Bone marrow CXCR4 induction by cultivation enhances therapeutic angiogenesis.
OBJECTIVE
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.


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 BMC(Fr) and BMC(Cul), 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 BMC(Cul) as compared with those in mice implanted with BMC(Fr). The stimulatory effect of BMC(Cul) on neovascularization was significantly impaired when BMC(Cul) derived from CXCR4(+/-) mice were implanted. The implanted BMC(Cul) showed high retention in the ischaemic limbs. Further, the implantation of BMC(Cul) significantly increased the expression of interleukin (IL)-1 beta and vascular endothelial growth factor-A in the ischaemic limbs.


CONCLUSIONS
The upregulation of CXCR4 expression by cultivation may serve as a useful source of BMCs for accelerating therapeutic angiogenesis in ischaemic cardiovascular diseases.
Shiba
Yuji
Y
Department of Cardiovascular Medicine, Shinshu University Graduate School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621, Japan.
Takahashi
Masafumi
M
Hata
Takeki
T
Murayama
Hideki
H
Morimoto
Hajime
H
Ise
Hirohiko
H
Nagasawa
Takashi
T
Ikeda
Uichi
U
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000378:metabolism; D004195:Disease Models, Animal; D006614:Hindlimb / Q000098:blood supply / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics* / Q000378:metabolism*; D012039:Regional Blood Flow / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; D053583:Interleukin-1beta; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D042461:Vascular Endothelial Growth Factor A