Differentiating multipotent mesenchymal stromal cells generate factors that exert paracrine activities on exogenous MSCs: Implications for paracrine activities in bone regeneration

The mechanisms by which multipotent mesenchymal stromal cells (MSCs) contribute to tissue repair following transplantation into host tissues remains poorly understood. Current concepts suggest that, in addition to differentiation into cells of the host tissues, MSCs also generate trophic factors that modulate host tissue microenvironment to aid in the repair process. In this communication, we assessed whether factors secreted by MSCs undergoing osteogenic differentiation induce expression of osteoblast markers in exogenous MSCs as well as their migration. Murine MSCs were cultured in osteogenic medium, and at different time points, medium conditioned by the cells was collected and assessed for its effects on differentiation and migration of exogenous MSCs. In addition, we determined whether MSCs infused into mice femurs expressed genes encoding for factors predicted to play a role in paracrine activities. The results showed that MSCs maintained in osteogenic medium, secreted factors at specific time points that induced alkaline phosphatase activity (ALP) in exogenous MSCs as well as their migration. MSCs infused into mice femurs and retrieved at different days expressed genes that encoded predicted factors that play a role in cell differentiation and migration. Neutralizing antibodies to bone morphogenetic protein-2 (BMP-2) led to the decrease in ALP activity by exogenous MSCs. These data demonstrated that, as MSCs differentiate toward osteogenic lineage, they secrete factors that induce recruitment and differentiation of endogenous progenitors. These data reveal mechanisms by which donor MSCs may contribute to the bone reparative process and provide a platform for designing approaches for stem cell therapies of musculoskeletal disorders.

► Mesenchymal stem cells undergoing osteoblast differentiation secrete factors that induce ALP activity in exogenous MSCs. ► Mesenchymal stem cells cultured in osteogenic medium produce factors that recruit exogenous MSCs. ► Bone morphogenetic protein-2 increases in expression during MSCs osteogenic differentiation. ► Pigment epithelial derived factor (PEDF) is secreted at high levels by MSCs undergoing osteogenic differentiation. ► Factors produced by differentiating MSCs play a role in bone repair and regeneration.