Electrophysiological Characterization of Inducible Pluripotent Stem Cell–Derived Human β-Like Cells and an SLC30A8 Disease Model Available to Purchase

Inducible pluripotent stem cell–derived human β-like cells (BLCs) hold promise for both therapy and disease modeling, but their generation remains challenging and their functional analyses beyond transcriptomic and morphological assessments remain limited. Here, we validate an approach using multicellular and single-cell electrophysiological tools to evaluate function of BLCs from pioneer protocols that can be easily adapted to more differentiated BLCs. The multi-electrode arrays (MEAs) measuring the extracellular electrical activity revealed that BLCs, like primary β-cells, are electrically coupled and produce slow potential (SP) signals that are closely linked to insulin secretion. We also used high-resolution single-cell patch clamp measurements to capture the exocytotic properties, and characterize voltage-gated sodium and calcium currents, and found that they were comparable with those in primary β- and EndoC-βH1 cells. The K_ATP channel conductance is greater than in human primary β-cells, which may account for the limited glucose responsiveness observed with MEA. We used MEAs to study the impact of the type 2 diabetes–protective SLC30A8 allele (p.Lys34Serfs50*) and found that BLCs with this allele have stronger electrical coupling activity. Our data suggest that BLCs can be used to evaluate the functional impact of genetic variants on β-cell function and coupling.

• Inducible pluripotent stem cell–derived β-like cells (BLCs) from pioneering protocols are widely used, and functional electrophysiological characterizations of BLCs are needed.

• In this proof-of-concept study we used single-cell and multicellular approaches to identify signal surrogate of BLCs functions and to capture functional differences resulting from a type 2 diabetes–protective SLC30A8 allele.

• We found that BLCs shared electrophysiological features with human β-cells and that a type 2 diabetes–protective SLC30A8 allele improves the BLCs electrical coupling activity.

• Our approach is fully applicable to more recent differentiation protocols and opens the perspective of live monitoring the differentiation quality of BLCs and of using them to determine the functional consequences of diabetes-associated variants.