[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Galimberti, Maura; Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases, Department of Biosciences, University of Milan, 20122, Milan, Italy ; INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy
Nucera, Maria R ; Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases, Department of Biosciences, University of Milan, 20122, Milan, Italy ; INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy ; Stem Cell Biology Department, Murdoch Children's Research Institute, Parkville, VIC, 3052, Australia
Bocchi, Vittoria D; Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases, Department of Biosciences, University of Milan, 20122, Milan, Italy ; INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy ; Center for Stem Cell Biology and Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
Conforti, Paola; Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases, Department of Biosciences, University of Milan, 20122, Milan, Italy ; INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy
Vezzoli, Elena; Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases, Department of Biosciences, University of Milan, 20122, Milan, Italy ; INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy ; ALEMBIC Advanced Light and Electron Microscopy BioImaging Center, San Raffaele Scientific Institute, DIBIT 1, Via Olgettina 58, 20132, Milan, Italy
Cereda, Matteo ; Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases, Department of Biosciences, University of Milan, 20122, Milan, Italy ; INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy
Maffezzini, Camilla ; Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases, Department of Biosciences, University of Milan, 20122, Milan, Italy ; INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy
Iennaco, Raffaele; Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases, Department of Biosciences, University of Milan, 20122, Milan, Italy ; INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy
Scolz, Andrea; Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases, Department of Biosciences, University of Milan, 20122, Milan, Italy ; INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy
Falqui, Andrea ; Department of Physics "Aldo Pontremoli", University of Milan, Via Celoria 16, 20133, Milan, Italy
Cordiglieri, Chiara ; INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy
Cremona, Martina; Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases, Department of Biosciences, University of Milan, 20122, Milan, Italy ; INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy ; Swiss Stem Cell Foundation, Via Petrini 2, 6900, Lugano, Switzerland
Espuny Camacho, Ira Mercedes ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques ; Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases, Department of Biosciences, University of Milan, 20122, Milan, Italy ; INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy
Faedo, Andrea; Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases, Department of Biosciences, University of Milan, 20122, Milan, Italy ; INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy ; Axxam, OpenZone, Via Meucci 3, 20091, Bresso, Milan, Italy
Felsenfeld, Dan P; CHDI Management/CHDI Foundation, New York, NY, USA
Vogt, Thomas F; CHDI Management/CHDI Foundation, New York, NY, USA
Ranzani, Valeria; INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy
Zuccato, Chiara; Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases, Department of Biosciences, University of Milan, 20122, Milan, Italy ; INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy
Besusso, Dario; Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases, Department of Biosciences, University of Milan, 20122, Milan, Italy ; INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy
Cattaneo, Elena ; Laboratory of Stem Cell Biology and Pharmacology of Neurodegenerative Diseases, Department of Biosciences, University of Milan, 20122, Milan, Italy. elena.cattaneo@unimi.it ; INGM, Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi", Milan, Italy. elena.cattaneo@unimi.it
We thank A. Fasciani of the Imaging Facility and M. Crosti of the Cytofluorometry Facility from INGM for scientific and technical assistance. We acknowledge Ernest Arenas (Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden) for discussions and comments. This study was supported by the European Union\u2019s funded Consortia \u201CNeurostemcellRepair: European stem cell consortium for neural cell replacement, reprogramming and functional brain repair\u201D (FP7, GA No. 602278) and by JPND (EU) ModelPolyQ (Grant No. 643417) and, partially, by the European Research Council (ERC) under the European Union\u2019s Horizon 2020 research and innovation programme (grant agreement No. 742436). Single cell RNA sequencing was partially supported by CHDI Foundation (No. JSC A11103). All the grants were referred to E.C.
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