The art of cellular communication: tunneling nanotubes bridge the divide

Abstract

The ability of cells to receive, process, and respond to information is essential for a variety of biological processes. This is true for the simplest single cell entity as it is for the highly specialized cells of multicellular organisms. In the latter, most cells do not exist as independent units, but are organized into specialized tissues. Within these functional assemblies, cells communicate with each other in different ways to coordinate physiological processes. Recently, a new type of cell-to-cell communication was discovered, based on de novo formation of membranous nanotubes between cells. These F-actin-rich structures, referred to as tunneling nanotubes (TNT), were shown to mediate membrane continuity between connected cells and facilitate the intercellular transport of various cellular components. The subsequent identification of TNT-like structures in numerous cell types revealed some structural diversity. At the same time it emerged that the direct transfer of cargo between cells is a common functional property, suggesting a general role of TNT-like structures in selective, long-range cell-to-cell communication. Due to the growing number of documented thin and long cell protrusions in tissue implicated in cell-to-cell signaling, it is intriguing to speculate that TNT-like structures also exist in vivo and participate in important physiological processes.

Fig. 1

Architecture of TNT between cultured PC12 cells. (a) 3D fluorescence image ((x−y)-maximum projection of 40 consecutive 400 nm sections) of a wheat germ agglutinin-stained TNT connecting two live PC12 cells. (a₁) (x−z)-projection in the plane of the TNT indicated in (a). (b) Scanning electron micrograph (SEM) showing the ultra-structure of a TNT between two PC12 cells. The boxed areas are shown as higher magnification images (b₁, b₂). Modified from Rustom et al. (2004) Science 303:1007–1010. Scale bars, a, a₁, b, 5 μm; b₁, b₂, 500 nm

Fig. 2

Transmission electron micrographs (TEM) showing the ultra-structure of distinct TNT-like bridges in different cell types. (a) Open-ended TNT connecting two PC12 cells reconstructed from images of two consecutive 80 nm sections. The boxed areas are shown as higher magnification images (a₁, a₂). A continuous membrane is observed between the nanotube and the plasma membrane of the two connected cells. Modified from Rustom et al. (2004) Science 303:1007–1010. (b) Close-ended TNT-like bridge connecting two T cells and displaying a junctional border, reconstructed from images of 13 consecutive 60 nm sections. The boxed areas are shown as higher magnification images (b₁, b₂). The nanotube formed by one cell (b₂) protrudes into an invagination (arrowhead) of the connected cell (b₁). Modified from Sowinski et al. (2008) Nat Cell Biol 10:211–219. Scale bars, a, b, 1 μm; a₁, a₂, b₁, b₂, 500 nm

Fig. 3

Schematic representations of three distinct nanoscaled cellular protrusions and proposed modes of cell-to-cell communication. (a) A TNT-mediating membrane continuity between cells. (a₁) Organelles like endocytic vesicles and mitochondria are transported uni-directionally between cells by an actin-dependent mechanism. (b) Nanotubular bridge between cells displaying a junctional border. (b₁) Distinct viral particles are transported either at the surface of the nanotube by a receptor-dependent mechanism using actin retrograde flow or inside the cellular nanotube by an actin-dependent mechanism. (c) Cellular nanotube (cytoneme) extending toward a target cell by chemotaxis. (c₁) Signaling molecules secreted by the target cell are proposed to be endocytosed by a receptor-mediated mechanism at the tip of the cytoneme and transported in a retrograde manner toward the cell body of the receiving cell. The arrows (a–c) indicate the direction of transfer

Fig. 4

Emerging physiological implications of TNT-like structures