SMALL MOLECULE MEDIATED p21 SUPPRESSION TO AID IN OSTEOGENIC DIFFERENTIATION OF MESENCHYMAL STEM CELLS

Abstract

p21, also known as a cyclin-dependent kinase inhibitor 1 (CDKN1A), plays a vital role in cell cycle regulation, including but not limited to cycle arrest, apoptosis, senescence, and DNA repair. Inhibition of p21 has been shown to improve bone healing and regeneration after injury. In this project, the aim is to investigate a small molecule inhibitor of p21, UC2288, in targeting and reducing p21 levels. It is hypothesized that reduction in p21 will lead to increased osteogenic capacity in MSCs. Murine mesenchymal stem cells (MSCs) were tested for increased osteogenic capacity followed by human umbilical cord derived-MSCs (HU UCMSCs). Cell viability was assessed in human MSCs, and no significant differences were observed between cells treated with or without the drug, confirming no cytotoxicity. Next, different concentrations of UC2288 were tested with both murine MSCs and human MSCs to determine changes in osteogenic capacity. Results indicate that UC2288 induces murine bone marrow MSC differentiation into osteoblasts but may not induce as much osteogenesis in Hu UCMSCs. One reason for this could be that umbilical cord MSCs inherently have reduced p21. However, results from the murine MSCs are promising as inducing osteogenesis in bone marrow MSCs could improve fracture healing. This is especially important in the aging population, and this line of study could ultimately lead to clinical applications.