Tunneling Nanotubes and Gap Junctions-Their Role in Long-Range Intercellular Communication during Development, Health, and Disease Conditions

Abstract

Cell-to-cell communication is essential for the organization, coordination, and development of cellular networks and multi-cellular systems. Intercellular communication is mediated by soluble factors (including growth factors, neurotransmitters, and cytokines/chemokines), gap junctions, exosomes and recently described tunneling nanotubes (TNTs). It is unknown whether a combination of these communication mechanisms such as TNTs and gap junctions may be important, but further research is required. TNTs are long cytoplasmic bridges that enable long-range, directed communication between connected cells. The proposed functions of TNTs are diverse and not well understood but have been shown to include the cell-to-cell transfer of vesicles, organelles, electrical stimuli and small molecules. However, the exact role of TNTs and gap junctions for intercellular communication and their impact on disease is still uncertain and thus, the subject of much debate. The combined data from numerous laboratories indicate that some TNT mediate a long-range gap junctional communication to coordinate metabolism and signaling, in relation to infectious, genetic, metabolic, cancer, and age-related diseases. This review aims to describe the current knowledge, challenges and future perspectives to characterize and explore this new intercellular communication system and to design TNT-based therapeutic strategies.

Keywords: Alzheimer; cancer; gap junctions; inflammation; reactivation.

Figure 1

Schematic of TNT formation and the potential role of gap junction channels during long rage communication. As described in the text, TNT have at least 3 different stages, including formation, stabilization, and the transport of the cargo. The last one is associated with several different roles in disease including viral spreading, chemoresistance, and disease dissemination as well as an energy associated survival, genetic disease rescue and stress survival. TNT formation is triggered by inflammation, infection, toxicity, in several disease, and embryogenesis/morphogenesis. Some of the proteins involved in the formation of TNT are actin, Myosin Va and X, synaptophysin, Cx43, and M-sec. Following the formation of the TNT process, there are at least 2 different types of tubes, a synaptic and open-ended process. The formation of these long rage TNT enable the connected cells to share multiple proteins and lipids.