Tunneling nanotubes and periodontal regeneration: a novel perspective on stem cell–immune cell interactions and osteoimmunity

The periodontal ligament (PDL) is a dynamic connective tissue essential for tooth support, homeostasis, and regeneration. Periodontal ligament stem cells (PDLSCs), located within the PDL, exhibit mesenchymal stem cell characteristics and represent a potential cell source for periodontal regeneration. Interactions between PDLSCs and immune cells are mediated by soluble factors, extracellular vesicles, and direct cell-to-cell contact. Tunneling nanotubes (TNTs) have emerged as specialized actin-based membranous structures that can establish intercellular connections and facilitate the transfer of mitochondria, proteins, nucleic acids, and other cellular components. TNT-associated communication has been implicated in cellular survival, inflammatory responses, and tissue repair in several experimental systems. However, the existence and functional significance of TNT-mediated communication between PDLSCs and immune cells in periodontal tissues remain insufficiently characterized. Findings from stem cell, immunological, and bone biology research provide a rationale for investigating whether TNT-associated communication influences periodontal osteoimmunity. Nevertheless, its effects on immune-cell function, osteoclastogenesis, and periodontal regeneration may depend on the participating cell types, transferred cargo, and inflammatory and metabolic conditions. This mini-review summarizes current knowledge of TNT biology, examines evidence relevant to PDLSC–immune cell interactions and osteoimmunity, and identifies knowledge gaps and research priorities for determining whether TNT modulation has therapeutic relevance to periodontal regeneration.