Administration of hematopoietic cytokines in the subacute phase after cerebral infarction is effective for functional recovery facilitating proliferation of intrinsic neural stem/progenitor cells and transition of bone marrow-derived neuronal cells

Hiroshi Kawada, Shunya Takizawa, Tomomi Takanashi, Yuko Morita, Jun Fujita, Keiichi Fukuda, Shigeharu Takagi, Hideyuki Okano, Kiyoshi Ando, Tomomitsu Hotta

Research output: Contribution to journalArticlepeer-review

190 Citations (Scopus)

Abstract

Background - Hematopoietic cytokines, granulocyte colony-stimulating factor (G-CSF), and stem cell factor (SCF) were reported to show a neuroprotective effect or to support neurogenesis. These cytokines also mobilize bone marrow (BM) cells into the brain, and the BM-derived cells differentiate into neuronal cells. We administered these hematopoietic cytokines after focal cerebral ischemia and assessed their effects and the therapeutic time window for neuronal regeneration. Methods and Results - We induced permanent middle cerebral artery occlusion in mice whose BM had been replaced with BM cells from green fluorescent protein (GFP)-transgenic mice. The occluded mice were treated with G-CSF and SCF in the acute phase (days 1 to 10) or subacute phase (days 11 to 20), and the brain functions and histological changes were evaluated. Separately, we injected bromodeoxyuridine during cytokine treatment to assess cell kinetics in the brain. Six mice were prepared for each experimental group. Administration of G-CSF and SCF in the subacute phase effectively improved not only motor performance but also higher brain function, compared with acute-phase treatment. Acute-phase and subacute-phase treatments identically reduced the infarct volume relative to vehicle treatment. However, subacute-phase treatment significantly induced transition of BM-derived neuronal cells into the peri-infarct area and stimulated proliferation of intrinsic neural stem/progenitor cells in the neuroproliferative zone. Conclusions - Administration of G-CSF and SCF in the subacute phase after focal cerebral ischemia is effective for functional recovery, enhancing cytokine-induced generation of neuronal cells from both BM-derived cells and intrinsic neural stem/progenitor cells. Because G-CSF and SCF are available for clinical use, these findings suggest a new therapeutic strategy for stroke.

Original languageEnglish
Pages (from-to)701-710
Number of pages10
JournalCirculation
Volume113
Issue number5
DOIs
Publication statusPublished - 2006 Feb

Keywords

  • Bone marrow
  • Cerebral infarction
  • Hematopoietic cytokines
  • Neural stem/progenitor cells
  • Regeneration

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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