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

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 (FTD). We used inducible pluripotent stem cells from neurotypic and C9orf72+ (C9+) ALS patients to derive neuronal progenitor cells (NPCs). We demonstrated that C9+ and neurotypic NPCs differentiate into neurons. The C9+ neurons, however, spontaneously reexpressed cyclin D1 after 12 weeks, suggesting cell cycle reengagement. 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, reengagement of cell cycle-associated proteins and a senescence-associated secretory phenotype, could be fundamental components of neuronal dysfunction in ALS and FTD.