Effects of myeloid immune cells on the metabolic process of biomimetic bone regeneration.

ABSTRACT

AIMS: As the process of bone regeneration is preceded by an inflammatory response, the immune system has long been considered important for fracture healing. Despite many studies on the contribution of immune cells to bone-related diseases, the role of immune cells in the regeneration therapy of lost bone is not well understood. In addition, various types of cells are involved in the clinical bone regeneration environment, but most of the osteo-biology studies are conducted in an osteoblast-only environment. MATERIALS AND METHODS: Here, we investigated the effects of macrophages and dendritic cells on osteogenic differentiation in a co-culture environment involving human periosteal cell-derived osteoblasts, human monocyte-derived osteoclasts, and myeloid-derived cells. In addition, the cluster of myeloid immune cells involved in the clinical bone regeneration process was analyzed through bone defect rat modeling. KEY FINDINGS: We found that specific types of myeloid cells and related cytokines increased osteogenic differentiation. These results were confirmed in experiments using myeloid cells originating from human primitive peripheral blood mononuclear cells and by measuring the colonization of macrophages and dendritic cells in an in vivo bone defect environment. In addition, Next generation sequencing (NGS) analysis was performed through RNA sequencing for osteogenesis caused by macrophages and dendritic cells in vitro, which implemented a clinical bone regeneration environment. The results of these experiments suggest that the role of M2 macrophages or dendritic cells is markedly increased during osteogenic differentiation. Therefore, we propose that the exchange of bioactive factors between macrophages and dendritic cells during the bone formation metabolic process is a crucial step of tissue regeneration rather than limited to the initial inflammatory response. SIGNIFICANCE: This study indicates that M2 macrophages, among myeloid cells, can be mediators that play a vital role in the effective bone regeneration process and shows the potential as a useful next-generation advanced cell therapy for bone regeneration treatment.