Mesenchymal Stem Cells Loaded with p5, Derived from CDK5 Activator p35, Inhibit Calcium‐Induced CDK5 Activation in Endothelial Cells

Abstract

The potential use of stem cells as therapeutics in disease has gained momentum over the last few years and recently phase-I clinical trials have shown favourable results in treatment of a small cohort of acute stroke patients. Similarly, they have been used in preclinical models drug-loaded for the effective treatment of solid tumours. Here we have characterized uptake and release of a novel p5-cyclin-dependent kinase 5 (CDK5) inhibitory peptide by mesenchymal stem cells and showed release levels capable of blocking aberrant cyclin-dependent kinase 5 (CDK5) signaling pathways, through phosphorylation of cyclin-dependent kinase 5 (CDK5) and p53. These pathways represent the major acute mechanism stimulating apoptosis after stroke and hence its modulation could benefit patient recovery. This work indicates a potential use for drug-loaded stem cells as delivery vehicles for stroke therapeutics and in addition as anticancer receptacles particularly, if a targeting and/or holding mechanism can be defined.

p5 Peptide-Loaded Human Adipose-Derived Mesenchymal Stem Cells Promote Neurological Recovery After Focal Cerebral Ischemia in a Rat Model

“…Previous work has identified that p5 offers protection to both neurons and endothelial cells [12,20]. Indeed, this present study has demonstrated a specific protection towards neurons in vitro.…”

“…Human adipose-derived mesenchymal stem cells (hADMSCs) were provided by Professor Giulio Alessandri and Professor Valentina Ceserani. hADMSCs were isolated from peri-umbilical fat tissue and characterized as described [20]. Human neuroblastoma neuroblastic type SH-SY5Y cells and bovine aortic endothelial cells (BAECs) were cultured in Dulbecco's modified Eagle's medium (DMEM; Lonza) supplemented with 10% FBS and 1% L-glutamine.…”

“…Therefore, a therapeutic approach directed specifically at CDK5-p25 complex might prove successful. To improve its therapeutic efficacy, several peptides consisting of amino acid residues of p35, such as CDK5 inhibitory peptide (CIP, a peptide of 125 amino acid residues), p10, and p5, have been generated and proven to specifically reduce CDK5-p25 increased activity without affecting the normal endogenous CDK5-p35 or other CDK activities [15][16][17][18][19][20][21]. In particular, p5 also reduced neuronal apoptosis induced by Ca 2+ in hypoxia/ ischemia brain injury [22,23].…”