Tunneling Nanotubeの発見（1999年）とその後の進展について

細胞の基本的な構造に関しては十分調べられ尽くしたと思っていました。今頃（といっても最初の発見は1999年ですが）になって新しい構造が発見されるとは夢にも思いませんでした。

トップジャーナルに掲載されたナノチューブ論文

  1. Ramírez-Weber FA, Kornberg TB. Cytonemes: cellular processes that project to the principal signaling center in Drosophila imaginal discs. Cell. 1999 May 28;97(5):599-607. doi: 10.1016/s0092-8674(00)80771-0. PMID: 10367889. 
  2. Amin Rustom et al. ,　Nanotubular Highways for Intercellular Organelle Transport.　Science 303,1007-1010(2004).DOI:10.1126/science.1093133　https://www.science.org/doi/10.1126/science.1093133
  3. Inaba, M., Buszczak, M. & Yamashita, Y. Nanotubes mediate niche–stem-cell signalling in the Drosophila testis. Nature 523, 329–332 (2015). https://doi.org/10.1038/nature14602
    1. https://www.natureasia.com/ja-jp/ndigest/v14/n12/細胞をつなぐナノチューブ/90179　遺伝子操作した細胞内で生産された一部のタンパク質が、全く異なる細胞群に「テレポート」したように見えた　　彼女らはこの現象が現実のものだと確信したが、どのような仕組みでそうなるのか突き止められなかったため、このプロジェクトをひとまず棚上げした。1年以上経ったある日、山下のところへ稲葉が細胞の画像を何枚か持ってきた。そこには、1個の細胞から別の細胞へと伸びる微小な管が写っていた。これらの微細な構造が、例の謎の輸送を担っているとも考えられた。
    2. 幹細胞に特異的な細胞突起である微小管依存性ナノチューブはニッチからのシグナルの受容を促進する 稲葉真弓・山下由起子 （米国Michigan大学Life Sciences Institute）　https://first.lifesciencedb.jp/archives/10476

 

Consensusによる総説。

Tunneling Nanotubes: Direct Intercellular Communication and Molecular Exchange

Tunneling nanotubes (TNTs) are thin, actin-based membranous structures that form direct cytoplasmic bridges between cells, enabling the exchange of a wide variety of molecules and organelles. This form of intercellular communication is distinct from other mechanisms like gap junctions or extracellular vesicles, as TNTs allow for long-range, bidirectional, and targeted transfer of cellular cargo, playing crucial roles in both normal physiology and disease.

Mechanisms and Types of Cargo Transferred

TNTs facilitate the direct transfer of diverse cellular components, including ions (such as Ca2+), proteins, nucleic acids (DNA, mRNA, miRNA, viral RNA), organelles (mitochondria, lysosomes), vesicles, and even pathogens between connected cells. This transfer can modulate gene expression, metabolism, and cell survival, and is observed in many cell types, including neurons, immune cells, and cancer cells (Driscoll et al., 2022; Khattar et al., 2022; Turos-Korgul et al., 2022; Ariazi et al., 2017; Kolba et al., 2019; Jansens et al., 2020; Marzo et al., 2012; DuPont et al., 2018; Lou et al., 2018; Chakraborty & Zurzolo, 2022; Zhu et al., 2021; Mittal et al., 2018; Wittig et al., 2012; Yamashita et al., 2018).

Functional Roles in Health and Disease

TNT-mediated communication is essential for tissue homeostasis, immune responses, and development. In the brain, TNTs contribute to neural development, calcium signaling, and the spread of protein aggregates linked to neurodegenerative diseases. In cancer, TNTs enable the transfer of survival signals, drug resistance factors, and mitochondria, supporting tumor progression and therapy resistance. Pathogens, including viruses and prions, can hijack TNTs for cell-to-cell spread (Driscoll et al., 2022; Khattar et al., 2022; Turos-Korgul et al., 2022; Ariazi et al., 2017; Kolba et al., 2019; Jansens et al., 2020; Marzo et al., 2012; DuPont et al., 2018; Lou et al., 2018; Chakraborty & Zurzolo, 2022; Mittal et al., 2018; Yamashita et al., 2018).

Comparison with Other Communication Pathways

Unlike gap junctions (which are limited to small molecules and require close cell proximity), TNTs can bridge distant cells and transport larger cargo. TNTs are also structurally and functionally distinct from cytonemes and extracellular vesicles, offering a unique, direct, and dynamic mode of intercellular exchange (Driscoll et al., 2022; Ariazi et al., 2017; Marzo et al., 2012; Nawaz & Fatima, 2017; Wittig et al., 2012; Yamashita et al., 2018).

Timeline of Key Research Developments

  • 2008
    • 1 paper: (Gerdes & Carvalho, 2008)- 2012
    • 2 papers: (Marzo et al., 2012; Wittig et al., 2012)- 2013
    • 2 papers: (Schiller et al., 2013; Suhail et al., 2013)- 2015
    • 1 paper: (Abounit et al., 2015)- 2017
    • 2 papers: (Ariazi et al., 2017; Nawaz & Fatima, 2017)- 2018
    • 4 papers: (DuPont et al., 2018; Lou et al., 2018; Mittal et al., 2018; Yamashita et al., 2018)- 2019
    • 1 paper: (Kolba et al., 2019)- 2020
    • 1 paper: (Jansens et al., 2020)- 2021
    • 1 paper: (Zhu et al., 2021)- 2022
    • 4 papers: (Driscoll et al., 2022; Khattar et al., 2022; Turos-Korgul et al., 2022; Chakraborty & Zurzolo, 2022)- 2024
    • 1 paper: (Gong et al., 2024)| Year | Key Focus/Discovery | Citation | |——|———————|———-| | 2004 | First description of TNTs and their role in vesicle/organelle transfer | (Gerdes & Carvalho, 2008; Marzo et al., 2012; Yamashita et al., 2018)| | 2012–2018 | TNTs in disease, immune function, and cancer; comparison with other pathways | (Ariazi et al., 2017; Marzo et al., 2012; DuPont et al., 2018; Lou et al., 2018; Nawaz & Fatima, 2017; Mittal et al., 2018; Wittig et al., 2012; Yamashita et al., 2018)| | 2019–2024 | TNTs in therapy resistance, neural modulation, and advanced imaging | (Kolba et al., 2019; Jansens et al., 2020; Gong et al., 2024; Chakraborty & Zurzolo, 2022; Zhu et al., 2021)|

Figure 1: Timeline of tunneling nanotube research and major discoveries. Larger markers indicate more citations.

Summary

Tunneling nanotubes are specialized cellular structures that enable direct, long-distance exchange of molecules and organelles between cells. They play vital roles in development, immune function, neural communication, and disease progression, distinguishing themselves from other intercellular communication mechanisms by their ability to transfer large and diverse cargo over significant distances. Understanding TNTs opens new avenues for therapeutic intervention in cancer, neurodegeneration, and infectious diseases.

These papers were sourced and synthesized using Consensus, an AI-powered search engine for research. Try it at https://consensus.app

References

  1. Driscoll, J., Gondaliya, P., & Patel, T. (2022). Tunneling Nanotube-Mediated Communication: A Mechanism of Intercellular Nucleic Acid Transfer. International Journal of Molecular Sciences, 23. https://doi.org/10.3390/ijms23105487
  2. Gerdes, H., & Carvalho, R. (2008). Intercellular transfer mediated by tunneling nanotubes.. Current opinion in cell biology, 20 4, 470-5. https://doi.org/10.1016/j.ceb.2008.03.005
  3. Khattar, K., Safi, J., Rodriguez, A., & Vignais, M. (2022). Intercellular Communication in the Brain through Tunneling Nanotubes. Cancers, 14. https://doi.org/10.3390/cancers14051207
  4. Turos-Korgul, L., Kolba, M., Chrościcki, P., Zieminska, A., & Piwocka, K. (2022). Tunneling Nanotubes Facilitate Intercellular Protein Transfer and Cell Networks Function. Frontiers in Cell and Developmental Biology, 10. https://doi.org/10.3389/fcell.2022.915117
  5. Ariazi, J., Benowitz, A., De Biasi, V., Boer, M., Cherqui, S., Cui, H., Douillet, N., Eugenin, E., Favre, D., Goodman, S., Gousset, K., Hanein, D., Israel, D., Kimura, S., Kirkpatrick, R., Kuhn, N., Jeong, C., Lou, E., Mailliard, R., Maio, S., Okafo, G., Osswald, M., Pasquier, J., Polak, R., Pradel, G., De Rooij, B., Schaeffer, P., Skeberdis, V., Smith, I., Tanveer, A., Volkmann, N., Wu, Z., & Zurzolo, C. (2017). Tunneling Nanotubes and Gap Junctions–Their Role in Long-Range Intercellular Communication during Development, Health, and Disease Conditions. Frontiers in Molecular Neuroscience, 10. https://doi.org/10.3389/fnmol.2017.00333
  6. Kolba, M., Dudka, W., Zaręba-Kozioł, M., Kominek, A., Ronchi, P., Turos, L., Chrościcki, P., Włodarczyk, J., Schwab, Y., Klejman, A., Cysewski, D., Srpan, K., Davis, D., & Piwocka, K. (2019). Tunneling nanotube-mediated intercellular vesicle and protein transfer in the stroma-provided imatinib resistance in chronic myeloid leukemia cells. Cell Death & Disease, 10. https://doi.org/10.1038/s41419-019-2045-8
  7. Jansens, R., Tishchenko, A., & Favoreel, H. (2020). Bridging the Gap: Virus Long-Distance Spread via Tunneling Nanotubes. Journal of Virology, 94. https://doi.org/10.1128/jvi.02120-19
  8. Gong, Z., Wu, T., Zhao, Y., Guo, J., Zhang, Y., Li, B., & Li, Y. (2024). Intercellular Tunneling Nanotubes as Natural Biophotonic Conveyors.. ACS nano. https://doi.org/10.1021/acsnano.4c12681
  9. Marzo, L., Gousset, K., & Zurzolo, C. (2012). Multifaceted Roles of Tunneling Nanotubes in Intercellular Communication. Frontiers in Physiology, 3. https://doi.org/10.3389/fphys.2012.00072
  10. DuPont, M., Souriant, S., Lugo-Villarino, G., Maridonneau-Parini, I., & Vérollet, C. (2018). Tunneling Nanotubes: Intimate Communication between Myeloid Cells. Frontiers in Immunology, 9. https://doi.org/10.3389/fimmu.2018.00043
  11. Lou, E., Zhai, E., Sarkari, A., Desir, S., Wong, P., Iizuka, Y., Yang, J., Subramanian, S., McCarthy, J., Bazzaro, M., & Steer, C. (2018). Cellular and Molecular Networking Within the Ecosystem of Cancer Cell Communication via Tunneling Nanotubes. Frontiers in Cell and Developmental Biology, 6. https://doi.org/10.3389/fcell.2018.00095
  12. Schiller, C., Huber, J., Diakopoulos, K., & Weiss, E. (2013). Tunneling nanotubes enable intercellular transfer of MHC class I molecules.. Human immunology, 74 4, 412-6. https://doi.org/10.1016/j.humimm.2012.11.026
  13. Chakraborty, R., & Zurzolo, C. (2022). Tunnelling nanotubes between neuronal and microglial cells allow bi-directional transfer of α-Synuclein and mitochondria. Cell Death & Disease, 14. https://doi.org/10.1101/2022.12.13.519450
  14. Zhu, C., Shi, Y., & You, J. (2021). Immune Cell Connection by Tunneling Nanotubes: The Impact of Intercellular Cross-Talk on the Immune Response and Its Therapeutic Applications.. Molecular pharmaceutics. https://doi.org/10.1021/acs.molpharmaceut.0c01248
  15. Nawaz, M., & Fatima, F. (2017). Extracellular Vesicles, Tunneling Nanotubes, and Cellular Interplay: Synergies and Missing Links. Frontiers in Molecular Biosciences, 4. https://doi.org/10.3389/fmolb.2017.00050
  16. Mittal, R., Karhu, E., Wang, J., Delgado, S., Zukerman, R., Mittal, J., & Jhaveri, V. (2018). Cell communication by tunneling nanotubes: Implications in disease and therapeutic applications. Journal of Cellular Physiology, 234, 1130 – 1146. https://doi.org/10.1002/jcp.27072
  17. Abounit, S., Delage, E., & Zurzolo, C. (2015). Identification and Characterization of Tunneling Nanotubes for Intercellular Trafficking. Current Protocols in Cell Biology, 67, 12.10.1 – 12.10.21. https://doi.org/10.1002/0471143030.cb1210s67
  18. Suhail, Y., , K., Lee, J., Walker, M., Kim, D., Brennan, M., Bader, J., & Levchenko, A. (2013). Modeling Intercellular Transfer of Biomolecules Through Tunneling Nanotubes. Bulletin of Mathematical Biology, 75, 1400 – 1416. https://doi.org/10.1007/s11538-013-9819-4
  19. Wittig, D., Wang, X., Walter, C., Gerdes, H., Funk, R., & Roehlecke, C. (2012). Multi-Level Communication of Human Retinal Pigment Epithelial Cells via Tunneling Nanotubes. PLoS ONE, 7. https://doi.org/10.1371/journal.pone.0033195
  20. Yamashita, Y., Inaba, M., & Buszczak, M. (2018). Specialized Intercellular Communications via Cytonemes and Nanotubes.. Annual review of cell and developmental biology, 34, 59-84. https://doi.org/10.1146/annurev-cellbio-100617-062932

その他の文献情報

  1. 2025.10.24【研究発表】細胞同士がつながっちゃう？丈夫なトンネルナノチューブを作る新たなメカニズム　東京都立大学　https://www.tmu.ac.jp/news/topics/38060.html　多くのTNTの細胞骨格はアクチンフィラメントですが、中にはより強い細胞骨格で、高速で方向性を持った輸送のレールとなる微小管を含むTNTもあります。今回、東京都立大学理学研究科の榎本美優(当時大学院生)、淺田明子助教、安藤香奈絵教授らは、TNTの形成を促進するタンパク質、CCT4を見つけました。
  2. Tunneling nanotubes enable intercellular transfer in zebrafish embryos Korenkova, Olga et al. Developmental Cell, Volume 60, Issue 4, 524 – 534.e3 February 24, 2025 https://www.cell.com/developmental-cell/fulltext/S1534-5807%2824%2900635-X
  3. Microglia rescue neurons from aggregate-induced neuronal dysfunction and death through tunneling nanotubes ミクログリアは凝集タンパク質による神経異常と細胞死をナノチューブのトンネルを形成して助ける Scheiblich et al. Neuron 112, 3106 – 3125.e8 (2024)　日本認知症学会（論文解説）
  4. Capobianco D. L. , Simone L. , Svelto M. , Pisani F. Intercellular crosstalk mediated by tunneling nanotubes between central nervous system cells. What we need to advance Frontiers in Physiology Volume 14 – 2023  https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2023.1214210 DOI=10.3389/fphys.2023.1214210
  5. Driscoll, J.; Gondaliya, P.; Patel, T. Tunneling Nanotube-Mediated Communication: A Mechanism of Intercellular Nucleic Acid Transfer. Int. J. Mol. Sci. 2022, 23, 5487. https://doi.org/10.3390/ijms23105487　https://www.mdpi.com/1422-0067/23/10/5487
  6. Khattar KE, Safi J, Rodriguez AM, Vignais ML. Intercellular Communication in the Brain through Tunneling Nanotubes. Cancers (Basel). 2022 Feb 25;14(5):1207. doi: 10.3390/cancers14051207. PMID: 35267518; PMCID: PMC8909287.　
  7. トンネルナノチューブを介した細胞間ミトコンドリア移送 三　 木　 敏　 生 日本大学医学部生体機能医学系生理学分野 日大医誌　79 (5): 313–315 (2020)  ミトコンドリアの細胞間移送には，大きく二つの可能性 が示されている．まず一つは，細胞外小胞 (Extracellular Vesicles) を介したもの，そしてもう一つは，トンネルナ ノチューブ (TNTs) と呼ばれる特殊なチューブ状の構造 物の接続によるものである．  https://www.jstage.jst.go.jp/article/numa/79/5/79_313/_pdf/-char/ja
  8. トンネル ナノチューブ: 骨髄細胞間の密接なコミュニケーション Maeva Dupont,Shanti Souriant,Geanncarlo Lugo-Villarino,Isabelle Maridonneau-Parini,Christel Vérollet, PMID：29422895DOI：10.3389/fimmu.2018.00043　Frontiers in immunology20180101Vol.9 https://bibgraph.hpcr.jp/abst/pubmed/29422895
  9. Hans-Hermann Gerdes, Amin Rustom, Xiang Wang, Tunneling nanotubes, an emerging intercellular communication route in development, Mechanisms of Development, Volume 130, Issues 6–8, 2013, Pages 381-387, ISSN 0925-4773, June–August 2013 https://doi.org/10.1016/j.mod.2012.11.006.
  10. Kolba, M.D., Dudka, W., Zaręba-Kozioł, M. et al. Tunneling nanotube-mediated intercellular vesicle and protein transfer in the stroma-provided imatinib resistance in chronic myeloid leukemia cells. Cell Death Dis 10, 817 (2019). https://doi.org/10.1038/s41419-019-2045-8
  11. Lou E, Fujisawa S, Barlas A, Romin Y, Manova-Todorova K, Moore MA, Subramanian S. Tunneling Nanotubes: A new paradigm for studying intercellular communication and therapeutics in cancer. Commun Integr Biol. 2012 Jul 1;5(4):399-403. doi: 10.4161/cib.20569. PMID: 23060969; PMCID: PMC3460850.
  12. 2009年11月23日 独立行政法人 理化学研究所 細胞間を連結する細胞膜ナノチューブの形成因子「M-Sec」を発見 －遠隔にある細胞間を連結し、素早く確実に情報伝達するシステム解明に貢献－　　https://www.riken.jp/press/2009/20091123/index.html
  13. Amin Rustom et al. ,　Nanotubular Highways for Intercellular Organelle Transport.　Science 303,1007-1010(2004).DOI:10.1126/science.1093133　https://www.science.org/doi/10.1126/science.1093133
  14. Ramírez-Weber FA, Kornberg TB. Cytonemes: cellular processes that project to the principal signaling center in Drosophila imaginal discs. Cell. 1999 May 28;97(5):599-607. doi: 10.1016/s0092-8674(00)80771-0. PMID: 10367889.