MSCs have the therapeutic potential to treat a wide variety of inflammatory and degenerative diseases in animals; however little is known about how the recipient environment affects the phenotype and function of transplanted MSCs. Similar to macrophages, MSCs polarize into pro-inflammatory MSC1, and immunomodulatory MSC2 phenotypes. In this proposal, we will address an important knowledge gap by investigating how recipient environment macrophages affect MSC1/2 phenotype and function, and the degree of plasticity of the MSC1/2 phenotype. The ability to generate a stable population of pro-regenerative MSCs, resistant to environmental influences, will improve the therapeutic potential of MSCs.