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Chemically induced senescence in human stem cell-derived neurons promotes phenotypic presentation of neurodegeneration.

ABSTRACT: Modeling age-related neurodegenerative disorders with human stem cells are difficult due to the embryonic nature of stem cell-derived neurons. We developed a chemical cocktail to induce senescence of iPSC-derived neurons to address this challenge. We first screened small molecules that induce embryonic fibroblasts to exhibit features characteristic of aged fibroblasts. We then optimized a cocktail of small molecules that induced senescence in fibroblasts and cortical neurons without causing DNA damage. The utility of the "senescence cocktail" was validated in motor neurons derived from ALS patient iPSCs which exhibited protein aggregation and axonal degeneration substantially earlier than those without cocktail treatment. Our "senescence cocktail" will likely enhance the manifestation of disease-related phenotypes in neurons derived from iPSCs, enabling the generation of reliable drug discovery platforms.

SUBMITTER: Fathi A

PROVIDER: S-EPMC8761019 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Chemically induced senescence in human stem cell-derived neurons promotes phenotypic presentation of neurodegeneration.

Fathi Ali A Mathivanan Sakthikumar S Kong Linghai L Petersen Andrew J AJ Harder Cole R K CRK Block Jasper J Miller Julia Marie JM Bhattacharyya Anita A Wang Daifeng D Zhang Su-Chun SC

Aging cell 20211224 1

Modeling age-related neurodegenerative disorders with human stem cells are difficult due to the embryonic nature of stem cell-derived neurons. We developed a chemical cocktail to induce senescence of iPSC-derived neurons to address this challenge. We first screened small molecules that induce embryonic fibroblasts to exhibit features characteristic of aged fibroblasts. We then optimized a cocktail of small molecules that induced senescence in fibroblasts and cortical neurons without causing DNA ...[more]

PMID: 34953016

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Project description:Anti-IgLON5 disease is a progressive neurological disorder associated with autoantibodies against a neuronal cell adhesion molecule, IgLON5. In human postmortem brain tissue, the neurodegeneration and accumulation of hyperphosphorylated tau (p-tau) are found. Whether IgLON5 antibodies induce neurodegeneration or neurodegeneration provokes an immune response causing inflammation and antibody formation remains to be elucidated. We investigated the effects of anti-IgLON5 antibodies on human neurons. Human neural stem cells were differentiated for 14-48 days and exposed from Days 9 to 14 (short-term) or Days 13 to 48 (long-term) to either (i) IgG from a patient with confirmed anti-IgLON5 antibodies or (ii) IgG from healthy controls. The electrical activity of neurons was quantified using multielectrode array assays. Cultures were immunostained for β-tubulin III and p-tau and counterstained with 4',6-Diamidine-2'-phenylindole dihydrochloride (DAPI). To study the impact on synapses, cultures were also immunostained for the synaptic proteins postsynaptic density protein 95 (PSD95) and synaptophysin. A lactate dehydrogenase release assay and nuclei morphology analysis were used to assess cell viability. Cultures exposed to anti-IgLON5 antibodies showed reduced neuronal spike rate and synaptic protein content, and the proportion of neurons with degenerative appearance including p-tau (T205)-positive neurons was higher when compared to cultures exposed to control IgG. In addition, cell death was increased in cultures exposed to anti-IgLON5 IgG for 21 days. In conclusion, pathological anti-IgLON5 antibodies induce neurodegenerative changes and cell death in human neurons. This supports the hypothesis that autoantibodies may induce the neurodegenerative changes found in patients with anti-IgLON5-mediated disease. Furthermore, this study highlights the potential use of stem cell-based in vitro models for investigations of antibody-mediated diseases. As anti-IgLON5 disease is heterogeneous, more studies with different IgLON5 antibody samples tested on human neurons are needed.

Dataset Information

Chemically induced senescence in human stem cell-derived neurons promotes phenotypic presentation of neurodegeneration.

Publications

Chemically induced senescence in human stem cell-derived neurons promotes phenotypic presentation of neurodegeneration.

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