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

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

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

A new study shows that sleep does much more, regulating the normal production of blood cells. This finding underlines how essential a healthy sleep routine is for a normal life. 

Introduction

Over half of adults get too little sleep. This has been linked to a higher blood count of myeloid cells in humans. In rats, one result of good sleep is that hematopoietic stem and progenitor cells (HSPCs) are prevented from cycling in the hemopoietic bone marrow (BM), preventing the build-up of excessive white 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 characteristics vary considerably over the lifespan, with a significant decline in the elderly. Even young and healthy adults have periods of good sleep fluctuating with inadequate sleep, altered by lifestyle factors as well as by the environment and genetic time-regulating mechanisms.

Many studies have shown that catch-up sleep cannot completely neutralize the adverse effects of lost sleep – the so-called sleep debt. The current study, published in the Journal of Experimental Medicine, looked at the effect of sleep fragmentation (SF) and recovery sleep on the epigenetic restructuring of HSPCs, modifying immune responses and disease outcomes. The measures included clonal diversity and hemopoietic genetic aging.

What did the study show?

The findings of the initial mouse study showed that SF affected hematopoiesis over a long period. The mice were roused 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 wake time during the light period.

Conversely, they showed increased SWS and decreased wake time during their active period, though only for the first two hours.

When SF was continued for 16 weeks, but with ten weeks of recovery sleep, the mice continued to show increased wake bout numbers for the whole SF period and the first two weeks of recovery sleep, but then it became normal. 

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

Thus, SF seems to affect sleep quality and white 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 made up over 60% of total white cells and monocytes up to 24 weeks from transplant.

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These findings point to stem-intrinsic mechanisms that regulate prolonged SF-mediated hematopoietic activity.”

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

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

Sleep also maintains the clonal diversity of hematopoietic cells. It has been established that the loss of diversity in such cells is part of clonal hematopoiesis (CH), a common age-associated premalignant disorder caused by the accumulation of somatic mutations. These affect mostly the epigenome at Tet2 and Dmnt3a.

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

These effects were observed in humans as well, with higher BM hematopoietic activity and increased monocyte counts 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 modifications of HSPCs, reducing their clonal diversity and possibly compromising immune function, emphasizes the need for good sleep hygiene even in modern societies when night-time is no longer a time when everything shuts down. Attention needs to be paid to the ubiquitous reasons for disturbed sleep, whether jet lag, insomnia, obstructive sleep apnea, or SF.

Earlier studies have shown an epigenetic modification of cellular function with various types of sleep disorders and perturbations. The current study provides evidence that epigenetic imprinting of HSPCs occurs over a sustained period following sleep disruption. This persists in part even after long periods of recovery sleep and drives hyperinflammatory responses by the hematopoietic system when faced with an 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 risk factors for CVD that enhance hematopoiesis accelerate the emergence of HSPC clones, neutral and mutants, making the individual more susceptible to disease. Different types of disturbed sleep produce similar effects on blood cell production and monocyte counts in peripheral blood, indicating a final common pathway.

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

Journal reference:
  • McAlpine, C. et al. (2022) "Sleep exerts lasting effects on hematopoietic stem cell function and diversity", Journal of Experimental Medicine, 219(11). doi: 10.1084/jem.20220081. https://rupress.org/jem/article/219/11/e20220081/213487/Sleep-exerts-lasting-effects-on-hematopoietic-stem?searchresult=1

Posted in: Medical Science News | Medical Research News | Disease/Infection News

Tags: Aging, Blood, Bone, Bone Marrow, Cancer, Cardiovascular Disease, Cell, Cell Cycle, Cell Production, Cycling, Cytokine, Eye, Genes, Genetic, Hematopoiesis, Hygiene, immunity, Insomnia, Interleukin, Jet Lag, Labor, Medicine, Monocyte, Neutrophils, Obstructive Sleep Apnea, Progenitor Cells, Proliferation, Sepsis, Sleep, Sleep Apnea, Stem Cells, Stress, TNFα, Transplant, Vascular

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Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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