Transplanted human striatal progenitors exhibit functional integration and modulate host circuitry in a Huntington’s disease animal model

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.