In a recent study published in the Journal of Experimental Medicine, researchers in the United States used mice models to understand how sleep fragmentation affects immunological responses and the epigenetic modifications of hematopoietic stem and progenitor cells (HSPCs). They also conducted a sleep restriction trial in humans to determine HPSC programming and hematopoiesis.
Study: Sleep exerts lasting effects on hematopoietic stem cell function and diversity. Image Credit: Yuganov Konstantin / Shutterstock
Sleep deprivation is known to impact human health on various levels. Studies have shown that sleep is necessary for optimal immune system functioning, influencing disease outcomes in cardiovascular diseases (CVD), neurodegenerative diseases, and cancer. Sleep is known to play a role in modulating the synthesis of various inflammation and immune response signaling molecules.
Research on sleep deprivation and disease in mice has shown that sufficient sleep reduces the cycling of HPSCs in the bone marrow, restricting leukocytosis. It has also been seen to reduce lesions in atherosclerotic CVD in mice and humans by lowering blood monocyte and neutrophil concentrations.
Despite the plethora of evidence linking sleep to various disease outcomes and overall health, chronic sleep disruption is a predominant issue of the modern age. Recent findings that suggest that catch-up sleep does not compensate for disrupted sleep further emphasize the role of sleep on human health. However, the cellular and epigenetic mechanisms through which insufficient sleep impacts the immune system remain unexplored.
About the study
In the present study, the researchers quantified sleep and wake states and the transition periods by measuring electroencephalography (EEG) and electromyography (EMG) signals from the brain and muscle, respectively, in mice models that were subjected to sleep fragmentation.
The epigenome of hematopoietic progenitor cells was profiled to understand stem-intrinsic mechanisms of how sleep mediates hematopoiesis. This included measuring histone deacetylase (HDAC) activity in the hematopoietic progenitor cells of sleep fragmented mice. Additionally, transposase-accessible chromatin sequencing (ATAC-seq) assays were carried out on mice that received habitual sleep, fragmented sleep, and fragmented sleep, followed by recovery sleep.
Circulating leukocytes were analyzed through flow cytometry. Enzyme-linked immunosorbent assay (ELISA) was used to measure the levels of granulocyte colony-stimulating factor (G-CSF), macrophage colony-stimulating factor (M-CSF), tumor necrosis factor alpha (TNFα), interleukin 6 (IL-6), and interleukin 1 beta (IL-1β).
The results reported that sleep fragmentation intensifies sleep-wake transitions, consequently increasing hematopoiesis and causing histone acetylation that altered the epigenome of HSPCs in mice. During sleep recovery, although hematopoiesis decreased, the epigenetic imprint of HSPCs remained, causing heightened inflammatory responses to subsequent immune challenges.
Using a multicolor fluorescent tracking system, the researchers found that hematopoietic clonal diversity reduced with interrupted sleep. The sleep restriction trials in humans revealed an increase of monocytes and HSPCs in blood and a reduction of HSPC histone acetylation. The authors believe that fragmented sleep increased HSPC myeloid cues. The ELISA results also showed that sleep-mediated HPSC increase is controlled by hypothalamic hypocretinergic signals, with fragmented sleep resulting in elevated levels of IL-6.
Earlier research has shown that sleep disorders such as insomnia and obstructive sleep apnea (OSA) caused epigenetic modifications in circulating leukocytes, the cardiovascular system, altered deoxyribonucleic acid (DNA) methylation in the liver and muscle tissue, and caused rapid epigenetic aging of blood leukocytes. The results from this study provided evidence that these epigenetic modifications are partially maintained and impact future immune function and disease pathology.
The murine model-based study indicated that even when followed with 10 weeks of recovery sleep, 16 weeks of sleep fragmentation results in elevated levels of monocytes, hematopoietic stem cells-containing Lin-Sca1+c-Kit+ (LSK) cells, and plasma IL-6 and TNFα. These changes were also found to be intrinsic to hematopoietic cells, with bone marrow transfer experiments eliciting aggressive inflammatory responses and augmented monocyte production and bone marrow hematopoiesis.
Overall, the study's findings suggested that fluctuations in the quality and duration of sleep cause sustained epigenetic changes in HSPCs and reduced the clonal hematopoietic diversity, resulting in exaggerated inflammatory responses to subsequent infections. The authors believe that the results highlighted the importance of sound sleep patterns in early life, which could reduce future disease severity, especially for inflammatory diseases such as CVD and cancer.
While previous studies have identified genetic mutations that result in hematopoietic stem cell proliferation, the present study demonstrated that sleep deprivation-induced stress on the hematopoietic system results in a similar proliferation of hematopoietic stem cells and subsequent exaggerated immune responses without the presence of driver mutations.
Sleep deprivation is a chronic problem, especially among younger adults. The study highlights the importance of establishing healthy sleep patterns early in life to maintain a normally functioning immune system.
- McAlpine, C. S., Kiss, M. G., Zuraikat, F. M., Cheek, D., Schiroli, G., Amatullah, H., Huynh, P., Bhatti, M. Z., Wong, L.-P., Yates, A. G., Poller, W. C., Mindur, J. E., Chan, C. T., Janssen, H., Downey, J., Singh, S., Sadreyev, R. I., Nahrendorf, M., Jeffrey, K. L., & Scadden, D. T. (2022). Sleep exerts lasting effects on hematopoietic stem cell function and diversity. Journal of Experimental Medicine, 219(11). https://doi.org/10.1084/jem.20220081, https://rupress.org/jem/article/219/11/e20220081/213487/Sleep-exerts-lasting-effects-on-hematopoietic-stem