Osteoimmunological implications in regenerative medicine: cross-talk between mesenchymal stem cells and immune cells

Bone fractures are one of the most common orthopedic cases, yet strategies to resolve excessive inflammation and non-unions still lack satisfactory treatment methods owing to the complex fracture microenvironment, as well as the interactions between the plethora of cell types involved. Fracture is a highly inflammatory process which involves the recruitment of various immune cells which in turn release various cytokines and growth factors to perpetuate inflammation and eventually healing resolution. Osteoimmunology is an interdisciplinary field investigating the extensive interactions between the immune system and skeletal system. Mesenchymal stem cells (MSCs) are resident in almost every adult tissue and are responsible for initiating reparative cascades in the event of injury. A key aspect of MSCs is their role as trophic mediators, secreting a milieu of signaling as well as immunomodulatory cytokines that play important roles in tissue regeneration. This paracrine signaling polarizes macrophages into their anti-inflammatory M2 phenotype, activates osteoblasts, inhibits osteoclasts, as well as suppresses conventional T cell proliferation and promotes regulatory T cell (Treg) proliferation. MSCs have been shown to resolve inflammation whilst also supporting osteogenesis; for these reasons, they are considered promising candidates for cellular therapies to treat musculoskeletal pathologies. Through pretreatment and genetic modifications, MSCs can be predisposed to release specific molecules that can modulate the microenvironment and regulate the activity of the immune system towards enhancing bone repair. By understanding the cross-talk between MSCs and the immune system in bone physiology, more targeted therapies directed towards specific cells and discrete signaling molecules become possible that may allow for expedited healing and improved standard of care in orthopedics. In this review, we discuss the interplay between immune cells and MSCs and the potential ways to harness this cross-talk to improve regenerative medicine strategies.