terça-feira, 18 de março de 2014

Organelle transfer: a special form of intercellular communication

Cell-to-cell communication is a crucial prerequisite for the development and maintenance of multicellular organisms. Since the report by Rustom et al. that cultured cells are capable of forming “nanotubes” that span up to several cell diameters in length and that they use these conduits to transport whole organelles between cells (1), the last decade has seen a burst of interest in the phenomenon of intercellular organelle exchange and transfer. Traditionally considered processes of intercellular communication include cell contact dependent and paracrine receptor-ligand interactions, synaptic vesicle release and uptake, and ion flow through gap junctions (2). However, organelle transfer is in a sense a special form of intercellular communication, because it represents the transfer not only of signals but also of defined intracellular structures.

Image from Science 303: 1007–1010, (2004). Figure 1

The tunneling nanotubes (TNTs) had a diameter of 50 to 200 nm and a length of up to several cell diameters (Fig. 1, A to G). TNTs rarely displayed a branched appearance (Fig. 1C, arrow). Furthermore, they were stretched between interconnected cells attached at their nearest distance and did not contact the substrate (Fig. 1D). TNTs contained F-actin but not microtubules (Fig. 1E). When was performed scanning electron microscopic (SEM) analysis, the stretched shape and structure of TNTs could be preserved, and their surface showed a seamless transition to the surface of both connected cells (Fig. 1F). Transmission electron microscopic (TEM) analysis changed the stretched morphology of TNTs into a bent configuration presumably because of mechanical stress during sample preparation. However, serial sectioning showed that, at any given point along TNTs, their membrane appeared to be continuous with the membranes of connected cells (Fig. 1G).
More than 40 variations of intercellular organelle transfer have been described, including endoplasmic reticulum/Golgi bodies, endosomes, lysosomes or the lysosome-related melanosome, and mitochondria originating in one cell (organelle donor) and being transported to another (organelle recipient).Intercellular organelle transfer has been demonstrated to be crucial to several experimental models of cell survival under external stress. However, evidence for its role in cellular reprogramming is less robust. The consequences of intercellular organelle transfer are: enhancing probability of cell survival and cellular reprogramming (3).The study of intercellular organelle transfer has burgeoned in parallel with the study of “tunneling nanotubes,” the principal conduit through which organelles travel from one cell to the other. In multiple studies, organelle motion in nanotubes has been visualized during the process of intercellular organelle transfer (1). Real-time studies by fluorescence microscopy indicate that that the nanotube protrudes from the initiating cell as an extension of the plasma membrane. Two lines of evidence suggest that nanotubes are both sufficient and necessary as the structural bridge for intercellular organelle transfer. They are sufficient because, when cultured under cooled conditions in which nanotube formation occurs, but other transfer processes such as endocytosis, exocytosis, and phagocytosis are blocked, intercellular organelle transfer is sustained between rat pheocromocytoma cells and rat kidney cells (1). However, the mechanism that preserves nanotube transport under cooled conditions remains unclear.
The future therapeutic implications of this research need to consider strategies to pharmacologically augment intercellular organelle transfer when desirable (i.e., to replenish dysfunctional mitochondrial and lysosomes in the cell under stress) or block its occurrence when it is deleterious, such as in the spread of infection or the maintenance of malignant cells. More recently, Julia Ranzinger, Amin Rustom and Vedat Schwenger (4) showed the existence of nanotubular connections between human primary peritoneal mesothelial cells (HPMCs) and provided insights to their actin/filopodia mediated building mechanism. They showed also that TNF significantly increased TNTs formation between HPMCs, pointing to a crucial role of TNTs during inflammatory processes (4).
1.      Rustom A, Saffrich R, Markovic I, Walther P, Gerdes HH. Nanotubular highways for intercellular organelle transport. Science 303: 1007–1010, (2004).
2.      Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P. Molecular.Biology of the Cell. New York: Garland Science, 2008.
3.      Robert S. Rogers, Jahar Bhattacharya. When cells become organelle donors. Physiology 28: 414–422,2013
4.      Julia Ranzinger, Amin Rustom, Vedat Schwenger. Potential role of nanotubes in context of clinical treatments? Communicative & Integrative Biology 2013 January 1, 6 (1): e22686
Phileno Pinge-Filho - UEL
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