Cyclin D1/CDK coordination with the cellular prion protein upregulated cell proliferation signaling and preserved neurological function in acute IS rats.

We tested how the coordination between cyclin D1/cyclin-dependent kinase (CDK) and the cellular prion protein (PrPC) activates mitogenic/cell proliferation signaling to improve neurological outcomes in acute ischemic stroke (AIS) rats. Compared with those in adipose-derived mesenchymal stem cells (ADMSCs) and the N2a cell line, the cell viability, cell proliferation, cell-stress signaling, and wound healing rates were significantly increased upon overexpression of PrPC (PrPC-OE) in ADMSCs (all P<0.001). The cell viability, proliferation. mitochondrial mass, and protein expression of mitogenic signaling markers (cyclin D1, cyclin E1, CDK2, and CDK4) were significantly increased upon PrPC-OE in ADMSCs compared to ADMSCs that were subjected to a significant reversal of PrPC-OE by treatment with promazine (a PrPC formation inhibitor) (all P<0.001). After 3 h of serum-free/hypoxic conditions, the protein expression levels of cyclin D1/CDK, p-Akt and mitogenic signaling markers were significantly increased upon PrPC-OE in ADMSCs compared with ADMSCs that were treated with palbociclib (a cyclin D1/CDK inhibitor). Adult male Sprague-Dawley rats (n=40) were grouped into Groups 1 (AC), 2 (AIS), 3 (AIS + ADMSCs), and 4 (AIS + ADMSCs with PrPC-OE). By Day 28 after AIS induction, the neurological function and numbers of NeuN+ cells and myelin basic protein (MBP)+ cells were lowest in Group 2, highest in Group 1 and significantly increased in Group 4 compared with Group 3, whereas the cellular levels of fibrosis and inflammation markers and protein levels of markers of apoptosis, mitochondrial and DNA damage and autophagy exhibited the opposite pattern to neurological function, and protein expression levels of cell-stress signaling proteins (PI3K, Akt, and m-TOR) and PrPC progressively increased from Groups 1 to 4 (all P<0.0001). In conclusion, activated cyclin D1/CDK coordinated with PrPC to improve neurological function in the AIS setting.