Neural Stem Cell-Derived Extracellular Vesicles Counteract Insulin Resistance-Induced Senescence of Neurogenic Niche

Abstract

Neural stem and progenitor cell (NSPC) depletion may play a crucial role in the cognitive impairment observed in many age-related non communicable diseases. Insulin resistance affects brain functions through a plethora of mechanisms that remain poorly understood. In an experimental model of insulin resistant NSPCs, we identified a novel molecular circuit relying on Insulin receptor substrate 1 (IRS1)/Forkhead box O (FoxO) signaling cascade and inhibiting the recruitment of transcription factors FoxO1 and FoxO3a on the promoters of genes regulating proliferation and self-renewal. Insulin resistance also epigenetically increased the expression of cyclin-dependent kinase inhibitor 1 (p21) and accelerated NSPC senescence. Of note, we found that stimulation of NSPCs with NSPC-derived exosomes (exo-NSPC) rescued IRS1/FoxO activation and counteracted both the reduced proliferation and senescence of stem cells. Accordingly, intranasal administration of exo-NSPC counteracted the high fat diet-dependent impairment of adult hippocampal neurogenesis in mice by restoring the balance between proliferating and senescent NSPCs in the hippocampus. Our findings suggest a novel mechanism underlying the metabolic control of NSPC fate potentially involved in the detrimental effects of metabolic disorders on brain plasticity. In addition, our data highlight the role of extracellular vesicle-mediated signals in the regulation of cell fate within the adult neurogenic niche.

Hippocampal Estrogen Signaling Mediates Sex Differences in Retroactive Interference

“…Western blot analyses were performed as previously described [ 28 ]. Thirty minutes after interference, animals were sacrificed, and both hippocampi were collected.…”

Neural stem/progenitor cell‐derived extracellular vesicles: A novel therapy for neurological diseases and beyond

“…173,174,180,181 Furthermore, the intranasal administration of NSC-EVs counteracted HFD-dependent impairment of neurogenesis in the hippocampus of adult mice by activating insulin receptor substrate-1/FoxO signaling cascade and inhibiting the recruitment of FoxO1 and FoxO3a on the promoters of genes that regulate proliferation and self-renewal of NSCs. 140 Vascular dementia (VD) is the number two cause of dementia after AD, causing around 15% of cases. 182 To date, no treatment has been licensed for VD, indicating the importance and urgency to develop novel effective therapeutic strategy for treating VD.…”

Dual role of brain-derived extracellular vesicles in dementia-related neurodegenerative disorders: cargo of disease spreading signals and diagnostic-therapeutic molecules

“…Importantly, EVs have the intrinsic ability to breach biological barriers including the complex BBB, whose restrictive nature represents a significant therapeutic challenge [ 173 ]. Applications of EVs in therapies for neurodegenerative diseases embrace two main aspects: these vesicles may represent a biocompatible cargo for drug delivery and, more importantly, the stem cell-derived exosomes can offer a novel therapeutic tool against neurodegenerative disorders as a vehicle of neurotrophic and anti-inflammatory molecules potentially fostering brain plasticity [ 174 , 175 ] (Fig. 2 ).…”

“…There are several potential advantages of using NSC-derived exosomes compared to NSC transplantation. First, many EVs can reach different regions of the brain through intranasal administration [ 174 , 175 , 177 ]. Second, unlike cell therapy, the risk of developing a tumor or malignant transformation after EV administration is significantly lower since they are not nucleated cells, cannot replicate, and quickly disintegrate after releasing their cargo [ 178 ].…”