ABSTRACT
Sleep is integral to life1. Although insufficient or disrupted sleep increases the risk of multiple pathological conditions, including cardiovascular disease2, we know little about the cellular and molecular mechanisms by which sleep maintains cardiovascular health. Here we report that sleep regulates haematopoiesis and protects against atherosclerosis in mice. We show that mice subjected to sleep fragmentation produce more Ly-6Chigh monocytes, develop larger atherosclerotic lesions and produce less hypocretin-a stimulatory and wake-promoting neuropeptide-in the lateral hypothalamus. Hypocretin controls myelopoiesis by restricting the production of CSF1 by hypocretin-receptor-expressing pre-neutrophils in the bone marrow. Whereas hypocretin-null and haematopoietic hypocretin-receptor-null mice develop monocytosis and accelerated atherosclerosis, sleep-fragmented mice with either haematopoietic CSF1 deficiency or hypocretin supplementation have reduced numbers of circulating monocytes and smaller atherosclerotic lesions. Together, these results identify a neuro-immune axis that links sleep to haematopoiesis and atherosclerosis.
Subject(s)
Atherosclerosis/prevention & control , Hematopoiesis/physiology , Sleep/physiology , Animals , Antigens, Ly/metabolism , Atherosclerosis/metabolism , Atherosclerosis/pathology , Bone Marrow Cells/metabolism , Female , Hematopoiesis/drug effects , Hypothalamic Area, Lateral/metabolism , Macrophage Colony-Stimulating Factor/biosynthesis , Macrophage Colony-Stimulating Factor/deficiency , Macrophage Colony-Stimulating Factor/metabolism , Male , Mice , Monocytes/drug effects , Monocytes/metabolism , Myelopoiesis/drug effects , Neutrophils/metabolism , Orexin Receptors/deficiency , Orexin Receptors/metabolism , Orexins/biosynthesis , Orexins/deficiency , Orexins/metabolism , Orexins/pharmacology , Sleep/drug effects , Sleep Deprivation/metabolism , Sleep Deprivation/physiopathology , Sleep Deprivation/prevention & controlABSTRACT
Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I-IV cancer patients and in half of 352 stage I-III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening.