A three-dimensional dementia model reveals spontaneous cell cycle re-entry and a senescence-associated secretory phenotype.
Neurobiol Aging
; 90: 125-134, 2020 06.
Article
in En
| MEDLINE
| ID: mdl-32184029
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Stem Cells
/
Cell Cycle
/
Cellular Senescence
/
Gene Expression Regulation, Developmental
/
DNA Repeat Expansion
/
Induced Pluripotent Stem Cells
/
Frontotemporal Dementia
/
C9orf72 Protein
/
Amyotrophic Lateral Sclerosis
Type of study:
Prognostic_studies
/
Risk_factors_studies
Limits:
Humans
Language:
En
Journal:
Neurobiol Aging
Year:
2020
Document type:
Article
Affiliation country:
United States