Autonomous neuronal resilience under metabolic stress highlights fundamental differences between hESC and hiPSC-derived neurons

Human induced pluripotent stem cells (hiPSCs) aim to replicate the developmental and functional capacity of human embryonic stem cells (hESCs). Here, we identify neuronal resilience under metabolic stress as a critical parameter for benchmarking equivalence. Without medium replenishment, hESC-derived cortical neurons underwent neural resurrection —a spontaneous recovery marked by increased cell density, preserved morphology, and sustained calcium signaling and mitochondrial function for 23 days. In contrast, hiPSC-derived neurons survived but showed reduced adaptability, deteriorating within 10–14 days despite higher initial densities. Our findings introduce a physiologically relevant assay for stress resilience and highlight the need to optimize hiPSC differentiation to achieve hESC-like performance, improving their translational value for disease modeling and regenerative therapy.