USF-LVHN SELECT
A three-dimensional dementia model reveals spontaneous cell cycle re-entry and a senescence-associated secretory phenotype.
Publication/Presentation Date
6-1-2020
Abstract
A hexanucleotide repeat expansion on chromosome 9 open reading frame 72 (C9orf72) is associated with familial amyotrophic lateral sclerosis (ALS) and a subpopulation of patients with sporadic ALS and frontotemporal dementia. We used inducible pluripotent stem cells from neurotypic and C9orf72+ (C9+) ALS patients to derive neuronal progenitor cells. We demonstrated that C9+ and neurotypic neuronal progenitor cells differentiate into neurons. The C9+ neurons, however, spontaneously re-expressed cyclin D1 after 12 weeks, suggesting cell cycle re-engagement. Gene profiling revealed significant increases in senescence-associated genes in C9+ neurons. Moreover, C9+ neurons expressed high levels of mRNA for CXCL8, a chemokine overexpressed by senescent cells, while media from C9+ neurons contained significant levels of CXCL8, CXCL1, IL13, IP10, CX3CL1, and reactive oxygen species, which are components of the senescence-associated secretory phenotype. Thus, re-engagement of cell cycle-associated proteins and a senescence-associated secretory phenotype could be fundamental components of neuronal dysfunction in ALS and frontotemporal dementia.
Volume
90
First Page
125
Last Page
134
ISSN
1558-1497
Published In/Presented At
Porterfield, V., Khan, S. S., Foff, E. P., Koseoglu, M. M., Blanco, I. K., Jayaraman, S., Lien, E., McConnell, M. J., Bloom, G. S., Lazo, J. S., & Sharlow, E. R. (2020). A three-dimensional dementia model reveals spontaneous cell cycle re-entry and a senescence-associated secretory phenotype. Neurobiology of aging, 90, 125–134. https://doi.org/10.1016/j.neurobiolaging.2020.02.011
Disciplines
Medical Education | Medicine and Health Sciences
PubMedID
32184029
Department(s)
USF-LVHN SELECT Program, USF-LVHN SELECT Program Students
Document Type
Article