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

ABSTRACT: Medial ganglionic eminence-derived inhibitory GABAergic pallial interneurons (MGE-pINs) are essential for cortical development and function. Dysfunction in MGE-pINs is associated with numerous neurological disorders. We developed a human MGE-pIN cell therapy candidate from pluripotent stem cells, which is undergoing clinical trial evaluation for drug-resistant epilepsy (NCT05135091). Here, we performed single nuclei RNA sequencing and analyzed the transcriptomes of xenografted hMGE-pINs over the lifespan of host mice. Comparative transcriptomic analyses with published human brain datasets revealed that over 97% of grafted human cells developed into pallial MGE-derived somatostatin (SST) and parvalbumin (PVALB) subtypes, including populations that exhibit selective vulnerability in Alzheimer’s disease. Transplanted hMGE-pINs progressed through distinct transcriptional states sequentially involving neuronal migration, synapse organization, and the maturation of electrophysiological properties, demonstrating a surprisingly rapid emergence of subclass-specific features within weeks after grafting. We present molecular, electrophysiological, and morphological data that collectively confirm the derivation of diverse bona-fide human SST and PVALB subtypes, providing a high-fidelity model to study human MGE-pIN development and functional maturation in both healthy and diseased states as well as a compositional atlas for regenerative cell therapy applications.

ORGANISM(S): Homo sapiens

PROVIDER: GSE283775 | GEO | 2025/07/07

REPOSITORIES: GEO

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

Project description:Medial ganglionic eminence-derived inhibitory GABAergic pallial interneurons (MGE-pINs) are essential for cortical development and function. Dysfunction in MGE-pINs is associated with numerous neurological disorders. We developed a human MGE-pIN cell therapy candidate from pluripotent stem cells, which is undergoing clinical trial evaluation for drug-resistant epilepsy (NCT05135091). Here, we performed single nuclei RNA sequencing and analyzed the transcriptomes of xenografted hMGE-pINs over the lifespan of host mice. Comparative transcriptomic analyses with published human brain datasets revealed that over 97% of grafted human cells developed into pallial MGE-derived somatostatin (SST) and parvalbumin (PVALB) subtypes, including populations that exhibit selective vulnerability in Alzheimer’s disease. Transplanted hMGE-pINs progressed through distinct transcriptional states sequentially involving neuronal migration, synapse organization, and the maturation of electrophysiological properties, demonstrating a surprisingly rapid emergence of subclass-specific features within weeks after grafting. We present molecular, electrophysiological, and morphological data that collectively confirm the derivation of diverse bona-fide human SST and PVALB subtypes, providing a high-fidelity model to study human MGE-pIN development and functional maturation in both healthy and diseased states as well as a compositional atlas for regenerative cell therapy applications.

2025-07-07 | GSE283776 | GEO

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Project description:The generation of neuronal subtypes in the mammalian central nervous system is driven by competing genetic programs. The medial ganglionic eminence (MGE) gives rise to two major cortical interneuron (cIN) populations, marked by Somatostatin (Sst) and Parvalbumin (Pvalb), which develop on different timelines. The extent to which external signals influence these identities remains poorly understood. Pvalb-positive cINs are particularly important for regulating cortical circuits through strong perisomatic inhibition, yet they have been difficult to model in vitro. Here we investigated the role of the environment in shaping and maintaining Pvalb cINs. We grafted mouse MGE progenitors into a variety of 2D and 3D coculture models, including mouse and human cortical, MGE, and thalamic systems with dissociated cells, organoids, organotypic cultures, and conditioned media. Across models, we observed distinct proportions of Sst- and Pvalb-positive cIN descendants. Strikingly, grafting MGE progenitors into 3D human, but not mouse, corticogenesis models led to efficient, non-autonomous differentiation of Pvalb-positive cINs. This differentiation was characterized by upregulation of Pvalb maturation markers, downregulation of Sst-specific markers, and the formation of perineuronal nets. Furthermore, lineage-traced postmitotic Sst-positive cINs, when grafted, also upregulated Pvalb expression. These results reveal an unexpected level of fate plasticity in MGE-derived cINs, demonstrating that their identities can be dynamically shaped by the surrounding environment.

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Sp9 regulates medial ganglionic eminence-derived cortical interneuron development

Project description:In the mammalian cortex, about 60% of GABAergic interneurons, mainly including parvalbumin-expressing (PV+) and somatostatin (SST+) interneurons are generated from the medial ganglionic eminence (MGE) in the subpallium and tangentially migrate to the cortex. Here we analyze the role of the Sp9 transcription factor in regulating the development of MGE-derived cortical interneurons. We show that SP9 is widely expressed in the MGE subventricular zone (SVZ) and in MGE-derived migrating interneurons. By analyzing Sp9 null and conditional mutant mice, we demonstrate that Sp9 promotes MGE progenitor proliferation in the SVZ and is required for the normal patterning of tangential migration and the laminar distribution of MGE-derived cortical GABAergic interneurons. Loss of Sp9 function results in a ~50% reduction of MGE-derived cortical interneurons, an ectopic aggregation of MGE-derived neurons in the embryonic ventral telencephalon, and an increased ratio of SST+/PV+ cortical interneurons. Finally, we provide evidence that Sp9 regulates MGE derived cortical interneuron development through promoting expression of the Lhx6 and Lhx8 transcription factors.

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Transcriptional maintenance of cortical somatostatin interneuron subtype identity during migration

Project description:Cortical interneuron diversity arises from the interplay of intrinsic developmental patterning and local extrinsic cues. While individual genetic programs underlying cardinal cell type identity are established in immature neurons prior to integration into cortical circuits, it remains unclear whether distinct interneuron subtype identities are pre-established, and if so, how their identity is maintained prior to circuit integration. Sox6 is a transcription factor with an established role in the maturation of interneurons derived from the medial ganglionic eminence and cell-type specification in other neuronal and non-neuronal cells. To determine a possible role in maintaining cortical somatostatin-expressing (Sst+) interneuron subtype identity, we conditionally removed Sox6 (Sox6-cKO) in migrating Sst+ interneurons and assessed the effects on their mature identity. In adolescent animals, five of eight molecular Sst+ subtypes were nearly absent in the cortex of Sox6-cKO mice. This reduced subtype diversity was not due to a decrease in the overall number of Sst+ interneurons and cells displayed electrophysiological maturity and expressed genes enriched within the broad class of Sst+ interneurons. Furthermore, we show that at embryonic day 18.5, prior to cortical integration, mature Sst+ cell subtype identity could already be inferred in both control and Sox6-cKO cortices, suggesting that the loss in subtype diversity observed in the mature cortex is due to a disrupted subtype maintenance. Importantly, Sox6 removal at postnatal day 7, after Sst+ interneurons have finished migrating and begun integration into the network, did not disrupt marker expression of Sst+ subtypes in the mature cortex. Therefore, Sox6 is necessary during this migratory phase for maintenance of Sst+ subtypes identity, indicating that subtype maintenance requires active transcriptional programs during migration.

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