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Cardiovascular Research Advance Access [Accepted Manuscript] published online on September 12, 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 Shiba, MD, PhD1, Masafumi Takahashi, MD, PhD1, Takeki Hata, MD1, Hideki Murayama, MD1, Hajime Morimoto, DVM, PhD1, Hirohiko Ise, PhD1, Takashi Nagasawa, MD, PhD2 and Uichi Ikeda, MD, PhD1

1 Department of Cardiovascular Medicine, Shinshu University Graduate School of Medicine, Matsumoto, Kyoto, Japan
2 Department of Medical Systems Control, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan

Address correspondence to: Masafumi Takahashi, MD, PhD, Department of Cardiovascular Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan Tel/ Fax: +81-263-37-3352/+81-263-37-2573 E-mail: masafumi{at}shinshu-u.ac.jp

Aims: The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor (CXCR4) 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 ischemia 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 BMCFr and BMCCul, respectively. The increased CXCR4 expression corresponded to the migratory capacity in response to SDF-1{alpha}. Real-time RT-PCR and immunohistochemical analyses revealed that SDF-1{alpha} expression was significantly increased in the ischemic limbs of mice. Blood flow perfusion and capillary density were significantly accelerated in mice implanted with BMCCul as compared to 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 ischemic limbs. Further, the implantation of BMCCul significantly increased the expression of interleukin (IL)-1β and vascular endothelial growth factor-A (VEGF-A) in the ischemic limbs.

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

KEYWORDS cardiovascular diseases; cytokines; ischemia; regeneration; paracrine effect

Time for primary review: 22 Days


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