Huntington’s disease cellular phenotypes are rescued non-cell autonomously by healthy cells in mosaic telencephalic organoids

Maura Galimberti, Maria R. Nucera, Vittoria D. Bocchi, Paola Conforti, Elena Vezzoli, Matteo Cereda, Camilla Maffezzini, Raffaele Iennaco, Andrea Scolz, Andrea Falqui, Chiara Cordiglieri, Martina Cremona, Ira Espuny-Camacho, Andrea Faedo, Dan P. Felsenfeld, Thomas F. Vogt, Valeria Ranzani, Chiara Zuccato, Dario Besusso and Elena Cattaneo ()
Additional contact information
Maura Galimberti: University of Milan
Maria R. Nucera: University of Milan
Vittoria D. Bocchi: University of Milan
Paola Conforti: University of Milan
Elena Vezzoli: University of Milan
Matteo Cereda: University of Milan
Camilla Maffezzini: University of Milan
Raffaele Iennaco: University of Milan
Andrea Scolz: University of Milan
Andrea Falqui: University of Milan
Chiara Cordiglieri: Istituto Nazionale Genetica Molecolare “Romeo ed Enrica Invernizzi”
Martina Cremona: University of Milan
Ira Espuny-Camacho: University of Milan
Andrea Faedo: University of Milan
Dan P. Felsenfeld: CHDI Management/CHDI Foundation
Thomas F. Vogt: CHDI Management/CHDI Foundation
Valeria Ranzani: Istituto Nazionale Genetica Molecolare “Romeo ed Enrica Invernizzi”
Chiara Zuccato: University of Milan
Dario Besusso: University of Milan
Elena Cattaneo: University of Milan

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Huntington’s disease (HD) causes selective degeneration of striatal and cortical neurons, resulting in cell mosaicism of coexisting still functional and dysfunctional cells. The impact of non-cell autonomous mechanisms between these cellular states is poorly understood. Here we generated telencephalic organoids with healthy or HD cells, grown separately or as mosaics of the two genotypes. Single-cell RNA sequencing revealed neurodevelopmental abnormalities in the ventral fate acquisition of HD organoids, confirmed by cytoarchitectural and transcriptional defects leading to fewer GABAergic neurons, while dorsal populations showed milder phenotypes mainly in maturation trajectory. Healthy cells in mosaic organoids restored HD cell identity, trajectories, synaptic density, and communication pathways upon cell-cell contact, while showing no significant alterations when grown with HD cells. These findings highlight cell-type-specific alterations in HD and beneficial non-cell autonomous effects of healthy cells, emphasizing the therapeutic potential of modulating cell-cell communication in disease progression and treatment.

Date: 2024
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DOI: 10.1038/s41467-024-50877-x

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