Circulating human CD34+ progenitor cells modulate neovascularization and inflammation in a nude mouse model.
CD34+ progenitor cells hold promise for therapeutic neovascularization in various settings. In this study, the role of human peripheral blood CD34+ cells in neovascularization and inflammatory cell recruitment was longitudinally studied in vivo. Human CD34+ cells were incorporated in Matrigel, implanted subcutaneously in nude mice, and explanted after 2, 4, 7, or 14 days. Cell-free Matrigels served as controls. Histochemical analyses demonstrated that neovascularization occurred almost exclusively in CD34+ implants. Cellular and capillary density were increased in cell-loaded Matrigels after 2 days and further increased at 14 days. Human CD34+ cells did not incorporate in neovessels, but formed vWF+/CD31+/VEGF+ cell clusters that were present up to day 14. However, CD34+ cells induced host neovascularization, as demonstrated by increased presence of murine CD31+ and vWF+ vasculature from day 7 to 14. Moreover, recruitment of murine monocytes/macrophages was significantly enhanced in CD34+ implants at all time points. Gene expression of chemotactic cytokines MCP-1 and IL-8 was detected on CD34+ cells in vitro and confirmed immunohistochemically in cell-loaded explants at all time points. Our data indicate that human CD34+ cells, implanted in a hypoxic environment, generate an angiogenic niche by secreting chemotactic and angiogenic factors, enabling rapid neovascularization, possibly via recruitment of monocytes/macrophages.
van der Strate
B W A
BW
Department of Pathology and Laboratory Medicine, Medical Biology Section, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. B.W.A.van.der.Strate@med.umcg.nl
Popa
E R
ER
Schipper
M
M
Brouwer
L A
LA
Hendriks
M
M
Harmsen
M C
MC
van Luyn
M J A
MJ
D000818:Animals; D018952:Antigens, CD34 / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D003094:Collagen; D004195:Disease Models, Animal; D004338:Drug Combinations; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006412:Hematopoietic Stem Cells / Q000276:immunology*; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology*; D007279:Injections, Subcutaneous; D016209:Interleukin-8 / Q000378:metabolism; D007797:Laminin; D008264:Macrophages / Q000166:cytology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009000:Monocytes / Q000166:cytology; D018919:Neovascularization, Physiologic / Q000276:immunology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011509:Proteoglycans; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D018952:Antigens, CD34; D018932:Chemokine CCL2; D004338:Drug Combinations; D016209:Interleukin-8; D007797:Laminin; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; C059485:matrigel; D003094:Collagen