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Cardiovascular Research Advance Access first published online on September 12, 2008
This version [Corrected Proof] published online on October 3, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn247
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org.

Bone marrow CXCR4 induction by cultivation enhances therapeutic angiogenesis

Yuji Shiba1, Masafumi Takahashi1,*, Takeki Hata1, Hideki Murayama1, Hajime Morimoto1, Hirohiko Ise1, Takashi Nagasawa2 and Uichi Ikeda1

1 Department of Cardiovascular Medicine, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan
2 Department of Medical Systems Control, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan

* Corresponding author. Tel: +81 263 37 3352; fax: +81 263 37 2573. E-mail address: masafumi{at}shinshu-u.ac.jp

Aims: The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor (CXCR4, CXC chemokine receptor 4) play a critical role in the process of post-natal neovascularization. Here, we investigated the role of CXCR4+ bone marrow cells (BMCs) in neovascularization in a murine hindlimb ischaemia model.

Methods and results: We found that the expression of CXCR4 in BMCs was specifically upregulated by cultivation; therefore, we used freshly isolated BMCs and cultivated BMCs, designated as BMCFr and BMCCul, respectively. The increased CXCR4 expression corresponded to the migratory capacity in response to SDF-1{alpha}. Real-time reverse transcription–polymerase chain reaction and immunohistochemical analyses revealed that SDF-1{alpha} expression was significantly increased in the ischaemic limbs of mice. Blood flow perfusion and capillary density were significantly accelerated in mice implanted with BMCCul as compared with those in mice implanted with BMCFr. The stimulatory effect of BMCCul on neovascularization was significantly impaired when BMCCul derived from CXCR4+/– mice were implanted. The implanted BMCCul showed high retention in the ischaemic limbs. Further, the implantation of BMCCul significantly increased the expression of interleukin (IL)-1β and vascular endothelial growth factor-A in the ischaemic limbs.

Conclusion: The upregulation of CXCR4 expression by cultivation may serve as a useful source of BMCs for accelerating therapeutic angiogenesis in ischaemic cardiovascular diseases.

KEYWORDS Cardiovascular diseases; Cytokines; Ischaemia; Regeneration; Paracrine effect

Time for primary review: 22 days


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