Abstract
Mesenchymal stem cells (MSCs) are ‘adult' multipotent cells that promote regeneration of injured tissues in vivo. However, differences in oxygenation levels between normoxic culture conditions (21% oxygen) and both the MSC niche (2–8% oxygen) and ischemic injury-induced oxidative stress conditions in vivo have resulted in low efficacy of MSC therapies in both pre-clinical and clinical studies. To address this issue, we examined the effectiveness of hypoxia preconditioning (2% oxygen) for enhancing the bioactivity and tissue-regenerative potential of adipose-derived MSCs. Hypoxia preconditioning enhanced the proliferative potential of MSCs by promoting the expression of normal cellular prion protein (PrPC). In particular, hypoxia preconditioning-mediated MSC proliferation was regulated by PrPC-dependent JAK2 and STAT3 activation. In addition, hypoxia preconditioning-induced PrPC regulated superoxide dismutase and catalase activity, and inhibited oxidative stress-induced apoptosis via inactivation of cleaved caspase-3. In a murine hindlimb ischemia model, hypoxia preconditioning enhanced the survival and proliferation of transplanted MSCs, ultimately resulting in improved functional recovery of the ischemic tissue, including the ratio of blood flow perfusion, limb salvage, and neovascularization. These results suggest that Hypo-MSC offer a therapeutic strategy for accelerated neovasculogenesis in ischemic diseases, and that PrPC comprises a potential target for MSC-based therapies.
Highlights
Mesenchymal stem cells (MSCs) are ‘adult’ multipotent cells that promote regeneration of injured tissues in vivo
Maximal levels of PrPC expression were observed after hypoxic stimulation for 12 h (Figure 2a). This hypoxia-induced expression of PrPC was attenuated by treatment of MSCs with HIF-1α-specific siRNAs (Figure 2b). These findings suggest that hypoxia preconditioning promotes the expression of PrPC via hypoxia-mediated increases in HIF-1α expression
The increase in proliferation observed in Hypo-MSC, compared with that of MSCs cultivated under normoxic conditions, was inhibited by siRNA-mediated PrPC knockdown (Figure 2f). These results suggest that hypoxia preconditioning enhances MSC proliferation potential through PrPC-mediated activation of janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway
Summary
Mesenchymal stem cells (MSCs) are ‘adult’ multipotent cells that promote regeneration of injured tissues in vivo. Differences in oxygenation levels between normoxic culture conditions (21% oxygen) and both the MSC niche (2–8% oxygen) and ischemic injury-induced oxidative stress conditions in vivo have resulted in low efficacy of MSC therapies in both pre-clinical and clinical studies To address this issue, we examined the effectiveness of hypoxia preconditioning (2% oxygen) for enhancing the bioactivity and tissue-regenerative potential of adipose-derived MSCs. Hypoxia preconditioning enhanced the proliferative potential of MSCs by promoting the expression of normal cellular prion protein (PrPC). In a murine hindlimb ischemia model, hypoxia preconditioning enhanced the survival and proliferation of transplanted MSCs, resulting in improved functional recovery of the ischemic tissue, including the ratio of blood flow perfusion, limb salvage, and neovascularization. 930, Republic of Korea hEGF, human epidermal growth factor; hVEGF, human vascular endothelial growth factor; hFGF, human fibroblast growth factor; hHGF, human hepatocyte growth factor; IGF-1, insulin-like growth factor-1; SDF-1, stromal cell-derived factor-1; EPO, erythropoietin; α-SMA, alpha-smooth muscle actin; HNA, human nuclear antigen; DAPI, 4′, 6-diaminido-2-phenylindol; FABP4, fatty acid-binding protein 4; GFP, green fluorescent protein; ERK, extracellular signal-regulated protein kinase; H2O2, hydrogen peroxide; ECL, enhanced chemiluminescence; HCl, hydrochloric acid; PI, propidium iodide; FITC, fluorescein isothiocyanate
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