Abstract
Induced pluripotent stem cells (iPSC) represent an innovative, somatic cell-derived, easily obtained and renewable stem cell source without considerable ethical issues. iPSC and their derived cells may have enhanced therapeutic and translational potential compared with other stem cells. We previously showed that human iPSC-derived smooth muscle cells (hiPSC-SMC) promote angiogenesis and wound healing. Accordingly, we hypothesized that hiPSC-SMC may be a novel treatment for human patients with chronic limb-threatening ischemia who have no standard options for therapy. We determined the angiogenic potential of hiPSC-SMC in a murine hindlimb ischemia model. hiPSC-SMC were injected intramuscularly into nude mice after creation of hindlimb ischemia. Functional outcomes and perfusion were measured using standardized scores, laser Doppler imaging, microCT, histology and immunofluorescence. Functional outcomes and blood flow were improved in hiPSC-SMC-treated mice compared with controls (Tarlov score, p < 0.05; Faber score, p < 0.05; flow, p = 0.054). hiPSC-SMC-treated mice showed fewer gastrocnemius fibers (p < 0.0001), increased fiber area (p < 0.0001), and enhanced capillary density (p < 0.01); microCT showed more arterioles (<96 μm). hiPSC-SMC treatment was associated with fewer numbers of macrophages, decreased numbers of M1-type (p < 0.05) and increased numbers of M2-type macrophages (p < 0.0001). Vascular endothelial growth factor (VEGF) expression in ischemic limbs was significantly elevated with hiPSC-SMC treatment (p < 0.05), and inhibition of VEGFR-2 with SU5416 was associated with fewer capillaries in hiPSC-SMC-treated limbs (p < 0.0001). hiPSC-SMC promote VEGF-mediated angiogenesis, leading to improved hindlimb ischemia. Stem cell therapy using iPSC-derived cells may represent a novel and potentially translatable therapy for limb-threatening ischemia.
Highlights
Peripheral artery disease (PAD) affects at least 8.5 million people in the UnitedStates [1] and more than 200 million people worldwide [2]
To determine the effects of Induced pluripotent stem cells (iPSC)-derived differentiated cells on hindlimb ischemia, we used human iPSC (hiPSC)-smooth muscle cells (SMC), a cell derivative that we have previously shown to have efficacy in wound healing [18]. hiPSC-derived SMC grown in SmGM-2 growth medium were early stage, proliferative SMC that expressed SMC markers including α-SMA
These early-stage hiPSC-SMC did not show expression of pluripotent markers OCT4, similar to proliferative human primary SMC. hiPSC-VSMC-P were matured using a low concentration of serum and TGFβ1 without EGF, bFGF or insulin; mature hiPSC-SMC showed significantly increased expression of SMC markers including α-SMA, CNN1 and MYH11, which primary SMC
Summary
Peripheral artery disease (PAD) affects at least 8.5 million people in the UnitedStates [1] and more than 200 million people worldwide [2]. Peripheral artery disease (PAD) affects at least 8.5 million people in the United. PAD causes a range of clinical manifestations, including intermittent claudication (IC) and chronic limb-threatening ischemia (CLTI), leading to rest pain, tissue damage, ulceration, and gangrene. Treatment options for patients with CLTI are usually limited to revascularization, including surgical and endovascular methods. Current interventions are unfeasible in many patients because extensive disease precludes effective revascularization [4]. About 20% of CLTI patients (‘no-option CLTI’) are not suitable for classical treatments due to a high postoperative re-occlusion rate, poor anatomical conditions, or severe co-morbidity [5]. Therapeutic angiogenesis offers the potential to restore blood supply to ischemic tissue and prevent amputation in patients who otherwise have no options for revascularization [6]. Trials of therapeutic angiogenesis using single factors have not been uniformly efficacious or widely adopted for clinical use [7]
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