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TRANSLATIONAL AND CLINICAL RESEARCH

Administrations of Peripheral Blood CD34-Positive Cells Contribute to Medial Collateral Ligament Healing via Vasculogenesis

^aDepartment of Orthopedic Surgery, Kobe University Graduate School of Medicine, Kobe, Japan;
^bStem Cell Translational Research, Kobe Institute of Biomedical Research and Innovation, RIKEN Center for Developmental Biology, Kobe, Japan;
^cDepartment of Regenerative Medicine Science, Tokai University School of Medicine, Isehara, Kanagawa, Japan

Key Words. Endothelial progenitor cells • Vascularization • Ligament healing

Correspondence: Ryosuke Kuroda, M.D., Ph.D., Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. Telephone: 81-78-382-5985; Fax: 81-78-351-6930; e-mail: kurodar{at}med.kobe-u.ac.jp

Received August 23, 2007; accepted for publication December 25, 2007.
First published online in STEM CELLS EXPRESS   January 10, 2008.



Neoangiogenesis is a key process in the initial phase of ligament healing. Adult human circulating CD34+ cells, an endothelial/hematopoietic progenitor-enriched cell population, have been reported to contribute to neoangiogenesis; however, the therapeutic potential of CD34+ cells for ligament healing is still unclear. Therefore, we performed a series of experiments to test our hypothesis that ligament healing is supported by CD34+ cells via vasculogenesis. Granulocyte colony-stimulating factor-mobilized peripheral blood (GM-PB) CD34+ cells with atelocollagen (CD34+ group), GM-PB mononuclear cells (MNCs) with atelocollagen (MNC group), or atelocollagen alone (control group) was locally transplanted after the creation of medial collateral ligament injury in immunodeficient rats. Reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemical staining at the injury site demonstrated that molecular and histological expression of human-specific markers for endothelial cells was higher in the CD34+ group compared with the other groups at week 1. Endogenous effect, assessed by capillary density and mRNA expression of vascular endothelial growth factor, was significantly higher in CD34+ cell group than the other groups. In addition to the observation that, as assessed by real-time RT-PCR, gene expression of ligament-specific marker was significantly higher in the CD34+ group than in the other groups, ligament healing assessed by macroscopic, histological, and biomechanical examination was significantly enhanced by CD34+ cell transplantation compared with the other groups. Our data strongly suggest that local transplantation of circulating human CD34+ cells may augment the ligament healing process by promoting a favorable environment through neovascularization.

Disclosure of potential conflicts of interest is found at the end of this article.