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Aims  Novel cell-based therapeutic angiogenic treatments for patients with critical limb ischemia may afford limb salvage. Mesenchymal stem cells (MSCs) do not overexpress E-selectin; however, we have previously demonstrated the cell-adhesion molecule's vital role in angiogenesis and wound healing. Thus, we created a viral vector to overexpress E-selectin on MSCs to increase their therapeutic profile.    Methods and Results  Femoral artery ligation induced hind limb ischemia in mice and intramuscular injections were administered of vehicle or syngeneic donor MSCs, transduced  ex vivo  with an adeno-associated viral vector to express either GFP +  (MSC GFP ) or E-selectin-GFP +  (MSC E−selectin−GFP ). Laser Doppler Imaging demonstrated significantly restored reperfusion in MSC E−selectin−GFP -treated mice vs. controls. After 3 weeks, the ischemic limbs in mice treated with MSC E−selectin−GFP  had increased footpad blood vessel density, hematoxylin and eosin stain (H&amp;amp;E) ischemic calf muscle sections revealed mitigated muscular atrophy with restored muscle fiber size, and mice were able to run further before exhaustion. PCR array-based gene profiling analysis identified nine upregulated pro-angiogenic/pro-repair genes and downregulated  Tumor necrosis factor (TNF)  gene in MSC E−selectin−GFP -treated limb tissues, indicating that the therapeutic effect is likely achieved  via  upregulation of pro-angiogenic cytokines and downregulation of inflammation.    Conclusion  This innovative cell therapy confers increased limb reperfusion, neovascularization, improved functional recovery, decreased muscle atrophy, and thus offers a potential therapeutic method for future clinical studies.

frontiers in cardiovascular medicine

E-Selectin-Overexpressing Mesenchymal Stem Cell Therapy Confers Improved Reperfusion, Repair, and Regeneration in a Murine Critical Limb Ischemia Model