Therapeutic potential of mesenchymal stem cell-derived extracellular vesicles in regenerative endodontics

Regenerative endodontic procedures are an alternative to conventional root-canal treatment and apexification. There are two different tissue engineering approaches that are currently followed, both aiming at the colonisation of the cleaned pulp space by pluripotent cells and subsequent pulp regeneration. Firstly, the transplantation of mesenchymal stem cells (MSCs), and secondly a cell-free strategy that relies on bioactive molecules to trigger the recruitment of the patient's own cells. The first approach is hampered by costs and regulatory issues. Despite great initial enthusiasm with a clinically used cell-free approach that relies on induced bleeding into the pulp space, results have been revealed to be rather unpredictable, and mere repair rather than regeneration of the pulp-dentin complex is what is typically achieved. Moreover, the extent of further root development is variable, and the concept is limited to immature teeth. This article discusses a third possible way of regenerative endodontics that involves the application of MSC-derived exosomes. These are extracellular vesicles that contain proteins, lipids, and nucleic acids, reflecting the secretome of MSCs. Based on the first in vitro and in vivo studies, exosomes appear to be a potent tool to improve pulp regeneration. This narrative review aims to investigate the therapeutic use of human MSCs or dental pulp-derived exosomes in regenerative endodontics. Furthermore, the focus of this review is on targeting important questions that should be investigated in future in-vivo and clinical studies, such as the choice of scaffold material for exosome delivery into the pulp space.