Novel therapeutic strategy for stroke in rats by bone marrow stromal cells and ex vivo HGF gene transfer with HSV-1 vector

Ming Zhu Zhao, Naosuke Nonoguchi, Naokado Ikeda, Takuji Watanabe, Daisuke Furutama, Daisuke Miyazawa, Hiroshi Funakoshi, Yoshinaga Kajimoto, Toshikazu Nakamura, Mari Dezawa, Masa Aki Shibata, Yoshinori Otsuki, Robert S. Coffin, Wei Dong Liu, Toshihiko Kuroiwa, Shin Ichi Miyatake

Research output: Contribution to journalArticlepeer-review

126 Citations (Scopus)

Abstract

Occlusive cerebrovascular disease leads to brain ischemia that causes neurological deficits. Here we introduce a new strategy combining mesenchymal stromal cells (MSCs) and ex vivo hepatocyte growth factor (HGF) gene transferring with a multimutated herpes simplex virus type-1 vector in a rat transient middle cerebral artery occlusion (MCAO) model. Gene-transferred MSCs were intracerebrally transplanted into the rats' ischemic brains at 2 h (superacute) or 24 h (acute) after MCAO. Behavioral tests showed significant improvement of neurological deficits in the HGF-transferred MSCs (MSC-HGF)-treated group compared with the phosphate-buffered saline (PBS)-treated and MSCs-only-treated group. The significant difference of infarction areas on day 3 was detected only between the MSC-HGF group and the PBS group with the superacute treatment, but was detected among each group on day 14 with both transplantations. After the superacute transplantation, we detected abundant expression of HGF protein in the ischemic brain of the MSC-HGF group compared with others on day 1 after treatment, and it was maintained for at least 2 weeks. Furthermore, we determined that the increased expression of HGF was derived from the transferred HGF gene in gene-modified MSCs. The percentage of apoptosis-positive cells in the ischemic boundary zone (IBZ) was significantly decreased, while that of remaining neurons in the cortex of the IBZ was significantly increased in the MSC-HGF group compared with others. The present study shows that combined therapy is more therapeutically efficient than MSC cell therapy alone, and it may extend the therapeutic time window from superacute to acute phase.

Original languageEnglish
Pages (from-to)1176-1188
Number of pages13
JournalJournal of Cerebral Blood Flow and Metabolism
Volume26
Issue number9
DOIs
Publication statusPublished - 2006 Sep 14
Externally publishedYes

Keywords

  • Gene transfer
  • Hepatocyte growth factor
  • Herpes simplex virus
  • Intracerebral transplantation
  • Mesenchymal stromal cell
  • Transient cerebral ischemia

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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