Mineralization is a key biological process that is required for the development and repair of tissues such as teeth, bone and cartilage. Exosomes (Exo) are a subset of extracellular vesicles (~50–150 nm) that are secreted by cells and contain genetic material, proteins, lipids, nucleic acids, and other biological substances that have been extensively researched for bone and oral tissue regeneration. However, Exo-free biomaterials or exosome treatments exhibit poor bioavailability and lack controlled release mechanisms at the target site during tissue regeneration. By encapsulating the Exos into biomaterials like hydrogels, these disadvantages can be mitigated. Several tissue engineering approaches, such as those for wound healing processes in diabetes mellitus, treatment of osteoarthritis (OA) and cartilage degeneration, repair of intervertebral disc degeneration, and cardiovascular diseases, etc., have been exploited to deliver exosomes containing a variety of therapeutic and diagnostic cargos to target tissues. Despite the significant efficacy of Exo-laden hydrogels, their use in mineralized tissues, such as oral and bone tissue, is very sparse. This review aims to explore and summarize the literature related to the therapeutic potential of hydrogel-encapsulated exosomes for bone and oral tissue engineering and provides insight and practical procedures for the development of future clinical techniques.

Autophagy is a cellular process that recycles intracellular macromolecules and degrades toxic cytoplasmic material to provide the cell with nutrients and facilitate survival. Although autophagy and its role in the differentiation of osteoblasts, osteoclasts, and odontoblasts has been described, the importance of autophagy during matrix mineralization remains unaddressed. This review aims to characterize the autophagy/matrix mineralization relationship and elucidate the significance of autophagy during matrix mineralization. During the mineralization process, autophagy is important for cell survival and promotes the differentiation of osteoblasts and odontoblasts, the key cells that facilitate bone and dentin formation. Differentiation of these cells results in the synthesis of an organic proteinaceous matrix which subsequently forms the template for the deposition of calcium and phosphate to ultimately form crystalline hydroxyapatite. In bone, autophagy influences osteoblastic/osteoclastic activity and bone remodeling. In dentin, autophagy participates in odontogenic differentiation and facilitates odontoblastic secretion of dentin matrix proteins. This review aims to show that autophagy is critical for bone mineralization and tooth formation by supporting intracellular signaling pathways required for cell differentiation and subsequent matrix mineralization.

Autophagy is a cellular process that recycles intracellular macromolecules and degrades toxic cytoplasmic material to provide the cell with nutrients and facilitate survival. Although autophagy and its role in the differentiation of osteoblasts, osteoclasts, and odontoblasts has been described, the importance of autophagy during matrix mineralization remains unaddressed. This review aims to characterize the autophagy/matrix mineralization relationship and elucidate the significance of autophagy during matrix mineralization. A NCBI PubMed search using MESH terms “autophagy”, “odontoblast”, “osteoblast”, “osteoclast”, “calcification, physiologic”, and “biomineralization” was used in the preparation of this review. During the mineralization process, autophagy is vital for cell survival and promotes the differentiation of osteoblast and odontoblasts, the key cells that facilitate bone and dentin formation. Differentiation of these cells results in the synthesis of an organic proteinaceous matrix which subsequently forms the template for deposition of calcium and phosphate to ultimately form crystalline hydroxyapatite. In bone, autophagy influences osteoblastic/osteoclastic activity and bone remodeling. In dentin, autophagy participates in odontogenic differentiation and facilitates odontoblastic secretion of dentin matrix proteins. Autophagy is critical to support bone mineralization and tooth formation by supporting intracellular signaling pathways required for cell differentiation and subsequent matrix mineralization.

Dental pulp tissue contains mesenchymal stem/progenitor cells that possess high proliferative potential for self-renewal. They are neural-crest derived cells and exhibit multi-lineage differentiation properties. These progenitor stem cells are now recognized as being vital to the dentin regeneration process following injury. Understanding the molecular mechanisms that mediate the differentiation of adult stem cells into odontoblasts and their use in the repair of the dentin–pulp complex is of significant interest in regenerative dental medicine. Dentin Phosphophoryn (DPP), synthesized and processed predominantly by the odontoblasts, functions both as a structural and signaling protein. We had previously demonstrated that DPP activates NF-κB and promotes Wnt5a expression in dental pulp stem cells. In this context, we observed that DPP can activate TAZ, a biologically potent transcriptional coactivator which serves as a downstream element of the NF-κB signaling cascade. Furthermore, binding of NF-κB p65 subunit to the TAZ promoter was facilitated by DPP stimulation, and their interaction was confirmed by ChIP analysis. In addition, DPP-dependent activation of the TAZ/TEAD reporter was confirmed by luciferase activity in DPSCs. Co-immunoprecipitation analysis confirmed the in vivo interaction between TAZ and β-catenin with DPP stimulation. This regulatory complex facilitated TAZ to bind to the conserved TEAD binding motifs of key gene targets involved in odontogenic differentiation such as RUNX2, OSX, OCN, ALP, BMP4, and WNT5A. Some of these genes also contain binding sites for the TCF/LEF transcription factors that interact with the Wnt effector, β-catenin. Activation of TAZ and β-catenin resulted in the upregulation of odontoblast gene expression and reduced expression in the presence of the TAZ–TEAD protein complex inhibitor. Using mandibles of DSPP KO and WT mice, we confirmed reduced TAZ and β-catenin protein levels in the dental pulp cells and in the odontoblasts of DSPP KO mice when compared with WT. Thus, DPP, an extracellular matrix protein, provides biological cues to activate the TAZ signaling pathway that can stimulate the terminal differentiation of DPSCs into functional odontoblasts.