[en] Machado-Joseph disease (MJD) is a neurodegenerative disorder characterized by widespread neuronal death affecting the cerebellum. Cell therapy can trigger neuronal replacement and neuroprotection through bystander effects providing a therapeutic option for neurodegenerative diseases. Here, human control (CNT) and MJD iPSC-derived neuroepithelial stem cells (NESC) were established and tested for their therapeutic potential. Cells' neuroectodermal phenotype was demonstrated. Brain organoids obtained from the Control NESC showed higher mRNA levels of genes related to stem cells' bystander effects, such as BDNF, NEUROD1, and NOTCH1, as compared with organoids produced from MJD NESC, suggesting that Control NESC have a higher therapeutic potential. Graft-derived glia and neurons, such as cells positive for markers of cerebellar neurons, were detected six months after NESC transplantation in mice cerebella. The graft-derived neurons established excitatory and inhibitory synapses in the host cerebella, although CNT neurons exhibited higher excitatory synapse numbers compared with MJD neurons. Cell grafts, mainly CNT NESC, sustained the bystander effects through modulation of inflammatory interleukins (IL1B and IL10), neurotrophic factors (NGF), and neurogenesis-related proteins (Msi1 and NeuroD1), for six months in the mice cerebella. Altogether this study demonstrates the long-lasting therapeutic potential of human iPSC-derived NESC in the cerebellum.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Mendonça, Liliana S; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal. liliana.mendonca@cnc.uc.pt ; Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal. liliana.mendonca@cnc.uc.pt ; Institute of Interdisciplinary Research, University of Coimbra, Coimbra, Portugal. liliana.mendonca@cnc.uc.pt
Henriques, Daniel; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal ; Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal ; Institute of Interdisciplinary Research, University of Coimbra, Coimbra, Portugal
Fernandes, Vanessa; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
Moreira, Ricardo; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal ; Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal ; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
Brás, João; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal
Duarte, Sónia; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal ; Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal ; Institute of Interdisciplinary Research, University of Coimbra, Coimbra, Portugal
SCHWAMBORN, Jens Christian ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology
de Almeida, Luís Pereira; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal. luispa@ci.uc.pt ; Center for Innovative Biomedicine and Biotechnology, University of Coimbra, Coimbra, Portugal. luispa@ci.uc.pt ; Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal. luispa@ci.uc.pt
External co-authors :
yes
Language :
English
Title :
Graft-derived neurons and bystander effects are maintained for six months after human iPSC-derived NESC transplantation in mice's cerebella.
European Regional Development Fund FCT – Fundação para a Ciência e a Tecnologia National Ataxia Foundation AFM-Téléthon EU Joint Programme – Neurodegenerative Disease Research Richard Chin and Lily Lock Machado-Joseph Disease Research Fund
Funding text :
This work was funded by the European Regional Development Fund (ERDF) through the Centro 2020 Regional Operational Programme under BrainHealth2020 projects (CENTRO-01–0145-FEDER-000008), through the COMPETE 2020—Operational Programme for Competitiveness and Internationalization and Portuguese national funds via FCT – Fundação para a Ciência e a Tecnologia, under projects—UIDB/04539/2020 and UIDP/04539/2020, POCI-01–0145-FEDER-030737 (NeuroStemForMJD, PTDC/BTM-ORG/30737/2017), CEECIND/04242/2017, PhD Scholarships 2020.04751.BD and 2020.07385.BD. It was also funded by the National Ataxia Foundation, the French Muscular Dystrophy Association (AFM-Téléthon) Trampoline Grant #20126, EU Joint Programme – Neurodegenerative Disease Research (JPND) Project (JPCOFUND/0005/2015-ModelPolyQ), and the Richard Chin and Lily Lock Machado-Joseph Disease Research Fund.
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