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An Instructive Neural Interface for Layer-Specific Cortical Repair with Human Brain Organoids

ABSTRACT: Repairing precise neural microcircuitry after cortical injury remains a pivotal challenge. While human brain organoids (hBOs) provide a promising cell source, their therapeutic potential is limited by disorganized integration. Here, we demonstrated that targeted neuromodulation, steered by endogenous narrowband gamma (NBG) rhythms, could instruct the structural and functional integration of hBOs grafts in the injured adult mouse visual cortex. Using a neural interface system, we first promoted general graft-host coupling and then delivered NBG-rhythmic stimulation to specific functional clusters during a critical period of plasticity. This two-phase strategy guided the emergence of layer 4-appropriate molecular and functional properties within the grafts, established bidirectional connectivity with the host visual pathway, and supported the development of advanced visual processing, including direction selectivity in hBOs neurons. Electrophysiologically, graft spiking phase-locked to host NBG oscillations. Our work established a new framework for circuit-level repair, highlighting a synergistic strategy that moves beyond cell replacement to actively direct the assembly of neural grafts.

ORGANISM(S): Homo sapiens

PROVIDER: GSE325024 | GEO | 2026/03/24

REPOSITORIES: GEO

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Project description:Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene, leading to progressive loss of striatal neurons and motor-cognitive decline. While current gene-targeting approaches aiming at reducing somatic instability show promise – especially in case of early treatment – they cannot restore the already compromised neuronal circuitry at advanced disease stages. Thus, cell replacement therapy offers a regenerative strategy to rebuild damaged striatal circuits. Here, we report that human striatal progenitors (hSPs) derived from embryonic stem cells via a morphogen-guided protocol survive long-term when transplanted into a rodent model of HD and recapitulate key aspects of ventral telencephalic development. By employing single-nucleus RNAseq (snRNAseq) of the grafted cells, we resolved their transcriptional profile with unprecedented resolution, identifying transcriptional signals of D1- and D2-type medium spiny neurons, MGE- and CGE-derived interneurons, and regionally specified astrocytes. Moreover, we demonstrate that grafted cells undergo further maturation 6 months post-transplantation (MPT), acquiring the expected regionally defined transcriptional identity. Immunohistochemistry confirmed stable graft composition over time and supported a neurogenic-to-gliogenic switch post-transplantation. A plethora of techniques exploiting virus-based tracing and electrophysiology assays demonstrated anatomical and functional integration of the grafts. Notably, chemogenetic modulation of graft activity regulated striatal-dependent behaviors, further supporting effective graft integration into host basal ganglia circuits. Altogether, these results provide preclinical evidence that hSP-grafts can reconstruct striatal circuits and modulate functionally relevant behaviors. The ability to generate a scalable, molecularly defined progenitor population capable of in vivo functional integration supports the potential of hSPs for clinical application in HD and related basal ganglia disorders.

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An Instructive Neural Interface for Layer-Specific Cortical Repair with Human Brain Organoids

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