Inhibition of neural stem cell aging through the transient induction of reprogramming factors

Abstract

Adult stem cells age during long-term in vitro culture, and neural stem cells (NSCs), which can self-renew and differentiate into neurons and glial cells, also display reduced differentiation potential after repeated passaging. However, the mechanistic details underlying this process remain unclear. In this study, we found that long-term in vitro culture of NSCs resulted in aging-related upregulation of inflammatory-and endoplasmic reticulum (ER) stress-related genes, including the proinflammatory cytokines interleukin (IL)1β and IL6, the senescence-associated enzyme matrix metallopeptidase 13 (MMP13), and the ER stress-responsive transcription factor activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP). However, the cyclic and transient induction of four reprogramming factors (POU domain, class 5, transcription factor 1, also known as octamer-binding transcription factor 4; SRY [sex determining region Y]-box 2; Kruppel-like factor 4; and myelocytomatosis oncogene; collectively referred to as OSKM) can inhibit NSC aging, as indicated by the decreased expression of the inflammatory and ER stress-related genes. We used ROSA-4F NSCs, which express OSKM from only one allele, to minimize the potential for full reprogramming or tumor formation during NSC rejuvenation. We expect that this novel rejuvenation method will enhance the potential of NSCs as a clinical approach to the treatment of neurological diseases.

Aging and Rejuvenation of Neural Stem Cells and Their Niches

“…Given the neurogenic benefits of these different interventions, one intriguing hypothesis is that combinatorial application of two or more of these strategies could have additive or even synergistic beneficial effects (Fabel et al, 2009;Hutton et al, 2015). Additional ''rejuvenating'' strategies, such as in vivo partial reprogramming (Han et al, 2020;Ocampo et al, 2016) or microbiome transfer (Ba ´rcena et al, 2019;Smith et al, 2017) could also be exploited to rejuvenate old NSCs and improve age-related sensorimotor decline. Although further studies will be required to determine the specific mechanisms of action of each strategy, the potential synergistic benefits of dietary interventions, exercise, and blood factors hold promise as a strategy to rejuvenate the brain for physiological and pathological aging.…”

The transcription factor C/EBPβ promotes vascular endothelial growth factor A expression and neural stem cell expansion

“…One potential explanation for these findings may relate to cell context‐specific effects that govern the DNA binding activity of CHOP‐10 or C/EBPβ [42]. As the endoplasmic reticulum stress effector, CHOP‐10 is involved in NSC dysfunction under different conditions, such as its involvement in the aging‐related decreased NSC differentiation potential [43] and amyloid‐beta‐induced toxicity in NSC [44]. Whether through promoter interference or direct inhibition, we predict that CHOP‐10‐dependent inhibitory effects on CEBPβ may serve to link conditions of some of the cellular stress with changes in basal NSC proliferation, differentiation, and survival in the CNS.…”

Maternal immune activation primes deficiencies in adult hippocampal neurogenesis

“…To overcome this technical issue, it might be worth artificially ageing the in vitro model ( Mertens et al, 2018 ). This can be done using various strategies; by manipulation of age-related genes or telomerases ( Cozzi et al, 2019 , Liang, 2020 , Miller et al, 2013 , Vera et al, 2016 ), by exposure to x-ray irradiation ( Carlessi et al, 2009 , Schneider et al, 2013 , Schneider and Zheng, 2014 , Zhu et al, 2019 , Limbad et al, 2020 ), hydroxyurea ( Daniele et al, 2016 , de Lucia et al, 2020 , Dong et al, 2014 ), repeated passaging ( de Lucia et al, 2020 , Han et al, 2021 , Liu et al, 2012 , Zhu et al, 2019 ) or long term culture ( Daniele et al, 2020 , Bigagli et al, 2016 ) to induce senescence-like changes into the hiPSC-derived cultures for a more aged-like phenotype.…”