title: Therapeutic angiogenesis by autologous adipose-derived regenerative cells: comparison with bone marrow mononuclear cells.
abstract: Transplantation of adipose-derived regenerative cell (ADRC) enhances ischemia-induced angiogenesis, but the underlying mechanism remains unknown. Here, we compared the efficacy between ADRC and bone marrow mononuclear cell (BM-MNC) transplantation in rabbits model of hindlimb ischemia and examined the possible roles of alternative phenotypic macrophages polarization in ADRC-mediated angiogenesis using mice model of hindlimb ischemia. ADRCs and BM-MNCs were isolated from New Zealand White rabbits and C57BL/6J mice. In rabbit studies, our data showed that ADRCs could incorporate into the endothelial vasculature in vitro and in vivo. Both ADRC-conditioned media (CM) and BM-MNC-CM enhanced the migratory ability and interrupted the process of apoptosis in human umbilical vein endothelial cells. Four weeks after cell transplantation, augmentation of postnatal neovascularization was observed in the ischemic muscle injected with either ADRCs or BM-MNCs. In mice studies, we presented that ADRCs polarized into the IL-10-releasing M2 macrophages through PGE2-EP2/4 axis and suppressed the expressions of TNF-α and IL-6 in the ischemic muscle. Gene expressions of several angiogenic cytokines were amplified in the macrophages cultured in ADRC-CM rather than BM-MNC-CM. Blockade of IL-10 using neutralizing MAb attenuated the ADRC-mediated angiogenesis and caused muscle apoptosis in vivo. In conclusion, ADRC transplantation harvested similar effect of neovascularization augmentation compared with BM-MNC in experimental rabbit model of hindlimb ischemia; ADRC displayed a unique immunoregulatory manner of accelerating IL-10-releasing M2 macrophages polarization through the PGE2-EP2/4 axis.
authors: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors: Changning
authors: C
authors: Hao
authors: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan shintani@med.nagoya-u.ac.jp.
authors: Satoshi
authors: S
authors: Shintani
authors: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors: Yuuki
authors: Y
authors: Shimizu
authors: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors: Kazuhisa
authors: K
authors: Kondo
authors: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors: Masakazu
authors: M
authors: Ishii
authors: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors: Hongxian
authors: H
authors: Wu
authors: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
authors: Toyoaki
authors: T
authors: Murohara
mesh_terms: D000273:Adipose Tissue / Q000166:cytology*; D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation; D002465:Cell Movement; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D006614:Hindlimb; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007511:Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D018919:Neovascularization, Physiologic; D010641:Phenotype; D011817:Rabbits; D018078:Receptors, Prostaglandin E / Q000378:metabolism; D012038:Regeneration; D044968:Regenerative Medicine / Q000379:methods*; D033581:Stem Cell Transplantation; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D018836:Inflammation Mediators; D015850:Interleukin-6; D018078:Receptors, Prostaglandin E; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D015232:Dinoprostone
keywords: adipose-derived regenerative cell; macrophage polarization; peripheral artery disease; therapeutic angiogenesis