The impact of sleep fragmentation on immune cell clonal diversity and genetic aging of the hematopoietic system

Sleep has long been celebrated as the ultimate pick-me-up after a period of excessive work, stress, illness or other cause of bodily fatigue. It affects immunity and inflammatory pathways, thus protecting against cardiovascular disease, neurodegenerative diseases like Alzheimer’s disease and cancer.

Study: Sleep exerts lasting effects on hematopoietic stem cell function and diversity. Image Credit: SB Arts Media/Shutterstock

Sleep does much more, regulating normal blood cell production, a new study shows. This discovery highlights how essential a healthy sleep routine is for a normal life.


More than half of adults sleep too little. This has been linked to higher blood counts of myeloid cells in humans. In rats, one of the results of good sleep is that hematopoietic stem and progenitor cells (HSPCs) cannot circulate in the hematopoietic bone marrow (BM), thus preventing the excessive accumulation of white blood cells in the blood. . Monocytes and neutrophils also decrease in number, preventing their entry into the vascular wall and thus reducing the size of atherosclerotic plaques.

Sleep patterns vary widely over the lifespan, with a significant decline in older people. Even young, healthy adults have fluctuating periods of good sleep with insufficient sleep, altered by lifestyle factors as well as environmental and genetic time-regulation mechanisms.

Numerous studies have shown that catch-up sleep cannot completely counteract the harmful effects of lost sleep – the so-called sleep debt. The current study, published in the Journal of Experimental Medicine, examined the effect of sleep fragmentation (SF) and recovery sleep on the epigenetic restructuring of HSPCs, altering immune responses and disease outcomes. Measures included clonal diversity and hemopoietic genetic aging.

What did the study show?

Results from the initial mouse study showed that SF affected hematopoiesis over a long period of time. The mice were awakened every two minutes from their rest. This resulted in a higher number of sleep-wake transitions during the rest period, but no change in slow-wave sleep (SWS), rapid eye movement (REM), or awake time during the light period.

Conversely, they showed an increase in SWS and a decrease in waking time during their active period, but only during the first two hours.

When SF was continued for 16 weeks, but with ten weeks of recovery sleep, mice continued to show an increased number of wakeful episodes throughout the SF period and the first two weeks of recovery sleep. , but then it became normal.

Blood cell production increased, with higher levels of myeloid colony-stimulating factor (M-CSF) but not granulocyte-CSF (G-CSF). SF also increased interleukin-(IL)6. In BM, a subset of cells called LSK cells proliferated, leading to an increase in Ly6Chi blood monocytes during the quiescent period. These changes persisted even after four weeks of recovery sleep, only returning to normal after ten weeks.

Thus, SF appears to affect sleep quality and white blood cell production for longer than expected. When this hypothesis was examined using cell transplant experiments in mice, they found that LSK cells from SF mice proliferated at higher levels and accounted for more than 60% of total white blood cells and monocytes up to 24 weeks after transplantation.

These results indicate rod-intrinsic mechanisms that regulate SF-mediated prolonged hematopoietic activity..”

SF also produced epigenomic changes in BM hematopoietic progenitor cells that persisted after ten weeks of recovery sleep for 70% of the alterations, leaving the rest. These then represent a potential epigenetic imprint involving cell senescence as part of the restructuring of the epigenome associated with SF. The likely result is biased towards myeloid proliferation, with reduced lymphoid differentiation, since stem cells inherently regulate lineage commitment genes.

Further experiments proved that, as expected, epigenetic modifications of LSKs alter the response of these cells to immune challenges. SF mice showed hyperinflammatory responses even after recovery sleep, with increased BM monocytes and LSKs, higher levels of cytokines including IL-6 and TNFα, and faster LSK proliferation. This was linked to a lower clinical score and lower survival rates.

Sleep also maintains the clonal diversity of hematopoietic cells. The loss of diversity in these cells has been established to be part of clonal hematopoiesis (CH), a common age-associated precancerous disorder caused by the accumulation of somatic mutations. These mainly affect the epigenome at Tet2 and Dmnt3a.

CH is linked to more rapid appearance of epigenetic aging markers on HPSCs, doubled risk of CVD and death from all causes. SF is associated with CH enriched in Tet2 mutations. Due to faster proliferation of HSPCs, mutant clones grow while their frequencies fluctuate randomly due to chance loss and self-renewal of HSPCs – a phenomenon called neutral drift, which occurs more rapidly when the cells proliferate rapidly. Sleep limits this drift by reducing cell renewal and maintaining clonal diversity.

These effects were also seen in humans, with higher hematopoietic BM activity and increased monocytes with sleep restriction for six weeks. Sleep prevented these changes, promoting balanced blood cell production and homeostatic HPSC epigenetic changes.

What are the implications?

The observation that reduced sleep quality and duration could lead to epigenetic changes in HSPCs, reducing their clonal diversity and possibly compromising immune function, underscores the need for good sleep hygiene even in modern societies where night is no longer a moment when everything stops. . Attention should be paid to the pervasive causes of sleep disturbances, whether jet lag, insomnia, obstructive sleep apnea or FS.

Previous studies have shown epigenetic modification of cell function with various types of sleep disorders and disturbances. The current study provides evidence that epigenetic imprinting of HSPCs occurs over an extended period after sleep disruption. This partly persists even after long periods of recovery sleep and results in hyperinflammatory responses of the hematopoietic system to immune challenge.

However, LSK cells return to normal during recovery sleep, despite the presence of the preserved epigenetic signature. This may be due to other epigenetic changes occurring simultaneously and the immense number of genes operating in the cell cycle to regulate proliferation.

The study also suggests that CVD risk factors that improve hematopoiesis accelerate the emergence of HSPC clones, both neutral and mutant, making the individual more susceptible to the disease. Different types of disturbed sleep produce similar effects on blood cell production and peripheral blood monocyte counts, indicating a common endpoint.

These data have important implications for inflammatory diseases such as sepsis, cardiovascular disease, and cancer, and may suggest that sleep behavior in early life dictates future disease severity..” Poor sleep affects immunological function in sustained ways that are not completely reversed by recovery sleep.

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