Metabolic and proteomic profiling identifies stress response and impaired neural stem cell functions associated with sleep restriction in women

Adequate sleep (AS) is essential for maintaining many behavioral and physiological functions; however, a third of adults in the United States sleep less than the recommended 7-9 h/night. The circadian rhythm controls tissue homeostasis, in part, through adult stem cell functions. However, little is known about the mechanistic interactions between insufficient sleep and stem cell functions. Using plasma collected from healthy women with adequate habitual sleep duration (7-9 h/night) who were randomized in a crossover design to a 6-week objectively monitored AS or mildly restricted sleep (RS; 1.5 h less than their AS), we identified metabolites and proteins differentially enriched after RS compared to AS. RS induced a stress-like state dominated by the ATF6 interactome, heat shock, and ubiquitination proteins. Joint network pathway analysis highlights a strong link between RS and neuronal development phenotypes. Using neural stem cells (NSCs) differentiated from human embryonic stem cells, we found treatment with metabolic candidates enriched in restricted sleep led to aberrant G1 phase of the cell cycle and defective differentiation of NSCs into neurons, astrocytes, and oligodendrocytes. Thus, restricted sleep that mimics “life-like” conditions can influence the daily dynamics of NSC divisions and differentiation, shedding light on how sleep can shape adult stem cell functions in neural development. RNA-seq of untreated and glutamic acid or methionine treated FUCCI-hNSCs for 30 days in neural expansion medium.