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HiPSC-derived 3D neural models reveal neurodevelopmental pathomechanisms of the Cockayne Syndrome B.

ABSTRACT: Cockayne Syndrome B (CSB) is a hereditary multiorgan syndrome which-through largely unknown mechanisms-can affect the brain where it clinically presents with microcephaly, intellectual disability and demyelination. Using human induced pluripotent stem cell (hiPSC)-derived neural 3D models generated from CSB patient-derived and isogenic control lines, we here provide explanations for these three major neuropathological phenotypes. In our models, CSB deficiency is associated with (i) impaired cellular migration due to defective autophagy as an explanation for clinical microcephaly; (ii) altered neuronal network functionality and neurotransmitter GABA levels, which is suggestive of a disturbed GABA switch that likely impairs brain circuit formation and ultimately causes intellectual disability; and (iii) impaired oligodendrocyte maturation as a possible cause of the demyelination observed in children with CSB. Of note, the impaired migration and oligodendrocyte maturation could both be partially rescued by pharmacological HDAC inhibition.

SUBMITTER: Kapr J

PROVIDER: S-EPMC11343962 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature

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HiPSC-derived 3D neural models reveal neurodevelopmental pathomechanisms of the Cockayne Syndrome B.

Kapr Julia J Scharkin Ilka I Ramachandran Haribaskar H Westhoff Philipp P Pollet Marius M Dangeleit Selina S Brockerhoff Gabriele G Rossi Andrea A Koch Katharina K Krutmann Jean J Fritsche Ellen E

Cellular and molecular life sciences : CMLS 20240823 1

Cockayne Syndrome B (CSB) is a hereditary multiorgan syndrome which-through largely unknown mechanisms-can affect the brain where it clinically presents with microcephaly, intellectual disability and demyelination. Using human induced pluripotent stem cell (hiPSC)-derived neural 3D models generated from CSB patient-derived and isogenic control lines, we here provide explanations for these three major neuropathological phenotypes. In our models, CSB deficiency is associated with (i) impaired cell ...[more]

PMID: 39179905

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Project description:Modeling the developmental etiology of viable human aneuploidies can be challenging in rodent models, where synteny with human chromosomes is affected, or primate-specific biology is implicated. In humans, monosomy-X (45,X) causes Turner syndrome (TS), altering craniofacial, skeletal, endocrine, and cardiovascular development, which remain largely unaffected in 39,X-mice. We derived human 45,X and isogenic euploid induced pluripotent stem cells (hiPSCs) from male and female mosaics to model how human monosomy-X may impact early embryonic development. Because several neural crest (NC) derived cell types are hypothesized to underpin craniofacial and cardiovascular changes in TS, we derived anterior neural crest from our hiPSCs and performed a highly-powered and extensive differential expression study. Across all three isogenic panels, 45,X neural crest cells (NCCs) show impaired acquisition of the PAX7/SOX10 double-positive NC state relative to euploid 46,XY controls. Monosomy-X NCCs also share similarly disrupted expression of NC-specific genes relative to their isogenic euploid control regardless of whether the latter carry an inactive X or Y. Gene-set enrichment analyses indicate monosomy-X NCCs increase cholesterol biosynthesis genes while dampening ribosomal protein and nuclear-encoded mitochondrial genes. These metabolic pathways are also over-represented in gene modules that are preserved in monogenic conditions involving neurocristopathy. Importantly, these gene modules are also significantly enriched in 28% of all TS-associated terms of the human phenotype ontology, and point to specific sex-linked genes that are expressed from two copies in euploid males and females alike, which may qualify as candidate haploinsufficient drivers of TS phenotypes in NC-derived lineages. Our study demonstrates that isogenic hiPSC-derived NCC panels representing monosomy-X can serve as a powerful model of early NC development in TS, and provides euploid and X-monosomic transcriptomic datasets relevant to exploration of TS and NC biology.

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HiPSC-derived 3D neural models reveal neurodevelopmental pathomechanisms of the Cockayne Syndrome B.

Publications

HiPSC-derived 3D neural models reveal neurodevelopmental pathomechanisms of the Cockayne Syndrome B.

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