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Human Neural Stem Cells Differentiate and Integrate, Innervating Implanted zQ175 Huntington's Disease Mouse Striatum

Thompson, L. M.; Holley, S. M.; Reidling, J. C.; Cepeda, C.; Lau, A.; Moore, C.; Orellana, I.; Fury, B.; Kopan, L.; Yeung, S.; Neel, M.; Coleal-Bergum, D.; Monuki, E.; K. Meshul, C.; Bauer, G.; Levine, M. S.

2021-01-19 neuroscience
10.1101/2021.01.18.427078 bioRxiv
Show abstract

Huntingtons disease (HD), a genetic neurodegenerative disorder, primarily impacts the striatum and cortex with progressive loss of medium-sized spiny neurons (MSNs) and pyramidal neurons, disrupting cortico-striatal circuitry. A promising regenerative therapeutic strategy of transplanting human neural stem cells (hNSCs) is challenged by the need for long-term functional integration. We previously described that hNSCs transplanted into the striatum of HD mouse models differentiated into electrophysiologically active immature neurons, improving behavior and biochemical deficits. Here we show that 8-month implantation of hNSCs into the striatum of zQ175 HD mice ameliorates behavioral deficits, increases brain-derived neurotrophic factor (BDNF) and reduces mutant Huntingtin (mHTT) accumulation. Patch clamp recordings, immunohistochemistry and electron microscopy demonstrates that hNSCs differentiate into diverse neuronal populations, including MSN- and interneuron-like cells. Remarkably, hNSCs receive synaptic inputs, innervate host neurons, and improve membrane and synaptic properties. Overall, the findings support hNSC transplantation for further evaluation and clinical development for HD.

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