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

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 telencephal...

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Bibliographic Details
Published in:	Nature communications Vol. 15; no. 1; pp. 6534 - 19
Main Authors:	Galimberti, Maura, Nucera, Maria R., Bocchi, Vittoria D., Conforti, Paola, Vezzoli, Elena, Cereda, Matteo, Maffezzini, Camilla, Iennaco, Raffaele, Scolz, Andrea, Falqui, Andrea, Cordiglieri, Chiara, Cremona, Martina, Espuny-Camacho, Ira, Faedo, Andrea, Felsenfeld, Dan P., Vogt, Thomas F., Ranzani, Valeria, Zuccato, Chiara, Besusso, Dario, Cattaneo, Elena
Format:	Journal Article Web Resource
Language:	English
Published:	London Nature Publishing Group UK 02-08-2024 Nature Publishing Group Nature Research Nature Portfolio
Subjects:	13 13/100 13/106 13/51 14 14/19 38 38/77 38/91 631/378/1689/1558 631/378/87 631/532/1360 Abnormalities Animals Biochemistry, biophysics & molecular biology Biochemistry, Genetics and Molecular Biology (all) Biochimie, biophysique & biologie moléculaire Cell adhesion Cell Communication Cell interactions Communication Degeneration GABAergic Neurons GABAergic Neurons - metabolism GABAergic Neurons - pathology Gene sequencing Genotypes Humanities and Social Sciences Humans Huntington Disease Huntington Disease - genetics Huntington Disease - metabolism Huntington Disease - pathology Huntington's disease Huntingtons disease Life sciences Mice Mosaicism Mosaics multidisciplinary Neostriatum Neurodevelopmental disorders Neurons Neurons - metabolism Neurons - pathology Organoids Organoids - metabolism Organoids - pathology Phenotype Phenotypes Science Science (multidisciplinary) Sciences du vivant Single-Cell Analysis Synaptic density Telencephalon Telencephalon - cytology Telencephalon - metabolism Telencephalon - pathology γ-Aminobutyric acid
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Summary:	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. Mosaic organoids where pathological and healthy cells are grown together, reveal the rescue of phenotypes in pathological cells due to communication with healthy cells without harming them, as demonstrated by single-cell RNA-sequencing data.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 scopus-id:2-s2.0-85200257677
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-024-50877-x