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Chromatin does not fully acquire the properties of post-mortem neurons during iPSCs-to-neurons differentiation.

ABSTRACT: Induced pluripotent stem cells (iPSCs) have fundamentally advanced the field of neuroscience, offering a highly adaptable methodology for generating patient-specific neurons and modeling neurological diseases. However, a critical question remains: how accurately do iPSC-derived neurons mimic the molecular and structural intricacies of post-mortem neurons? In this study, we embark on a comprehensive investigation of chromatin architecture in both iPSC-derived and post-mortem neurons. We collected and uniformly processed the largest collection of publicly available Hi-C datasets for human and mouse neurons, along with our newly generated maps. The thorough analysis on the resulting data reveals that iPSC-derived neurons retain properties of non-differentiated cells and resemble developing stages of neurons rather than fully mature neurons. Our study not only provides a detailed comparison of chromatin architecture between iPSC-derived and post-mortem neurons but also offers the largest dataset of uniformly processed Hi-C data for human and mouse neurons.

ORGANISM(S): Homo sapiens

PROVIDER: GSE291967 | GEO | 2026/06/17

REPOSITORIES: GEO

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Project description:Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases with interlinked pathophysiology. Mutations in CCNF, encoding the E3 ubiquitin ligase, Cyclin F, can cause either ALS or FTD or both, within the same family. The majority of previous published research on CCNFS621G in ALS/FTD has used overexpression of exogenous Cyclin F, and as a result may have encountered artefacts of pathology caused by dysregulation of native or wild-type Cyclin F. In this study, we generated the first reported mouse model of endogenous CcnfS621G using CRISPR/Cas9. Neither heterozygous nor homozygous CcnfS621G mice exhibited motor decline or neuronal loss within 18 months. However, through this period mice presented behavioural alterations congruent with early FTD phenotypes. Immunohistochemistry identified alterations in hippocampal astrocyte morphology, including increased ramification, and proteomic analyses identified significant alterations in pathways linked to translation, mitochondrial function, cytoskeletal remodeling and neuroinflammatory signaling. Consistent with this, increased astrocyte ramification was also identified in human sporadic ALS and ALS-FTD post mortem tissue, as well as in human CCNFS621G induced pluripotent stem cell (iPSC)-derived astrocytes. A common phenotype observed in familial and sporadic ALS is alterations in neuronal excitability and loss of repetitive action potential firing. ALS patients and cell and animal models display an early increase in neuronal excitability (hyperexcitability), followed by a decrease in excitability (hypoexcitability) as neurodegeneration progresses. Thus, we reasoned that alterations in CCNFS621G iPSC-derived astrocytes may impact neuronal excitability in co-cultures. CCNFS621G iPSC-derived motor neurons cultured without astrocytes exhibited increased action potential firing, compared to isogenic control neurons, consistent with neuronal hyperexcitability. However, the addition of CCNFS621G astrocytes, but not isogenic control astrocytes, abolished repetitive action potential firing in both CCNFS621G and isogenic control neurons. CCNFS621G astrocytes also increased the population of neurons that failed to fire action potentials and reduced voltage-gated sodium currents in either CCNFS621G or isogenic control neurons. Together, these results suggest that astrocyte activation is an early feature of neurodegenerative disease, occurring in the absence of neuronal loss in CcnfS621G mice and is present with region-specific severity in sporadic ALS and ALS-FTD post mortem tissue. Furthermore, astrocyte-mediated loss of repetitive firing could play a critical role in pre-symptomatic disease stages of CCNF-mediated ALS and FTD pathology.

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Chromatin does not fully acquire the properties of post-mortem neurons during iPSCs-to-neurons differentiation.

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