Human stem cell-derived GABAergic interneuron development reveals early emergence of subtype diversity followed by gradual electrochemical maturation

SUMMARY

Medial ganglionic eminence-derived inhibitory GABAergic pallial interneurons (MGE-pINs) are essential regulators of cortical circuits; their dysfunction is associated with numerous neurological disorders. We developed human (h) MGE-pINs from pluripotent stem cells for the treatment of drug-resistant epilepsy. Here, we analyzed xenografted hMGE-pINs over the lifespan of host mice using single nuclei RNA sequencing. Comparative transcriptomics against endogenous human brain datasets revealed that 97% of grafted cells developed into somatostatin (SST) and parvalbumin (PVALB) subtypes, including populations that exhibit selective vulnerability in Alzheimer’s disease. Transplanted hMGE-pINs demonstrated rapid emergence of subclass features, progressing through distinct transcriptional states sequentially involving neuronal migration, synapse organization, and membrane maturation. We present molecular, electrophysiological, and morphological data that collectively confirm the derivation of diverse bona-fidehuman SST and PVALB subtypes, providing a high-fidelity model to study human MGE-pIN development and functional maturation as well as a compositional atlas for regenerative cell therapy applications.