Ischemic Stroke Activates Hematopoietic Bone Marrow Stem Cells

Abstract

Rationale The mechanisms leading to an expanded neutrophil and monocyte supply after stroke are incompletely understood. Objective To test the hypothesis that transient middle cerebral artery occlusion (tMCAO) in mice leads to activation of hematopoietic bone marrow stem cells. Methods and Results Serial in vivo bioluminescence reporter gene imaging in mice with tMCAO revealed that bone marrow cell cycling peaked 4 days after stroke (p<0.05 versus pre tMCAO). FACS and cell cycle analysis showed activation of the entire hematopoietic tree, including myeloid progenitors. The cycling fraction of the most upstream hematopoietic stem cells increased from 3.34%±0.19 to 7.32±0.52 after tMCAO (p<0.05). In vivo microscopy corroborated proliferation of adoptively transferred hematopoietic progenitors in the bone marrow of mice with stroke. The hematopoietic system’s myeloid bias was reflected by increased expression of myeloid transcription factors, including PU.1 (p<0.05), and by a decline in lymphocyte precursors. In mice after tMCAO, tyrosine hydroxylase levels in sympathetic fibers and bone marrow noradrenaline levels rose (p<0.05, respectively), associated with a decrease of hematopoietic niche factors that promote stem cell quiescence. In mice with genetic deficiency of the β3 adrenergic receptor, hematopoietic stem cells did not enter the cell cycle in increased numbers after tMCAO (naive control, 3.23±0.22; tMCAO, 3.74±0.33, p=0.51). Conclusions Ischemic stroke activates hematopoietic stem cells via increased sympathetic tone, leading to a myeloid bias of hematopoiesis and higher bone marrow output of inflammatory Ly6Chigh monocytes and neutrophils.

Lifestyle Effects on Hematopoiesis and Atherosclerosis

“…Sympathetic activity after acute myocardial infarction in mice also activates HSC migration, leading to extramedullary monocyte production and aggravated atherosclerosis in ApoE ‒/‒ mice 24 . Ischemic stroke in mice similarly triggers bone marrow activation 83 .…”

“…Interestingly, injection of epinephrin into humans cause similar changes in blood leukocyte levels as exercise does. Similar to stress exposure 84 , acute MI 24 , stroke 83 and during circadian regulation of hematopoiesis 82 , exercise may acutely elevate sympathetic tone in the bone marrow and lower bone marrow CXCL12 signaling. Decrease of this chemokine may then lead to stem and myeloid cell release into blood, and contribute, in addition to demargination of cells, to blood leukocytosis acutely after strenuous physical activity.…”

Advancing biomedical imaging

“…Important questions that microscopic imaging can help to answer are those related to survival, proliferation, and differentiation of stem and progenitor cells. In vivo microscopy can follow individual fluorescently tagged hematopoietic stem cells over several days and report on their propensity to divide or migrate as a function of their localization in the hematopoietic niche and as a function of disease: for instance, in mice with increased sympathetic tone after ischemic stroke (65). Intravital imaging has become a workhorse for deciphering the role of bone marrow stem cells (66)(67)(68)(69).…”

Matthias Nahrendorf

“…One area that I'm very excited about is understanding better how the bone marrow behaves in cardiovascular disease 12 and the signals that lead to an increased or decreased production of immune cells. One area we're looking at is how the central nervous system may or may not be involved in it.…”