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.

Potential hydrodynamic cytoplasmic transfer between mammalian cells: Cell-projection pumping

“…Cancer rarely generates new biology, but instead usually perverts established mechanisms. From this, and given altered phenotype following cytoplasmic transfer (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)19), we suggest CPP may contribute to cell differentiation and phenotypic control in other biological settings including: embryogenesis, development, inflammation and wound healing.…”

“…TNT differ markedly from the transferring cell-projections in the current study. Unlike the transient, fast-moving, short, and branching structures here seen to be mechanically supported by the culture surface or cells; TNT often persist hours, extend long distances, are non-branching, and are suspended free above the culture surface (6,7,12,13,(20)(21)(22). Cytoplasmic transfer via cellprojections in the size range of filopodia seems a novel function.…”

“…We earlier described the exchange of membrane and cytoplasmic protein between cultured human fibroblasts (Fib) and malignant cells (MC) (1). Others have made similar observations, and describe this as via either tunneling nanotubes (TNT) or exosomes and other shed membrane vesicles, and this is often associated with changes in cell phenotype (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17), while we have also seen phenotypic change (1,18). Mitochondrial exchange has been considered particularly interesting (2,4,5,19).…”

Tunneling nanotubes contribute to the stroma-mediated imatinib resistance of leukemic cells

“…Intercellular communication within the bone marrow niche is an important element that influences leukemogenesis and the biology of leukemic cells. Previous studies demonstrated the possibility of intercellular communication through the formation of TNTs, thin membrane connections that enable direct communication between cells (Ariazi et al, 2017;Ady et al, 2014;Lou et al, 2012a;Gerdes et al, 2013). We investigated whether these connections can be formed within the leukemia microenvironment and participate in leukemia-stroma cross-talk.…”

“…Cellular vesicles (Rustom et al, 2004;Onfelt et al, 2006), organelles (Vallabhaneni et al, 2012;Yasuda et al, 2011;Abounit et al, 2016b;Ahmad et al, 2014), miRNAs , viral particles (Sowinski et al, Nat Cell Biol 2008) and proteins (Schiller et al, 2013;Costanzo et al, 2013) can be actively transported directly from cell to cell, travelling along the actin or microtubule backbone of TNTs. Soon after their discovery, TNTs were recognized as a novel mode of intercellular communication Ariazi et al, 2017;Baker, 2017;Nawaz & Fatima, 2017). They have been found in a plethora of cell types to date, including immune cells (Önfelt et al, 2004;Onfelt et al, 2006), neurons (Gousset et al, 2009), cardiomyocytes (Figeac et al, 2014), endothelial cells (Liu et al, 2014;Yasuda et al, 2010), mesenchymal stromal cells (Pasquier et al, 2013), and cancer cells (Lou et al, 2012b;Thayanithy et al, 2014;Pasquier et al, 2012).…”