title: Glycogen synthase kinase-3β inhibition augments diabetic endothelial progenitor cell abundance and functionality via cathepsin B: a novel therapeutic opportunity for arterial repair.
abstract: 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 DM had fewer EPCs and increased rates of apoptosis. DM EPCs also exhibited higher levels of GSK3β activity resulting in increased levels of phosphorylated β-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 GSK3β activity contributes to accelerated EPC cellular senescence, an effect reversed by small molecule antagonism of GSK3β, which enhanced cell-based therapy after vascular injury.
authors.affiliation: Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Hibbert
authors.forename: Jessie R
authors.initials: JR
authors.lastname: Lavoie
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Ma
authors.forename: Tara
authors.initials: T
authors.lastname: Seibert
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Raizman
authors.forename: Trevor
authors.initials: T
authors.lastname: Simard
authors.forename: Yong-Xiang
authors.initials: YX
authors.lastname: Chen
authors.forename: Duncan
authors.initials: D
authors.lastname: Stewart
authors.forename: Edward R
authors.initials: ER
authors.lastname: O'Brien
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002401:Cathepsin B / Q000378:metabolism*; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D003925:Diabetic Angiopathies / Q000188:drug therapy*; D042783:Endothelial Cells / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005263:Femoral Artery / Q000293:injuries; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D013234:Stem Cells / Q000187:drug effects*
chemical_list: D004791:Enzyme Inhibitors; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D002401:Cathepsin B