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Stem cell implantation can be used to induce neovascularization and has been tested as a therapy for ischemia treatment. However, stem cell implantation as a therapy for ischemia treatment may have limitations for clinical applications. Since the methods of stem cell harvest are invasive, it may not be feasible to harvest autologous stem cells from aged patients or patients with cardiovascular risk. Furthermore, poor cell survival after engraftment in ischemic tissue may lower the therapeutic efficacy of stem cells. hADSCs implanted to ischemic tissues support tissue revascularization in large part through secreted angiogenic factors. The goal of this study is to demonstrate that medium collected from human adipose-derived stromal cells (hADSCs) cultured as spheroids can exhibit improved therapeutic efficacy for ischemia treatment. Conditioned medium derived from hADSC monolayer culture (M-CM) or spheroid culture (S -CM), fresh medium (FM), or hADSCs were injected intramuscularly into the muscle in the medial thigh after mouse hindlimb ischemia modeling. Due to a mild hypoxic environment formed in hADSC spheroid, spheroid culture was effective to precondition the hADSCs to upregulate hypoxia-inducible factor-1α gene expression following significant enhancement in both angiogenic and anti-apoptotic factor secretion to the culture medium compared to monolayer cultures. S-CM administration to ischemic hindlimbs in mice significantly enhanced neovasclurization, protected muscles from incipient ischemic apoptosis, and improved limb survival as compared to M-CM or FM administration or hADSC implantation. These data suggest that injection of conditioned medium obtained from hADSC spheroid culture may be more effective therapeutic option for treatment of ischemic diseases than hADSC implantation.