Therapeutic angiogenesis of bone marrow mononuclear cells (MNCs) and peripheral blood MNCs: transplantation for ischemic hindlimb.
We investigated bone marrow mononuclear cells (BM-MNCs) and peripheral blood mononuclear cells (PB-MNCs) for therapeutic angiogenesis in the ischemic hindlimb. BM-MNCs were isolated and injected into ischemic skeletal muscles in mice. Laser Doppler and histological evaluation were performed after the surgical procedure. Fifteen patients suffering from critical lower limb ischemia received subcutaneous injections of recombinant human granulocyte colony-stimulating factor (G-CSF) to mobilize progenitor cells, and PB-MNCs were harvested and transplanted directly into the ischemic limb. Endothelial cells derived from BM-MNCs were plated, then induced to form three-dimensional networks by invading a Matrigel. Four weeks after implantation of BM-MNCs, laser Doppler analysis showed that the blood flow ratio was significantly increased (0.67 +/- 0.02 vs. 0.44 +/- 0.02). Alkaline phosphatase and immunohistochemical analyses showed that capillary density was significantly increased (95.25 +/- 0.07% vs. 39.6 +/- 0.04%). Two months after implantation of PB-MNCs, in both subgroups, ankle-brachial index values, walking distance, pain scale, and transcutaneous oxygen pressure (TcO(2)) were significantly improved (p < 0.005). A total of six of 15 limb ulcers of transplanted patients were healed after cell transplantation. BM-MNC implantation was able to induce functional angiogenesis in mice ischemic hindlimb. This clinical trial shows that G-CSF-based PB-MNC transplantation is a feasible treatment for the ischemic hindlimb.
Zhang
Hongkun
H
Department of Vascular Surgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People's Republic of China. doczhk@yahoo.com.cn
Zhang
Nan
N
Li
Ming
M
Feng
Hua
H
Jin
Wei
W
Zhao
Haige
H
Chen
Xudong
X
Tian
Lu
L
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001854:Bone Marrow Cells; D016026:Bone Marrow Transplantation; D002196:Capillaries / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007273:Injections, Intramuscular; D007511:Ischemia / Q000628:therapy*; D017078:Laser-Doppler Flowmetry; D007866:Leg / Q000098:blood supply*; D007963:Leukocytes, Mononuclear / Q000637:transplantation*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D018482:Muscle, Skeletal; D018919:Neovascularization, Physiologic; D011994:Recombinant Proteins; D012039:Regional Blood Flow
D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor