The impact of immune response on endochondral bone regeneration

Abstract

Tissue engineered cartilage substitutes, which induce the process of endochondral ossification, represent a regenerative strategy for bone defect healing. Such constructs typically consist of multipotent mesenchymal stromal cells (MSCs) forming a cartilage template in vitro, which can be implanted to stimulate bone formation in vivo. The use of MSCs of allogeneic origin could potentially improve the clinical utility of the tissue engineered cartilage constructs in three ways. First, ready-to-use construct availability can speed up the treatment process. Second, MSCs derived and expanded from a single donor could be applied to treat several patients and thus the costs of the medical interventions would decrease. Finally, it would allow more control over the quality of the MSC chondrogenic differentiation. However, even though the envisaged clinical use of allogeneic cell sources for bone regeneration is advantageous, their immunogenicity poses a significant obstacle to their clinical application. The aim of this review is to increase the awareness of the role played by immune cells during endochondral ossification, and in particular during regenerative strategies when the immune response is altered by the presence of implanted biomaterials and/or cells. More specifically, we focus on how this balance between immune response and bone regeneration is affected by the implantation of a cartilaginous tissue engineered construct of allogeneic origin.

Fig. 1

Schematic overview of the cell types involved in the endochondral ossification process induced by an allogeneic tissue engineered construct and the immune response elicited. After implantation, the phenotype of MSC-derived chondrocytes progresses until the late hypertrophic stage, a stage that is characterized by increased secretion of proangiogenic factors and MMPs to promote matrix remodeling and new bone formation. However, the implantation of a biomaterial, together with the presence of allogeneic cells, at the same time induces the recruitment of host immune cells. In particular, the immune response against the carrier biomaterial (left panel) is mainly characterized by the presence of cells from the innate branch of the immune system while the presence of allogeneic cells triggers mostly an adaptive response (right panel). Nonetheless, the recruited cells can influence each other through the engagement of common players (e.g., dendritic cells and the complement system) and through the secretion of soluble factors such as cytokines that can promote the induction of a pro-inflammatory or anti-inflammatory environment. The final outcome of the bone regeneration process is determined by the balance between the promotion of endochondral ossification and the exacerbation of the immune response by the allogeneic construct