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1.
Mol Psychiatry ; 2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-39227432

RESUMEN

Valproic acid (VPA) is an effective and widely used anti-seizure medication but is teratogenic when used during pregnancy, affecting brain and spinal cord development for reasons that remain largely unclear. Here we designed a genetic recombinase-based SOX10 reporter system in human pluripotent stem cells that enables tracking and lineage tracing of Neural Crest cells (NCCs) in a human organoid model of the developing neural tube. We found that VPA induces extensive cellular senescence and promotes mesenchymal differentiation of human NCCs. We next show that the clinically approved drug Rapamycin inhibits senescence and restores aberrant NCC differentiation trajectory after VPA exposure in human organoids and in developing zebrafish, highlighting the therapeutic promise of this approach. Finally, we identify the pioneer factor AP1 as a key element of this process. Collectively our data reveal cellular senescence as a central driver of VPA-associated neurodevelopmental teratogenicity and identifies a new pharmacological strategy for prevention. These results exemplify the power of genetically modified human stem cell-derived organoid models for drug discovery.

2.
Sci Adv ; 10(23): eadj4735, 2024 Jun 07.
Artículo en Inglés | MEDLINE | ID: mdl-38838150

RESUMEN

Why individuals with Down syndrome (DS) are more susceptible to SARS-CoV-2-induced neuropathology remains elusive. Choroid plexus (ChP) plays critical roles in barrier function and immune response modulation and expresses the ACE2 receptor and the chromosome 21-encoded TMPRSS2 protease, suggesting its substantial role in establishing SARS-CoV-2 infection in the brain. To explore this, we established brain organoids from DS and isogenic euploid iPSC that consist of a core of functional cortical neurons surrounded by a functional ChP-like epithelium (ChPCOs). DS-ChPCOs recapitulated abnormal DS cortical development and revealed defects in ciliogenesis and epithelial cell polarity in ChP-like epithelium. We then demonstrated that the ChP-like epithelium facilitates infection and replication of SARS-CoV-2 in cortical neurons and that this is increased in DS. Inhibiting TMPRSS2 and furin activity reduced viral replication in DS-ChPCOs to euploid levels. This model enables dissection of the role of ChP in neurotropic virus infection and euploid forebrain development and permits screening of therapeutics for SARS-CoV-2-induced neuropathogenesis.


Asunto(s)
Encéfalo , COVID-19 , Plexo Coroideo , Síndrome de Down , Organoides , SARS-CoV-2 , Serina Endopeptidasas , Plexo Coroideo/virología , Plexo Coroideo/metabolismo , Plexo Coroideo/patología , Organoides/virología , Organoides/metabolismo , Organoides/patología , Humanos , SARS-CoV-2/fisiología , COVID-19/virología , COVID-19/patología , COVID-19/metabolismo , Serina Endopeptidasas/metabolismo , Serina Endopeptidasas/genética , Síndrome de Down/metabolismo , Síndrome de Down/patología , Síndrome de Down/genética , Encéfalo/virología , Encéfalo/patología , Encéfalo/metabolismo , Neuronas/metabolismo , Neuronas/virología , Neuronas/patología , Replicación Viral , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/virología , Furina/metabolismo , Furina/genética , Enzima Convertidora de Angiotensina 2/metabolismo , Enzima Convertidora de Angiotensina 2/genética , Tropismo Viral
3.
STAR Protoc ; 4(4): 102725, 2023 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-37976154

RESUMEN

In response to the scarcity of advanced in vitro models dedicated to human CNS white matter research, we present a protocol to generate neuroectoderm-derived embedding-free human brain organoids enriched with oligodendrocytes. We describe steps for neuroectoderm differentiation, development of neural spheroids, and their transferal to Matrigel. We then detail procedures for the development, maturation, and application of oligodendrocyte-enriched brain organoids. The presence of myelin-producing cells makes these organoids useful for studying human white matter diseases, such as leukodystrophy.


Asunto(s)
Encéfalo , Oligodendroglía , Humanos , Vaina de Mielina , Organoides
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