Activating Endogenous Condylar Stem Cells to Enhance TMJ Repair

The temporomandibular joint (TMJ) plays a critical role in the daily activities of mastication and communication, with disorders of the TMJ significantly impairing quality of life. Temporomandibular disorders (TMDs) are highly prevalent, presenting a pressing need for regenerative therapies. The TMJ's key components-condyle, TMJ disc, and glenoid fossa-are crucial for proper function; however, the limited self-repair capability of these tissues makes managing TMJ pathology particularly challenging. Emerging research in animal models has emphasized the importance of fibrocartilage stem/progenitor cells (FCSCs) located in and around the superficial layers of the condyle. Lineage tracing of condylar FCSCs in vivo has identified subpopulations with different contributions to growth and homeostasis, providing potential targets for regenerative therapies. In addition to the FCSCs, niche-supporting cells have been recently identified in the superficial layers of the condyle, further highlighting the complex cellular environment of the TMJ. Several signaling pathways, including Wnt, Hedgehog, and Notch, play pivotal roles in establishing cell fate in the developing and growing TMJ and have been additionally implicated in both the control of FCSC populations and progression of TMDs. Recent research has used this understanding of the signaling pathways involved in the creation of the joint to stimulate the endogenous stem cells/FCSCs of the adult in vivo, leading to enhancement of regenerative capacity in mouse, rat, rabbit, and porcine injury and disease models. Manipulation of signaling pathways has been combined with advanced bioengineering techniques, providing scaffolds to allow controlled dispersal of activators and inhibitors. Such advances in understanding the triggers and molecular mechanisms that control TMJ FCSCs, combined with improved targeting of specific signaling pathways, have opened new avenues for regenerative therapies. These insights have begun to be leveraged in the development of novel hydrogel-based injectable regenerative therapeutic approaches to not only alleviate symptoms but also promote true regeneration of TMJ structures.