A three-dimensional dementia model reveals spontaneous cell cycle re-entry and a senescence-associated secretory phenotype

Porterfield, Veronica M.; Khan, Shahzad S.; Foff, Erin P.; Köseoğlu, M. Murat; Blanco, Isabella K.; Jayaraman, Sruthi; Lien, Eric L.; McConnell, Michael J.; Bloom, George S.; Lazo, John S.; Sharlow, Elizabeth R.

doi:10.1016/j.neurobiolaging.2020.02.011

Cited by 15 publications

(10 citation statements)

References 72 publications

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“…Finally, the first C9ORF72 three dimensional neuronal model revealed re-engagement of cell cycle-associated proteins and a senescence-associated secretory phenotype in C9ORF72 patient-derived neurons (229). Specifically, C9ORF72 patient-derived neurons grown on Alvetex scaffold spontaneously re-expressed cyclin D1 12 weeks post-differentiation, suggesting cell cycle re-engagement.…”

Section: Ii) Investigating C9orf72 Function In Ipsc-neuronsmentioning

confidence: 94%

Modelling frontotemporal dementia using patient-derived induced pluripotent stem cells

Lines

Casey

Preza

et al. 2020

Molecular and Cellular Neuroscience

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Section: Ii) Investigating C9orf72 Function In Ipsc-neuronsmentioning

confidence: 94%

Modelling frontotemporal dementia using patient-derived induced pluripotent stem cells

Lines

Casey

Preza

et al. 2020

Molecular and Cellular Neuroscience

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“…For example, SMN depletion in mice resulted in retained introns and skipped exons, including genes of the IL-8 pathway [54]. In familial ALS associated with C9orf72 hexanucleotide repeat expansion, stem cellderived neurons demonstrate dysregulated cell cycle re-entry accompanied by increased IL-8 mRNA and protein levels [55]. In trauma, CSF IL-8 levels are influenced by blood brain barrier permeability [56].…”

Section: Discussionmentioning

confidence: 99%

CSF IL-8 Associated with Response to Gene Therapy in a Case Series of Spinal Muscular Atrophy

et al. 2023

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Gene therapies have greatly changed the outlook in spinal muscular atrophy (SMA), and this disorder provides a rare opportunity to study longitudinal biomarker changes correlated with reduced disease burden and improved clinical outcomes. Recent work suggests clinical response to correlate with declining cerebrospinal fluid (CSF) levels of the neurodegenerative marker neurofilament light chain (NfL) in children receiving serial anti-sense oligonucleotide therapy. However, change in CSF NfL levels is no longer a practical biomarker as more children undergo single-dose gene replacement therapy. Here we leverage serial CSF samples (median of 4 per child) collected in 13 children with SMA undergoing anti-sense oligonucleotide therapy to characterize the longitudinal profiles of NfL as well as inflammatory and neuronal proteins. In contrast to neurodegeneration in adults, we found NfL levels to first decrease following initiation of treatment but then increase upon further treatment and improved motor functions. We then examined additional CSF inflammatory and neuronal markers for linear association with motor function during SMA treatment. We identified longitudinal IL-8 levels to inversely correlate with motor functions determined by clinical examination (F(1, 47) = 12.903, p = 0.001) or electromyography in the abductor pollicis brevis muscle (p = 0.064). In keeping with this, lower baseline IL-8 levels were associated with better longitudinal outcomes, even though this difference diminished over 2 years in the younger group. We thus propose CSF IL-8 as a biomarker for baseline function and short-term treatment response in SMA, and a candidate biomarker for future treatment trials in other neurodegenerative disorders.

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“…iPS neuronal progenitor cells (NPCs) and culturing procedures. iPS-derived NPC lines (i.e., 7545-5b and 7753) were derived by and obtained from the University of Virginia Stem Cell Core (Charlottesville, VA) and were previously described 31 . The original fibroblast lines, GM07753 and GM07545 were purchased from the NIGMS Human Genetic Cell Repository at the Coriell Institute for Medical Research (Camden, NJ) by the University of Virginia Stem Cell Core (Charlottesville, VA).…”

Section: Methodsmentioning

confidence: 99%

Extracellular cues accelerate neurogenesis of induced pluripotent stem cell derived neurons

Sharlow

Llaneza

Mendelson

et al. 2021

Preprint

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Neurogenesis is a complex process encompassing neuronal progenitor cell expansion/proliferation and differentiation, followed by neuron maturation. In vivo models are most commonly used to study neurogenesis; however, human induced pluripotent stem cell-derived (iPSC) neurons are increasingly used to establish cellular models of human neurological processes. Unfortunately, the differentiation and maturation of iPSC-derived neurons varies in methodology, is asynchronous, and has restricted experimental utility because of extended differentiation/maturation times. To accelerate and standardize iPS neuronal maturation, we differentiated and matured feeder layer-free iPSC-derived neuronal cultures under physiological oxygen levels (5%), and modified the underlying extracellular matrix and medium composition. Our results demonstrate that calretinin gene expression occurred earlier under our optimized iPS conditions and the corresponding neurogenesis burst associated with proliferative expansion occurred more synchronously, reliably emerging two and three weeks after differentiation. As expected, the expression of mature neuronal markers (i.e., NeuN+/Calbindin+) started at 4-weeks post-differentiation. qPCR microarray, western blot and single cell analyses using high content imaging indicated that 4-week iPS neuronal cultures were non-cycling with decreased expression of cyclin D1 and Ki67. Our data demonstrate that extracellular cues influence the kinetics of neurogenesis models and that feeder layer-free iPSC-derived neurogenesis can be reproducibly miniaturized.

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A three-dimensional dementia model reveals spontaneous cell cycle re-entry and a senescence-associated secretory phenotype

Cited by 15 publications

References 72 publications

Modelling frontotemporal dementia using patient-derived induced pluripotent stem cells

Modelling frontotemporal dementia using patient-derived induced pluripotent stem cells

CSF IL-8 Associated with Response to Gene Therapy in a Case Series of Spinal Muscular Atrophy

Extracellular cues accelerate neurogenesis of induced pluripotent stem cell derived neurons

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