Gabriel Courties1, Fanny Herisson1, Hendrik B Sager1, Timo Heidt1, Yuxiang Ye1, Ying Wei1, Yuan Sun1, Nicolas Severe1, Partha Dutta1, Jennifer Scharff1, David T Scadden1, Ralph Weissleder1, Filip K Swirski1, Michael A Moskowitz1, Matthias Nahrendorf2. 1. From the Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston (G.C., H.B.S., T.H., Y.Y., Y.S., P.D., J.S., R.W., F.K.S., M.N.); Stroke and Neurovascular Regulation Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital/Harvard Medical School, Charlestown (F.H., Y.W., M.A.M.); Center for Regenerative Medicine, Massachusetts General Hospital, Boston (N.S., D.T.S.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.). 2. From the Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston (G.C., H.B.S., T.H., Y.Y., Y.S., P.D., J.S., R.W., F.K.S., M.N.); Stroke and Neurovascular Regulation Laboratory, Departments of Radiology and Neurology, Massachusetts General Hospital/Harvard Medical School, Charlestown (F.H., Y.W., M.A.M.); Center for Regenerative Medicine, Massachusetts General Hospital, Boston (N.S., D.T.S.); and Department of Systems Biology, Harvard Medical School, Boston, MA (R.W.). mnahrendorf@mgh.harvard.edu.
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). Flow cytometry 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 Ly6C(high) monocytes and neutrophils.
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). Flow cytometry 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 Ly6C(high) monocytes and neutrophils.
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