Abstract
AimsNovel 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 ResultsFemoral 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+ (MSCGFP) or E-selectin-GFP+ (MSCE−selectin−GFP). Laser Doppler Imaging demonstrated significantly restored reperfusion in MSCE−selectin−GFP-treated mice vs. controls. After 3 weeks, the ischemic limbs in mice treated with MSCE−selectin−GFP had increased footpad blood vessel density, hematoxylin and eosin stain (H&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 MSCE−selectin−GFP-treated limb tissues, indicating that the therapeutic effect is likely achieved via upregulation of pro-angiogenic cytokines and downregulation of inflammation.ConclusionThis 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.
Highlights
Critical limb ischemia (CLI), the most severe form of peripheral arterial disease (PAD), is the clinical syndrome that includes ischemic rest pain and tissue loss due to severely diminished perfusion to the affected limb
We further demonstrated that coating mesenchymal stem cells (MSCs), which normally do not express E-selectin, with nanocarrier complexed with soluble E-selectin, improved cell homing to the ischemic environment and improved repair and regeneration in a mouse model of hind limb ischemia [22]
This study demonstrated that the MSCs overexpressing E-selectin are more biologically potent and can interact with E-selectin ligands elevated on activated endothelial cells, actively contributing to the budding tip of vessel sprouts to promote angiogenesis
Summary
Critical limb ischemia (CLI), the most severe form of peripheral arterial disease (PAD), is the clinical syndrome that includes ischemic rest pain and tissue loss due to severely diminished perfusion to the affected limb. Of all patients with PAD, 11% will go on to develop CLI that confers a 50% 5-year mortality rate and a 70% 10-year mortality rate [1, 2]. Cell Therapy for Limb Salvage as smoking, obesity, and diabetes mellitus increase one’s risk of developing PAD. The treatment modalities available for patients with CLI include medical risk reduction strategies as well as procedural revascularization such as endovascular angioplasty/stenting or bypass surgeries [3]. Due to the reduced quality of life, significant financial costs, and poor survival outcomes among patients with CLI, vascular regenerative therapies that aim to increase limb salvage in these high-risk patients are a promising therapeutic option
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