Multiomics reveal biomolecular shifts and ER stress in sleep-restricted women affecting NSC functions.

Adequate sleep (AS) is vital for physiological functions, yet a third of US adults sleep less than recommended. While circadian rhythms regulate adult stem cell functions, the impact of insufficient sleep remains unclear. We previously completed a clinical trial in healthy women in a randomized crossover design of 6-week periods with AS or mildly restricted sleep (RS; 1.5 h less). Here, we performed metabolomic and proteomic profiling of plasma samples. RS induced a stress-like state, highlighted by ER stress, heat shock, ubiquitination proteins, and amino acid biosynthesis. RS was strongly linked to disrupted neural development. Treating neural stem cells (NSCs) derived from human embryonic stem cells with RS-enriched metabolites disrupted G1 cell cycle phase and impaired differentiation into neurons, astrocytes, and oligodendrocytes. Our findings reveal how mild RS, mimicking "real-life" conditions, disrupts NSC divisions and differentiation, highlighting the critical role of sleep in adult stem cell regulation and neural development.