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chemotherapy which has many different mechanisms of action within the cell preventing proliferation. However, p53, being in high concentration in cancers, may have the ability to form TNTs. The questions that need to be asked are: 1) Do cancers cells with high concentrations of p53 also produce TNTs? 2) Does the treatment of chemotherapy drugs increase TNT formation? 3) Do resistant cancers have the ability to produce TNTs when treated with chemotherapy drugs? Virus and prion exchange TNTs also provide a way for pathogens to migrate from one cell to another and proliferate. HIV was discovered to use TNTs to migrate from one cell to another, evading the extracellular environment in human monocyte-derived macrophages (MDM) and avoiding the host’s immune cells (Kadiu and Gendelman, 2011; Eugenin et al., 2009). It was found that HIV depended upon entering a MDM via clathrin-mediated endocytosis. This process encapsulates the virus and allows it to pass through F-actin and microtubule derived TNTs to a neighbouring cell (Kadiu and Gendelman, 2011). Again with T-cells, HIV was found to use TNTs as a way of infecting neighbouring cells and also increase the numbers of TNT formations without having to spread via the extracellular fluid (Sowinski et al., 2008). These data demonstrate how viruses have the ability to use host immune cells to migrate and proliferate in vitro without contacting the extracellular fluid. Prions have also been identified to migrate between cells using TNTs (Gousset et al., 2009). Prions are misfolded proteins that are capable of entering a cell and altering wild-type proteins leading to diseases like Creutzfeldt-Jakob disease (CJD) and can cause necrosis (Brundin et al., 2010). It was identified that TNTs can aid the spreading of prions in cultured cells from Cath. a-differentiated (CAD) cell line (Gousset et al., 2009). The use and passage of mitochondria from damaged to healthy cells in the brain may be a cause of spreading neural diseases, e.g. AD and PD. Three research questions arise in this area, which are 1) Does a damaged cell have the ability to both form and pass ROS-induced damaged mtDNA to a healthy neighbouring cell? 2) Do the damaged mitochondria have the ability to begin apoptosis in the neighbouring cell and again signal for TNT formation? 3) Can this process be reversed using stem cells as previously described? The process of viral entry and migration through TNTs has now been documented and Tunneling nanotubes 15 accepted. The ability to move from cell to cell using TNTs without having to exit and migrate through the extracellular fluid have provided a new mechanism of infection for viruses and prions. This process of “hijacking” TNTs will no doubt be of interest to virology and more so for the spread of HIV amongst immune cells. We now know that viruses promote TNT formation in the infected cell and allow safe passage to a recipient, can the same process be blocked and prevent these “hijackers” from migrating between cells using TNTs? Stem cells and their ability to repair damage via TNTs Stem cells are very much at the forefront of medical sciences and the hope of curing many diseases rests upon these progenitor cells. It is surprising, though, to discover their additional abilities and possible mechanisms of aiding cells in distress in vitro. It was discovered that endothelial progenitor cells (EPC) – a precursor cell to endothelial cells – could couple with both types of TNT sizes from HUVEC (Yasuda et al., 2011). It was observed that EPC cocultured with stressed HUVEC could produce TNTs and traffic cellular components both ways, but mainly observed to pass from EPC to HUVEC (Yasuda et al., 2011). This promoted HUVEC to recover from stress and to proliferate. Additionally, mesenchymal stem cells (MSC) were also found to traffic cellular components via TNTs to damaged cardiomyoblasts and promote recovery (Cselenyak et al., 2010). From the research it seems that stem cells have the ability to repair cells which have sustained stress. This process of repair rather than salvaging (as found in non-stem cells in previous sections of this review) may demonstrate how stem cells can rescue damaged cells. Discussion With the discovery of TNTs and the subsequent abilities they have in trafficking the molecules, disease-spreading prions and viruses, it is clear that these TNTs have a valid place in cellular biology. It can be agreed that TNTs do provide a function in cellular communication. There is still a mystery to TNT-genesis in that it is not fully understood what mechanisms are in place that signal aid via TNTs. We do know that stress is a key factor and that repair/apoptosis mechanisms are in place prior to TNT development. With further research TNTgenesis and key communication signals for coupling may become better understood. This review paper ventured into diseases associated with intracellular molecules and viruses
16 Marc McGOWAN with the notion of finding ways in which TNTs move (and in some cases potentially) them from one cell to another. This will require further investigation as to the spreading of disease amongst cells via TNTs as suggested in this review. This, along with cancer research, provide great opportunity to study mechanisms of TNT formation within cell lines resistant to chemotherapy drugs by the movement of surface proteins associated with multidrug resistance. This would be very interesting to see if cancer cells can help each other when subjected to cytotoxic drugs. Since the initial discovery by Gerdes’ team (Rustom et al., 2004), TNTs have added another level to our understanding of biological processes for molecular and cell biologists. With each year since their discovery, more and more cells are being characterized as forming TNTs with their own unique way of using them. It is now accepted that TNTs provide direct cell-cell communication along with gap junctions and synaptic signalling. It is useful to find new and potential mechanisms of disease spreading and observe how these pathogens and mutated genes can migrate from one cell to another without being targeted by the host’s immune system. They also demonstrate a plausible method of cellular repair such as the way stem cells can meet the needs of a damaged cell. It thus can be concluded here that TNTs are becoming very important in direct cell-cell communication, repair and disease transfer. There will no doubt be more research papers coming to light after this review is published and thus would not do justice to the new work currently being conducted. Acknowledgements The author thanks to both Dr Stephen Merry and Renate Simonsen for their time and support in evaluating this paper. References Agnati LF, Guidolin D, Baluska F, Barlow P. W, Carone C and Genedani S. A New Hypothesis of Pathogenesis Based on the Divorce between Mitochondria and their Host Cells: Possible Relevance for Alzheimers Disease. Current Alzheimer Research. 7: 307-322, 2010. Brundin P, Melki R and Kopito R. Prion-like transmission of protein aggregates in neurodegenerative diseases. Nat Rev Mol Cell Biol. 11: 301-307, 2010. Chinnery HR, Pearlman E and McMenamin PG. Cutting Edge: Membrane Nanotubes In Vivo: A Feature of MHC Class II+ Cells in the Mouse Cornea. The Journal of Immunology. 180: 5779- 5783, 2008. Cselenyak A, Pankkotai E, Horvath E, Kiss L and Lacza, Z. Mesenchymal stem cells rescue cardiomyoblasts from cell death in an in vitro ischemia model via direct cell-to-cell connections. BMC Cell Biology. 11: 29, 2010. Eugenin EA, Gaskill PJ and Bermann JW. Tunneling nanotubes (TNT) are induced by HIV-infection of macrophages: A potential mechanism for intercellular HIV trafficking. Cellular Immunology. 254: 142-148, 2009. Freund D, Bauer N. Boxberger S, Feldmann S, Streller U, Ehninger G, Werner C, Bornhäuser M, Oswald J and Corbeil D. Polarization of Human Hematopoietic Progenitors During Contact with Multipotent Mesenchymal Stromal Cells: Effects on Proliferation and Clonogenicity. Stem Cells and Developmen. 15: 815-829, 2006. Gerdes H-H, Bukoreshtliev NV and Barroso JFV. Tunneling nanotubes: A new route for the exchange of components between animal cells. FEBS letters. 581: 2194-2201, 2007. Gerdes H-H and Carvalho RN. Intercellular transfer mediated by tunneling nanotubes. Current Opinion in Cell Biology. 20: 470-475, 2008. Gong J, Jaiswal R, Mathys JM, Combes V, Grau GER. and Bebawy M. Microparticles and their emerging role in cancer multidrug resistance. Cancer Treatment Reviews. In Press, Corrected Proof, 2011. Gottesman MM and Pastan I. Biochemistry of Multidrug Resistance Mediated by the Multidrug Transporter. Annual Review of Biochemistry. 62: 385-427, 1993. Gousset K, Schiff E, Langevin C, Marijanovic Z, Caputo A, Browman DT, Chenouard N, DE Chaumont F, Martino A, Enninga J, Olivo- Marin JC, Manne, D and Zurzolo C. Prions hijack tunneling nanotubes for intercellular spread. Nat Cell Biol. 11: 328-336, 2009. He K, Shi X, Zhang X, Dang S, Ma X, Liu F, Xu M, Lv Z, Han D, Fang X and Zhang Y. Long- Distance Intercellular Connectivity between Cardiomyocytes and Cardiofibroblasts Mediated by Membrane Nanotubes. Cardiovascular Research. 92: 39-49, 2011.
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