title: Ischemic stroke activates hematopoietic bone marrow stem cells.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: 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.).
authors.forename: Gabriel
authors.initials: G
authors.lastname: Courties
authors.affiliation: 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.).
authors.forename: Fanny
authors.initials: F
authors.lastname: Herisson
authors.affiliation: 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.).
authors.forename: Hendrik B
authors.initials: HB
authors.lastname: Sager
authors.affiliation: 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.).
authors.forename: Timo
authors.initials: T
authors.lastname: Heidt
authors.affiliation: 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.).
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Ye
authors.affiliation: 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.).
authors.forename: Ying
authors.initials: Y
authors.lastname: Wei
authors.affiliation: 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.).
authors.forename: Yuan
authors.initials: Y
authors.lastname: Sun
authors.affiliation: 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.).
authors.forename: Nicolas
authors.initials: N
authors.lastname: Severe
authors.affiliation: 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.).
authors.forename: Partha
authors.initials: P
authors.lastname: Dutta
authors.affiliation: 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.).
authors.forename: Jennifer
authors.initials: J
authors.lastname: Scharff
authors.affiliation: 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.).
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
authors.affiliation: 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.).
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.affiliation: 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.).
authors.forename: Filip K
authors.initials: FK
authors.lastname: Swirski
authors.affiliation: 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.).
authors.forename: Michael A
authors.initials: MA
authors.lastname: Moskowitz
authors.affiliation: 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.
authors.forename: Matthias
authors.initials: M
authors.lastname: Nahrendorf
mesh_terms: D000320:Adrenergic Fibers / Q000378:metabolism / Q000502:physiology; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000473:pathology*; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D038042:Myelopoiesis; D009638:Norepinephrine / Q000378:metabolism; D022702:Receptors, Adrenergic, beta-3 / Q000235:genetics / Q000378:metabolism; D055153:Stem Cell Niche; D014157:Transcription Factors / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D022702:Receptors, Adrenergic, beta-3; D014157:Transcription Factors; D014446:Tyrosine 3-Monooxygenase; D009638:Norepinephrine
keywords: bone marrow; hematopoietic stem cells; monocyte; stroke