Tunneling nanotubes and long-range intercellular transfer

Funk (2015) asked how electric fields could spread over distances of up to millimeters in an organism. He named gap junctions as one route. He also noted that dividing cells which move apart can stay in contact over a distance of up to 1 mm via TNTs.¹ He described this as a 'TNT leash' that is supposed to matter for cell migration, for example of neural crest cells. He stated that this remains to be proven.² For guidance information he turned back to the endogenous electric field, which he called the easiest and fastest way to build a gradient.²

Ariazi and colleagues (2017) described TNTs as long cytoplasmic bridges that enable long-range, directed communication between connected cells.³ They wrote that the proposed functions are diverse and not well understood. Transfer of vesicles, organelles, electrical stimuli and small molecules has been shown.⁴ The same review states that the exact role of TNTs and gap junctions in intercellular communication and in disease is still uncertain and the subject of much debate.⁵ The authors therefore present TNTs as a young field in which structure, triggers and selectivity remain open questions.

McMillen and colleagues (2021) reviewed TNTs in development and cancer. They reported that when neurons are injured, nearby astrocytes form TNTs that exchange calcium and mitochondria with the injured neurons to support their survival.⁶ They wrote that TNT formation has been linked to a stress response thought to be an attempt to reestablish homeostasis.⁷ They also wrote that cancer cells seem to have co-opted TNTs to redistribute molecules between cells and maintain homeostasis as a means of survival. This was said to include reactive astrocytes forming TNTs with melanoma cells after chemotherapy.⁶

Iorio and colleagues (2024) listed TNTs among several routes of mitochondrial transfer, alongside extracellular vesicles, gap junction channels, cell fusion and mitochondrial extrusion.⁸ They cited in vitro and in vivo models in which TNTs carry mitochondria between cells. In one simulated ischemia/reperfusion model, mesenchymal stem cells moved mitochondria to injured cardiomyoblasts via TNTs, protecting the cardiac cells against apoptosis.⁹ The review lists many other donor cell types besides mesenchymal stem cells, including astrocytes, lung epithelial cells and cancer cells.⁹