Abstract
Objective: Due to the poor prognosis of therapeutic angiogenesis by bone marrow-mononuclear cells (BM-MNCs) to severe atherosclerotic patients, we focused on adipose-derived regenerative cells (ADRCs) as an alternative choice. Here, we compared the therapeutic efficacy between these two cells in two animal models of hindlimb ischemia (HLI) and further tested the hypothesis that ADRC augments angiogenesis by regulating local hemostasis through macrophage polarization. Methods and Results: We observed that fluorescence labeled ADRCs incorporated into vasculature in vitro and vivo. Then, we compared the paracrine manner between ADRCs and BM-MNCs using conditioned media (CM). Accelerated migratory ability and prevented apoptosis of human umbilical vein endothelial cells (HUVECs) were observed treated by both CM compared with control. In vivo study, implantation of either ADRCs or BM-MNCs revealed more angiographically detectable collateral vessels formation, higher capillary density, greater cuff blood pressure ratio, and stronger laser Doppler blood perfusion signals than control in rabbit HLI model. In mice study, we proved ADRCs changed the polarity of infiltrated macrophage into M2 phenotype through prostaglandin E2 (PGE2) and EP2/4 receptors. Next, the mRNA expression of several angiogenic cytokines were up-regulated in the macrophages cultured in ADRC-CM compared with BM-MNC-CM. ADRCs implantation also muted local inflammation and apoptosis via down-regulating the gene expression of pro-inflammatory cytokines, as well as increasing interleukin (IL)-10. Finally, blockade of IL-10 by neutralizing monoclonal antibody resulted in harsher microenvironment and attenuated ischemic-induced angiogenesis in mouse HLI model. Conclusions: In conclusion, the safety and efficacy of therapeutic angiogenesis by ADRCs implantation was comparable with BM-MNCs in rabbit HLI model. Moreover, slanted M2 polarity of infiltrated macrophages was observed after ADRCs implantation through PGE2 - EP2/4 - IL-10 axis, leading to facilitation of postnatal neovascularization via their angiogenic, anti-inflammatory and anti-apoptotic manners.
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