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

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.