Highly angiogenic CXCR4+ CD31+ monocyte subset derived from 3D culture of human peripheral blood

• Published in: Biomaterials 2013-03, Vol.34 (8), p.1929-1941
• Main Authors: Hur, Jin, Choi, Jae-Il, Yun, Ji-Yeon, Yoon, Chang-Hwan, Jang, Jae Hee, Im, Seung-Gyun, Ko, Seung-Bum, Kang, Jin-A, Park, Jonghanne, Lee, Sang Eun, Kim, Ju-Young, Yang, Han-Mo, Park, Young-Bae, Kim, Hyo-Soo
• Format: Article
• Language: English
• Subjects: Adult; Advanced Basic Science; Angiogenesis; Animals; Biomedical materials; Blood; Cell Culture Techniques - methods; Cells, Cultured; Cellular Microenvironment - drug effects; Collagen - pharmacology; Culture; Dentistry; Diseases; Drug Combinations; Flow cytometry; Formations; Hematosphere; Hindlimb - blood supply; Hindlimb - pathology; Human; Humans; Ischemia - pathology; Ischemia - therapy; Ischemic diseases; Laminin - pharmacology; Lipopolysaccharide Receptors - metabolism; Mice; Mice, Nude; Microenvironment; Monocytes - cytology; Monocytes - drug effects; Monocytes - metabolism; Monocytes - transplantation; Myeloid cells; Neovascularization, Physiologic - drug effects; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism; Proteoglycans - pharmacology; Receptors, CXCR4 - metabolism; Receptors, Vascular Endothelial Growth Factor - metabolism; Signal Transduction - drug effects; Spheroids, Cellular - cytology; Spheroids, Cellular - drug effects; Spheroids, Cellular - metabolism; Surgical implants; Three dimensional; Vascular Endothelial Growth Factor A - metabolism
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2012.11.015

Abstract Ex vivo expansion of human circulating angiogenic cells is a major challenge in autologous cell therapy for ischemic diseases. Here, we demonstrate that hematosphere-derived CXCR4+ CD31+ myeloid cells using peripheral blood possess robust proangiogenic capacity such as formation of vessel-like structures and tip cell-like morphology in Matrigel. We also found that CD31 positive myeloid cells are principal cellular component of hematospheres by magnetic cell sorting. Flow cytometry analysis showed that fresh peripheral blood contained 40.3 ± 15.2% of CXCR4+ CD31+ myeloid cells, but at day 5 of hematosphere culture, most of myeloid cells were CXCR4+ CD31+ by 86.9 ± 5.4%. Hematosphere culture significantly increased the production of angiogenic niche-supporting cytokines. Moreover, CD31-homophilic interaction and VEGF–VEGF receptor loop signaling were essential for sphere formation and acquisition of angiogenic capacity in hematospheres. Matrigel plug and ischemic hindlimb model provide in vivo evidence that hematosphere-derived myeloid cells have highly vasculogenic capacities, participate in new and mature vessel formation, and exert therapeutic effects on ischemic hindlimb. In conclusion, our strategy for ex vivo expansion of human CXCR4+ CD31+ angiogenic cells using hematospheres provides an autologous therapeutic cell source for ischemic diseases and a new model for investigating the microenvironment of angiogenesis.