Divergent cell-type specific hypoxia responses in human stem cell-derived and primary islets

The success of stem cell-derived islet (SC-islet) therapy for type 1 diabetes is limited by poor graft survival in the hypoxic post-transplantation microenvironment. While the response of SC-islets to chronic hypoxia has been studied, a direct comparison to primary human islets during the acute hypoxic phase has not been performed. Here, we conduct a comparative single-cell transcriptomic and functional analysis of human SC-islets and primary islets exposed to acute hypoxia (1% O₂) over 48 h. Our analysis reveals two divergent response patterns. Primary islets exhibit an energy-conserving response, suppressing β-cell identity genes (PDX1, MAFA) and pro-apoptotic factors like DDIT3, while shifting toward metabolic quiescence. In contrast, the SC-islet response is characterized by lineage instability, a significant metabolic shift toward glycolysis, and the activation of pro-apoptotic pathways. Functionally, these transcriptomic differences result in a loss of glucose-stimulated insulin secretion in both islet types, but through different mechanisms: a suppression of secretion in primary islets versus dysregulated, glucose-unresponsive insulin release in SC-islets. These findings demonstrate that SC-islets are particularly vulnerable under hypoxic stress, exhibiting an unstable, plastic phenotype. This comparative dataset provides a resource for developing source-specific therapeutic interventions to overcome the hypoxic barrier and improve the efficacy of cell replacement therapies.