CXCR4 blockade augments bone marrow progenitor cell recruitment to the neovasculature and reduces mortality after myocardial infarction

Kentaro Jujo, Hiromichi Hamada, Atsushi Iwakura, Tina Thorne, Haruki Sekiguchi, Trevor Clarke, Aiko Ito, Sol Misener, Toshikazu Tanaka, Ekaterina Klyachko, Koichi Kobayashi, Jörn Tongers, Jérôme Roncalli, Yukio Tsurumi, Nobuhisa Hagiwara, Douglas W. Losordo

Research output: Contribution to journalArticlepeer-review

171 Scopus citations

Abstract

We hypothesized that a small molecule CXCR4 antagonist, AMD3100 (AMD), could augment the mobilization of bone marrow (BM)-derived endothelial progenitor cells (EPCs), thereby enhancing neovascularization and functional recovery after myocardial infarction. Single-dose AMD injection administered after the onset of myocardial infarction increased circulating EPC counts and myocardial vascularity, reduced fibrosis, and improved cardiac function and survival. In mice transplanted with traceable BM cells, AMD increased BM-derived cell incorporation in the ischemic border zone. In contrast, continuous infusion of AMD, although increasing EPCs in the circulation, worsened outcome by blocking EPC incorporation. In addition to its effects as a CXCR4 antagonist, AMD also up-regulated VEGF and matrix metalloproteinase 9 (MMP-9) expression, and the benefits of AMD were not observed in the absence of MMP-9 expression in the BM. These findings suggest that AMD3100 preserves cardiac function after myocardial infarction by enhancing BM-EPC-mediated neovascularization, and that these benefits require MMP-9 expression in the BM, but not in the ischemic region. Our results indicate that AMD3100 could be a potentially useful therapy for the treatment of myocardial infarction.

Original languageEnglish (US)
Pages (from-to)11008-11013
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number24
DOIs
StatePublished - Jun 15 2010

Keywords

  • Angiogenesis
  • Stem cell
  • Vasculogenesis

ASJC Scopus subject areas

  • General

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