Informing β-cell regeneration strategies using studies of heterogeneity

Abstract

Background: Current therapeutic strategies for type 1 (T1DM) and type 2 diabetes mellitus (T2DM) rely on increasing or substituting endogenous insulin secretion in combination with lifestyle changes. β-cell regeneration, a process whereby new β-cells arise from progenitors, self-renewal or transdifferentiation, has the potential to become a viable route to insulin self-sufficiency. Current regeneration strategies capture many of the transcriptomic and protein features of native β-cells, generating cells capable of glucose-dependent insulin secretion in vitro and alleviation of hyperglycemia in vivo. However, whether novel β-cells display appreciable heterogeneity remains poorly understood, with potential consequences for long-term functional robustness.

Scope of review: The review brings together crucial discoveries in the β-cell regeneration field with state-of-the-art knowledge regarding β-cell heterogeneity. Aspects that might aid production of longer-lasting and more plastic regenerated β-cells are highlighted and discussed.

Major conclusions: Different β-cell regeneration approaches result in a similar outcome: glucose-sensitive, insulin-positive cells that mimic the native β-cell phenotype but which lack normal plasticity. The β-cell subpopulations identified to date expand our understanding of β-cell survival, proliferation and function, signposting the direction for future regeneration strategies. Therefore, regenerated β-cells should exhibit stimulus-dependent differences in gene and protein expression, as well as establish a functional network with different β-cells, all while coexisting with other cell types on a three-dimensional platform.

Keywords: Beta cell; Diabetes; Heterogeneity; Regenerative medicine; Stem cell.

Figure 1

Summary of β-cell regeneration strategies. Novel β-cells can be derived through transdifferentiation of human pluripotent stem cells (hPSC) and induced pluripotent stem cells (iPSC), reprogramming of mature, non-endocrine (ductal and gastrointestinal) cell populations, α-to β-cell conversion and β-cell proliferation.

Figure 2

Overview of selected β-cell subpopulations. A combination of technologies and approaches identified β-cell subpopulations based on: differential expression of cell-specific markers, differences in their transcriptomic and protein blueprint and activity patterns. Abbreviations used: Pdx1, pancreatic and duodenal homeobox 1; Ins, insulin; GFP, green fluorescent protein; Ucn3, urocortin-3; Fltp, Flattop/Cfap126; RBP4, Retinol binding protein 4; C1/C2/C3, cell clusters with different protein signatures ; smFISH, single molecule fluorescent in situ hybridisation; RNA-seq, RNA sequencing; Patch-seq, patch sequencing; CyTOF, mass cytometry; UPR, unfolded protein response.

Figure 3

Tweaking regenerated β-cell function. Integration of islet components is essential to maintain β-cell heterogeneity and survival of the regenerated cells. α and δ-cells monitor β-cells and prevent hypersecretion through glucagon, acetylcholine and somatostatin. Stromal cells and the ECM may promote revascularisation and mediate cell-cell communications. Abbreviations used: Ach, Acetylcholine; Ucn3, urocortin-3; ECM, extracellular matrix.