Glycogen Synthase Kinase-3b Inhibition Augments Diabetic Endothelial Progenitor Cell Abundance and Functionality via Cathepsin B: A Novel Therapeutic Opportunity for Arterial Repair
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چکیده
Progenitor cell therapy is hindered in patients with diabetes mellitus (DM) due to cellular senescence. Glycogen synthase kinase-3b (GSK3b) activity is increased in DM, potentially exacerbating impaired cell-based therapies. Thus, we aimed to determine if and how GSK3b inhibitors (GSKi) can improve therapeutic efficacy of endothelial progenitor cells (EPC) from patients with DM. Patients with DM had fewer EPCs and increased rates of apoptosis. DM EPCs also exhibited higher levels of GSK3b activity resulting in increased levels of phosphorylated b-catenin. Proteomic profiling of DM EPCs treated with GSKi identified 37 nonredundant, differentially regulated proteins. Cathepsin B (cathB) was subsequently confirmed to be differentially regulated and showed 40% less baseline activity in DM EPCs, an effect reversed by GSKi treatment. Finally, in vivo efficacy of cell-based therapy was assessed in a xenotransplant femoral wire injury mouse model. Administration of DM EPCs reduced the intima-to-media ratio, an effect that was further augmented when DM EPCs were pretreated with GSKi yet absent when cathB was antagonized. In DM, increased basal GSK3b activity contributes to accelerated EPC cellular senescence, an effect reversed by small molecule antagonism of GSK3b, which enhanced cell-based therapy after vascular injury.
منابع مشابه
Glycogen synthase kinase-3β inhibition augments diabetic endothelial progenitor cell abundance and functionality via cathepsin B: a novel therapeutic opportunity for arterial repair.
Progenitor cell therapy is hindered in patients with diabetes mellitus (DM) due to cellular senescence. Glycogen synthase kinase-3β (GSK3β) activity is increased in DM, potentially exacerbating impaired cell-based therapies. Thus, we aimed to determine if and how GSK3β inhibitors (GSKi) can improve therapeutic efficacy of endothelial progenitor cells (EPC) from patients with DM. Patients with D...
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تاریخ انتشار 2014