Therapeutic potential of vasculogenesis and osteogenesis promoted by peripheral blood CD34-positive cells for functional bone healing.
Failures in fracture healing are mainly caused by a lack of vascularization. Adult human circulating CD34+ cells, an endothelial/hematopoietic progenitor-enriched cell population, have been reported to differentiate into osteoblasts in vitro; however, the therapeutic potential of CD34+ cells for fracture healing is still unclear. Therefore, we performed a series of experiments to test our hypothesis that functional fracture healing is supported by vasculogenesis and osteogenesis via regenerative plasticity of CD34+ cells. Peripheral blood CD34+ cells, isolated from total mononuclear cells of adult human volunteers, showed gene expression of osteocalcin in 4 of 20 freshly isolated cells by single cell reverse transcriptase-polymerase chain reaction analysis. Phosphate-buffered saline, mononuclear cells, or CD34+ cells were intravenously transplanted after producing nonhealing femoral fractures in nude rats. Reverse transcriptase-polymerase chain reaction and immunohistochemical staining at the peri-fracture site demonstrated molecular and histological expression of human-specific markers for endothelial cells and osteoblasts at week 2. Functional bone healing assessed by biomechanical as well as radiological and histological examinations was significantly enhanced by CD34+ cell transplantation compared with the other groups. Our data suggest circulating human CD34+ cells have therapeutic potential to promote an environment conducive to neovascularization and osteogenesis in damaged skeletal tissue, allowing the complete healing of fractures.
Matsumoto
Tomoyuki
T
Stem Cell Translational Research, Kobe Institute of Biomedical Research and Innovation/Riken Center for Developmental Biology, 2-2 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047.
Kawamoto
Atsuhiko
A
Kuroda
Ryosuke
R
Ishikawa
Masakazu
M
Mifune
Yutaka
Y
Iwasaki
Hiroto
H
Miwa
Masahiko
M
Horii
Miki
M
Hayashi
Saeko
S
Oyamada
Akira
A
Nishimura
Hiromi
H
Murasawa
Satoshi
S
Doita
Minoru
M
Kurosaka
Masahiro
M
Asahara
Takayuki
T
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis*; D002465:Cell Movement; D002478:Cells, Cultured; D042783:Endothelial Cells; D005260:Female; D005264:Femoral Fractures / Q000473:pathology / Q000628:therapy*; D005269:Femur / Q000098:blood supply* / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000737:chemistry / Q000637:transplantation*; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D015675:Osteocalcin / Q000235:genetics; D010012:Osteogenesis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D011923:Rats, Nude
D020533:Angiogenesis Inhibitors; D018952:Antigens, CD34; D012333:RNA, Messenger; D015675:Osteocalcin