Enhanced hypoxia resistance distinguishes human pluripotent stem cell-derived islets from primary islets.

Hypoxia during the early posttransplant period represents a major barrier to successful cellular transplantation. This limitation is particularly relevant for pancreatic islet transplantation, a clinical treatment option for diabetes. Stem cell-derived islets are an emerging potential alternative to current primary islets obtained from deceased donors. Although stem cell-derived cells are generally assumed to be more hypoxia-tolerant than primary cells, direct quantitative evidence supporting this assumption has been limited, particularly in comparisons between stem cell-derived islets and primary islets. Here, we applied a recently developed Po2__survivalmetric to objectively compare hypoxia resistance between human primary adult islets and human-induced pluripotent stem cell-derived islet spheroids. Using controlled hypoxic culture, live/dead imaging, and computational oxygen modeling, we quantified the Po2_survival as a local oxygen tension at the boundary between viable and nonviable regions within three-dimensional islet constructs. Po2_survival of stem cell-derived islets was significantly lower than that of primary islets (0.01 mmHg vs. 2.24 mmHg; P < 0.0001), quantitatively demonstrating enhanced hypoxia resistance of stem cell-derived islet cells. Computational analyses integrating intraspheroidal oxygen distributions and hypoxia resistance further demonstrated improved estimated survival of stem cell-derived islets under large spheroid and hypoxic conditions. Together, these findings provide quantitative evidence that stem cell-derived islets possess enhanced hypoxia resistance compared with primary human islets. This property may expand feasible transplantation sites and reduce early graft loss in stem cell-derived islet therapies.NEW & NOTEWORTHY This study provides the first quantitative evidence that human stem cell-derived islets are more resistant to hypoxia than primary human islets. Stem cell-derived islets maintain viability at substantially lower oxygen levels and exhibit markedly reduced variability in hypoxia tolerance. These findings identify hypoxia resistance as a key functional advantage of stem cell-derived islets, with important implications for transplantation into low-oxygen environments and for scalable islet fabrication strategies.