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

Hypoxia during the early post-transplant 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_survival metric 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 non-viable 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.