Skeletogenesis is initiated during foetal development and persists through adult life as either a remodelling process in response to homeostatic regulation or as a regenerative process in response to physical injury. MSCs play a crucial role providing progenitor cells from which osteoblasts, bone matrix forming cells, are differentiated. The mechanical environment plays an important role in regulating stem cell differentiation into osteoblasts, however, the mechanisms by which MSCs respond to mechanical stimuli are yet to be fully elucidated. To increase understanding of MSC mechanotransuction and osteogenic differentiation, this study aimed to identify novel, mechanically augmented genes and pathways with pro-osteogenic functionality. Using collagen glycoaminoglycan (CG) scaffolds as mimics of native extracellular matrix, to create a 3D environment more representative of that found in bone, MSC seeded constructs were mechanically stimulated in a flow-perfusion bioreactor. Global gene expression profiling techniques were utilised to identify potential candidates warranting further investigation. Of these, placental growth factor (PGF) was selected and expression levels were shown to strongly correlate to both the magnitude and duration of mechanical stimulation. We demonstrated that PGF gene expression was modulated through an actin polymerisation-mediated mechanism. The functional role of PGF in modulating MSC osteogenic differentiation was interrogated and we showed a concentration dependent response whereby low concentrations exhibited the strongest pro-osteogenic effect. Furthermore, pre-osteoclast migration and differentiation, as well as endothelial cell tubule formation also maintained concentration-dependent responses to PGF, suggesting a potential role for PGF in bone resorption and angiogenesis, processes key to bone remodelling and fracture repair. Stem Cells 2013.
Royal College of Surgeons in Ireland ->