listed near the cell type. The black arrow indicates the developmental trajectory. CP, common progenitors; EP, endocrine progenitors. Pdx1, pancreatic and duodenal homeobox 1; Sox9, SRY-box transcription factor 9; Foxa2, forkhead box protein A2; Nr2f2, nuclear receptor subfamily 2 group F member 2; Ptf1a, pancreas associated transcription factor 1A; Cpa1, carboxypeptidase A1; Nkx6.1, NK6 homeobox 1; Dcdc2a, doublecortin domain containing 2a; Gcg, glucagon; Mafb, MAF bZIP transcription factor B; Pou3f4, POU class 3 homeobox 4; Rbpjl, recombination signal binding protein for immunoglobulin kappa J region like; Amy1, amylase 1, salivary; Atf3, activating transcription factor 3; Klf5, KLF transcription factor 5; Nr1h4, nuclear receptor subfamily 1 group H member 4; Hnf1b, HNF1 homeobox B; Atoh8, atonal bHLH transcription factor 8; Rfx6, regulatory factor X6; Neurog3, neurogenin 3; Prdx2, peroxiredoxin 2; Neurod2, neurogenic differentiation 2; Vim, vimentin; Isl1, ISL LIM homeobox 1; Chga, chromogranin A; Glis3, GLIS family zinc finger 3; Meis2, Meis homeobox 2; Mnx1, motor neuron and pancreas homeobox 1; Irx2, iroquois homeobox 2; Ins, insulin; Mlxipl, MLX interacting protein like; Ucn3, urocortin 3; Sst, somatostatin; Hhex, hematopoietically expressed homeobox; Ghrl, ghrelin and obestatin prepropeptide; PP, pancreatic polypeptide.

• 

  Fig. 2. Heterogeneity of newly generated β-cells surrounded by a heterogenous spatial environment. (A) Proposed model of β-cell genesis. Endocrine progenitors differentiate into two types of β-cells; newborn β-cells near the ductal regions (βduct) and newborn β-cells adjacent to blood vessels (βvessel) cells. The βduct cells are observed in the ductal region where neurogenin 3 (Neurog3)-expressing endocrine progenitors emerge. In contrast, a subpopulation of endocrine progenitors migrates away from the ductal area toward the region near the blood vessels, and differentiate into βvessel cells. (B) Cell-type transitions in mouse β-cell development are shown. Cell-specific markers are listed near the cell type. The black arrows indicate the developmental trajectory. MafA, MAF bZIP transcription factor A; Sst, somatostatin; Gcg, glucagon; MafB, MAF bZIP transcription factor B; Nnat, neuronatin; Iapp, islet amyloid polypeptide; G6pc2, glucose-6-phosphatase catalytic subunit 2; Slc2a2, solute carrier family 2 member 2.

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