Transplanted human neural stem cells rescue phenotypes in zQ175 Huntington’s disease mice and innervate the striatum.

Huntington’s disease (HD) is a genetic neurodegenerative disorder that impacts specific regions of the brain, primarily the striatum and cortex, with progressive dysfunction and loss of neurons, thereby disrupting necessary circuitry and cellular communication. A promising regenerative therapeutic strategy of transplanting human neural stem cells (hNSCs) into patient brains is challenged by the need for long-term functional integration. We previously described that upon short-term hNSC transplantation into the brains of HD modeled mice, human cells were able to develop from these precursor cells into active immature neurons, improving behavior and pathological deficits. In a new publication, we show that long-term (8 months) implantation of hNSCs into the brains of a long-lived HD mouse also ameliorates behavioral deficits, increases beneficial brain-derived trophic factor levels and reduces the aberrant accumulation of the protein responsible for HD, mutant Huntingtin (mHTT). Multiple analytical methods demonstrate that the transplanted hNSCs differentiate into diverse neuronal populations and form new connections with each other and with the host mouse brain cells. Investigation of single cell gene expression levels shows restoration of several mHTT-mediated changes in the HD mouse brain cells. Remarkably, engrafted cells receive synaptic inputs (connections), stimulate host neurons, and improve specific neuron properties. Overall, the findings support hNSC transplantation for further evaluation and clinical development for HD.