Abstract
Stem cells and progenitor cells have been identified as potential new therapeutic options for severe limb ischemia to induce angiogenesis, and hyaluronic acid (HA) is commonly applied as a biomaterial in tissue engineering. However, the efficiency of HA combined with human umbilical cord blood-derived endothelial colony forming cells (ECFCs) and human umbilical-derived mesenchymal stem cells (MSCs) on angiogenesis is unclear. In the present study, we showed that HA promoted angiogenesis induced by MSCs-ECFCs in Matrigel plugs and promoted blood perfusion of murine ischemic muscles. Laser confocal microscopy revealed that human-derived cells grew into the host vasculature and formed connections, as shown by mouse-specific CD31+/human-specific CD31+ double staining. In vitro assays revealed that HA supported cell proliferation and migration, enhanced CD44 expression and reduced microRNA (miR)-139-5p expression. Further analysis revealed that miR-139-5p expression was negatively regulated by CD44 in ECFCs. Flow cytometry assays showed that HA increased CD31 positive cells proportion in MSC-ECFC and could be reversed by miR-139-5p mimics transfection. Moreover, the improvement of MSC-ECFC proliferation and migration induced by HA could be blocked by upregulation of miR-139-5p expression. In conclusion, HA facilitates angiogenesis of MSCs-ECFCs, and this positive effect be associated with activation of the CD44/miR-139-5p pathway, providing a promising strategy for improving severe limb ischemia.
Highlights
Peripheral arterial disease (PAD) is a progressive disorder characterized by stenosis and/or occlusion of large and medium-sized arteries, most of which occur in the lower extremities
Wound scratch assays showed that mesenchymal stem cells (MSCs) or endothelial colony forming cells (ECFCs) treated with hyaluronic acid (HA) dilution displayed significantly accelerated migration and achieved confluence within 24 h, while no differences in migration are observed between two HA concentrations (Figures 1A,B,D,E)
These results indicated that MSC-ECFC coculture improved migration compared with MSCs or ECFCs cultured alone, and HA exposure further accelerated the migration rate of MSCsECFCs
Summary
Peripheral arterial disease (PAD) is a progressive disorder characterized by stenosis and/or occlusion of large and medium-sized arteries, most of which occur in the lower extremities. It is estimated that more than 200 million patients suffer from PAD worldwide (Shu and Santulli, 2018). Patients with PAD suffer an increased risk of coronary and cerebrovascular mortality and morbidity (Criqui and Aboyans, 2015), especially those with diabetes (Fadini et al, 2020). HA-MSC-ECFC Promote Angiogenesis via CD44/miR-139-5p disease stage without appropriate treatment: critical limb ischemia (CLI). Traditional treatment strategies are aimed at restoring perfusion of the ischemic limb and involve surgical bypass or endovascular interventions. As 40% of patients miss the chance for surgical revascularization and intervention (Das, 2009), improving therapeutic measures for PAD is necessary
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