TY - JOUR
T1 - Bone marrow CXCR4 induction by cultivation enhances therapeutic angiogenesis
AU - Shiba, Yuji
AU - Takahashi, Masafumi
AU - Hata, Takeki
AU - Murayama, Hideki
AU - Morimoto, Hajime
AU - Ise, Hirohiko
AU - Nagasawa, Takashi
AU - Ikeda, Uichi
N1 - Funding Information:
This study was supported by research grants from the Ministry of Education, Culture, Sports, Science and Technology (to M.T.), the Ministry of Health, Labor and Welfare (to M.T. and U.I.), and Takeda Science Foundation (to M.T.).
PY - 2009/1
Y1 - 2009/1
N2 - Aims: 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. 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 as BMCFr and BMC Cul, respectively. The increased CXCR4 expression corresponded to the migratory capacity in response to SDF-1α. Real-time reverse transcription-polymerase chain reaction and immunohistochemical analyses revealed that SDF-1α expression was significantly increased in the ischaemic limbs of mice. Blood flow perfusion and capillary density were significantly accelerated in mice implanted with BMCCul as compared with those in mice implanted with BMCFr. The stimulatory effect of BMCCul on neovascularization was significantly impaired when BMC Cul derived from CXCR4+/- mice were implanted. The implanted BMCCul showed high retention in the ischaemic limbs. Further, the implantation of BMCCul significantly increased the expression of interleukin (IL)-1β and vascular endothelial growth factor-A in the ischaemic limbs. Conclusion: The upregulation of CXCR4 expression by cultivation may serve as a useful source of BMCs for accelerating therapeutic angiogenesis in ischaemic cardiovascular diseases.
AB - Aims: 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. 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 as BMCFr and BMC Cul, respectively. The increased CXCR4 expression corresponded to the migratory capacity in response to SDF-1α. Real-time reverse transcription-polymerase chain reaction and immunohistochemical analyses revealed that SDF-1α expression was significantly increased in the ischaemic limbs of mice. Blood flow perfusion and capillary density were significantly accelerated in mice implanted with BMCCul as compared with those in mice implanted with BMCFr. The stimulatory effect of BMCCul on neovascularization was significantly impaired when BMC Cul derived from CXCR4+/- mice were implanted. The implanted BMCCul showed high retention in the ischaemic limbs. Further, the implantation of BMCCul significantly increased the expression of interleukin (IL)-1β and vascular endothelial growth factor-A in the ischaemic limbs. Conclusion: The upregulation of CXCR4 expression by cultivation may serve as a useful source of BMCs for accelerating therapeutic angiogenesis in ischaemic cardiovascular diseases.
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U2 - 10.1093/cvr/cvn247
DO - 10.1093/cvr/cvn247
M3 - Article
C2 - 18791205
AN - SCOPUS:57749188855
SN - 0008-6363
VL - 81
SP - 169
EP - 177
JO - Cardiovascular research
JF - Cardiovascular research
IS - 1
ER -
