Glycogen Synthase Kinase-3β Inhibition Augments Diabetic Endothelial Progenitor Cell Abundance and Functionality via Cathepsin B: a Novel Therapeutic Opportunity for Arterial Repair

  1. Edward R. O’Brien, MDa,e
  1. aDivision of Cardiology, University of Ottawa Heart Institute, Ottawa, ON, Canada
  2. bDepartment of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
  3. cOttawa Hospital Research Institute, Sprott Stem Cell Centre and Regenerative Medicine Program, The Ottawa Hospital, Ottawa, ON, Canada
  4. dDepartment of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
  5. eDivision of Cardiology, Libin Cardiovascular Institute of Alberta, Calgary, AB, Canada
  1. Corresponding author: Dr. Edward R. O’Brien Email: ed.obrien{at}albertahealthservices.ca

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 non-redundant, 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:media – an effect that was further augmented when DM EPCs were pre-treated 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 enhances cell based therapy following vascular injury.

  • Received June 23, 2013.
  • Accepted November 21, 2013.

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