Endocrine-enriched stem cell-derived islets improve long-term safety in vivo

Fully differentiated stem cell-derived islets (SC-islets) are proven to normalise blood glucose in type 1 diabetic patients. However, the presence of off-target cell types and the immature SC-islet function upon transplantation remain unresolved problems. Here, we established sorting strategies to generate SC-islets with defined glucagon-producing SC-α- and insulin-producing β-cell ratios and assessed their safety and efficacy in vitro and in vivo . Engineering SC-islets is beneficial to the insulin response in vitro , which does not translate to improved glycaemic regulation in vivo . Importantly, hormone-producing endocrine cell enrichment and thus off-target cell type depletion eliminated the risk for unwanted outgrowth in vivo . Single cell analysis defined off-target cells in vitro and in vivo and identified marker genes to assess SC-islet quality and define safety release criteria before graft transplantation. This study highlights the importance of determining the SC-islet composition and establishing rigorous quality controls to ensure long-term safety for β-cell replacement therapy.