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TRANSLATIONAL AND CLINICAL RESEARCH

Local Delivery of Granulocyte Colony Stimulating Factor-Mobilized CD34-Positive Progenitor Cells Using Bioscaffold for Modality of Unhealing Bone Fracture

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

Key Words. CD34 stem cells • CD34 progenitors • CD34 cell dose • Cellular therapy • Cell transplantation • Osteoblast • Endothelial cell • Stem cell transplantation

Correspondence: Takayuki Asahara, M.D., Ph.D., Stem Cell Translational Research, Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, 2-2 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan. Telephone: 81-78-304-5772; Fax: 81-78-304-5263; e-mail: Asa777{at}aol.com; or Tomoyuki Matsumoto, M.D., Ph.D., Stem Cell Translational Research, Institute of Biomedical Research and Innovation/RIKEN Center for Developmental Biology, 2-2 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan. Telephone: 81-78-304-5772; Fax: 81-78-304-5263; e-mail: matsun{at}m4.dion.ne.jp

Received October 18, 2007; accepted for publication March 23, 2008.
First published online in STEM CELLS EXPRESS   April 3, 2008.

We recently reported that i.v. transplantation of adult human circulating CD34+ cells, an endothelial/hematopoietic progenitor-enriched cell population, contributes to fracture healing through the enhancement of vasculogenesis and osteogenesis. However, the scarcity of CD34+ cells in the adult human is a critical issue for the future clinical application of this method. To overcome this issue, we assessed in vitro and in vivo capacity of granulocyte colony-stimulating factor-mobilized peripheral blood (GM-PB) human CD34+ cells for vasculogenesis and osteogenesis. First, we confirmed the differentiation capability of GM-PB CD34+ cells into osteoblasts in vitro. Second, local transplantation of GM-PB CD34+ cells on atelocollagen scaffold was performed in nude rats in a model of unhealing fractures. Immunostaining for human leukocyte antigen-ABC of tissue samples 1 week after fracture and cell therapy showed the superior incorporation after local transplantation compared with systemic infusion. Third, the effects of local transplantation of 10⁵ (Hi), 10⁴ (Mid), or 10³ (Lo) doses of GM-PB CD34+ cells or phosphate-buffered saline (PBS) on fracture healing were compared. Extrinsic vasculogenic and osteogenic differentiation of GM-PB CD34+ cells, enhancement of the intrinsic angio-osteogenesis by recipient cells, augmentation of blood flow recovery at the fracture sites, and radiological and histological confirmation of fracture healing were observed only in the Hi and Mid groups but not in the Lo and PBS groups. These results strongly suggest that local transplantation of GM-PB CD34+ cells with atelocollagen scaffold is a feasible strategy for therapeutic vasculogenesis and osteogenesis needed for fracture healing.

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