Exosome uptake through clathrin-mediated endocytosis and macropinocytosis and mediating miR-21 delivery
Open accessAbstract
Exosomes are nanoscale membrane vesicles secreted from many types of cells. Carrying functional molecules, exosomes transfer information between cells and mediate many physiological and pathological processes. In this report, utilizing selective inhibitors, molecular tools, and specific endocytosis markers, the cellular uptake of PC12 cell-derived exosomes was imaged by high-throughput microscopy and statistically analyzed. It was found that the uptake was through clathrin-mediated endocytosis and macropinocytosis. Furthermore, PC12 cell-derived exosomes can enter and deliver microRNAs (miRNAs) into bone marrow-derived mesenchymal stromal cells (BMSCs), and decrease the expression level of transforming growth factor β receptor II (TGFβRII) and tropomyosin-1 (TPM1) through miR-21. These results show the pathway of exosome internalization and demonstrate that tumor cell-derived exosomes regulate target gene expression in normal cells.
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miR-21 has been demonstrated to be packaged within exosomes and released from different cancer types.
“Moreover, miR-21 has been demonstrated to be packaged within exosomes and released from different cancer types (51–54).”
From Potential Therapeutic Effects of Exosomes Packed With a miR-21-Sponge Construct in a Rat Model of Glioblastoma (2019) · cites this paper as [52]
The Discussion states that PC12 cell-derived exosomes enclosed abundant miR-21, and the section on delivery into BMSCs reports miR-21 in those exosomes. This demonstrates packaging by one tumor-cell type, but the paper does not demonstrate miR-21 release in exosomes from different cancer types. (LLM, conf=0.86)
Experimental — accuracy not yet measuredmiRNAs enter recipient cells by endocytosis and micropinocytosis.
“Indeed, several studies have shown that miRNAs enter recipient cells by endocytosis and micropinocytosis (141, 142).”
From Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation (2018) · cites this paper as [142]
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Cites
Isolation and Characterization of Exosomes from Cell Culture Supernatants and Biological Fluids
Théry, C., Amigorena, S., Raposo, G., & Clayton, A. (2006) · Current Protocols in Cell Biology · doi:10.1002/0471143030.cb0322s30 · Cited by 5,766 · see citing works
Regulated portals of entry into the cell
Conner, S. D., & Schmid, S. L. (2003) · Nature · doi:10.1038/nature01451 · Cited by 3,816 · see citing works
Exosomes: Extracellular organelles important in intercellular communication
Mathivanan, S., Ji, H. L., & Simpson, R. J. (2010) · Journal of Proteomics · doi:10.1016/j.jprot.2010.06.006 · Cited by 2,539 · see citing works
Membrane vesicles, current state-of-the-art: emerging role of extracellular vesicles
György, B., Szabó, T. G., Pásztói, M., Pál, Z., Misják, P., Aradi, B., László, V., Pállinger, É., Pap, E., Kittel, Á., et al. (2011) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-011-0689-3 · Cited by 2,075 · see citing works
Vlassov, A. V., Magdaleno, S. M., Setterquist, R. A., & Conrad, R. (2012) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2012.03.017 · Cited by 1,936 · see citing works
Pathways of clathrin-independent endocytosis
Mayor, S., & Pagano, R. E. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2216 · Cited by 1,556 · see citing works
Uptake Pathways and Subsequent Intracellular Trafficking in Nonviral Gene Delivery
Khalil, I. A., Kogure, K., Akita, H., & Harashima, H. (2006) · Pharmacological Reviews · doi:10.1124/pr.58.1.8 · Cited by 1,241 · see citing works
Secreted Monocytic miR-150 Enhances Targeted Endothelial Cell Migration
Zhang, Y., Liu, D., Chen, X., Li, J., Li, L., Bian, Z., Sun, F., Lu, J., Yin, Y., Cai, X. F., et al. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.06.010 · Cited by 1,190 · see citing works
Identification of Tim4 as a phosphatidylserine receptor
Miyanishi, M., Tada, K., Koike, M., Uchiyama, Y., Kitamura, T., & Nagata, S. (2007) · Nature · doi:10.1038/nature06307 · Cited by 1,180 · see citing works
Cellular Internalization of Exosomes Occurs Through Phagocytosis
Feng, D., Zhao, W.-L., Ye, Y.-Y., Bai, X., Liu, R.-Q., Chang, L.-F., Zhou, Q., & Sui, S. (2010) · Traffic · doi:10.1111/j.1600-0854.2010.01041.x · Cited by 981 · see citing works
OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma
Medina, P. P., Nolde, M., & Slack, F. J. (2010) · Nature · doi:10.1038/nature09284 · Cited by 971 · see citing works
Christianson, H. C., Svensson, K. J., van Kuppevelt, T. H., Li, J.-P., & Belting, M. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1304266110 · Cited by 903 · see citing works
The Biogenesis and Functions of Exosomes
Stoorvogel, W., Kleijmeer, M. J., Geuze, H. J., & Raposo, G. (2002) · Traffic · doi:10.1034/j.1600-0854.2002.30502.x · Cited by 848 · see citing works
Selective transfer of exosomes from oligodendrocytes to microglia by macropinocytosis
Fitzner, D., Schnaars, M., van Rossum, D., Krishnamoorthy, G., Dibaj, P., Bakhti, M., Regen, T., Hanisch, U.-K., & Simons, M. (2011) · Journal of Cell Science · doi:10.1242/jcs.074088 · Cited by 775 · see citing works
Secreted microRNAs: a new form of intercellular communication
Chen, X., Liang, H., Zhang, J., Zen, K., & Zhang, C. (2012) · Trends in Cell Biology · doi:10.1016/j.tcb.2011.12.001 · Cited by 761 · see citing works
Exosome Function: From Tumor Immunology to Pathogen Biology
Schorey, J. S., & Bhatnagar, S. (2008) · Traffic · doi:10.1111/j.1600-0854.2008.00734.x · Cited by 758 · see citing works
Svensson, K. J., Christianson, H. C., Wittrup, A., Bourseau-Guilmain, E., Lindqvist, E., Svensson, L. M., Mörgelin, M., & Belting, M. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.445403 · Cited by 690 · see citing works
Kerr, M. C., & Teasdale, R. D. (2009) · Traffic · doi:10.1111/j.1600-0854.2009.00878.x · Cited by 685 · see citing works
Actions of TGF-β as tumor suppressor and pro-metastatic factor in human cancer
Pardali, K., & Moustakas, A. (2006) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2006.06.004 · Cited by 532 · see citing works
Tumour-released exosomes and their implications in cancer immunity
Iero, M., Valenti, R., Huber, V., Filipazzi, P., Parmiani, G., Fais, S., & Rivoltini, L. (2007) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402237 · Cited by 483 · see citing works
Bierie, B., & Moses, H. (2005) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2005.09.006 · Cited by 476 · see citing works
Visualizing of the cellular uptake and intracellular trafficking of exosomes by live‐cell microscopy
Tian, T., Wang, Y., Wang, H., Zhu, Z., & Xiao, Z. (2010) · Journal of Cellular Biochemistry · doi:10.1002/jcb.22733 · Cited by 457 · see citing works
Self-citationMicroRNAs and their target gene networks in breast cancer
O’Day, E. M., & Lal, A. (2010) · Breast Cancer Research · doi:10.1186/bcr2484 · Cited by 437 · see citing works
Chen, X., Gao, C., Li, H., Huang, L., Sun, Q., Dong, Y., Tian, C., Gao, S., Dong, H., Guan, D., et al. (2010) · Cell Research · doi:10.1038/cr.2010.80 · Cited by 381 · see citing works
Dynamics of exosome internalization and trafficking
Tian, T., Zhu, Y., Hu, F., Wang, Y., Huang, N., & Xiao, Z. (2012) · Journal of Cellular Physiology · doi:10.1002/jcp.24304 · Cited by 336 · see citing works
Self-citationIntegrin-mediated adhesion regulates membrane order
Gaus, K., Lay, S. L., Balasubramanian, N., & Schwartz, M. A. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200603034 · Cited by 272 · see citing works
Horizontal transfer of microRNAs: molecular mechanisms and clinical applications
Chen, X., Liang, H., Zhang, J., Zen, K., & Zhang, C. (2012) · Protein & Cell · doi:10.1007/s13238-012-2003-z · Cited by 257 · see citing works
Chiba, M., KIMURA, M., & ASARI, S. (2012) · Oncology Reports · doi:10.3892/or.2012.1967 · Cited by 232 · see citing works
Argonaute 2 Complexes Selectively Protect the Circulating MicroRNAs in Cell-Secreted Microvesicles
Li, L., Zhu, D., Huang, L., Zhang, J., Bian, Z., Chen, X., Liu, Y., Zhang, C., & Zen, K. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046957 · Cited by 216 · see citing works
Nesterov, A., Carter, R. E., Sorkina, T., Gill, G. N., & Sorkin, A. D. (1999) · The EMBO Journal · doi:10.1093/emboj/18.9.2489 · Cited by 214 · see citing works
Cancer secretomics reveal pathophysiological pathways in cancer molecular oncology
Karagiannis, G. S., Pavlou, M. P., & Diamandis, E. P. (2010) · Molecular Oncology · doi:10.1016/j.molonc.2010.09.001 · Cited by 159 · see citing works
Exosome Secretion: The Art of Reutilizing Nonrecycled Proteins?
Gassart, A. D., Géminard, C., Hoekstra, D., & Vidal, M. (2004) · Traffic · doi:10.1111/j.1600-0854.2004.00223.x · Cited by 156 · see citing works
Cai, Z., Zhang, W., Yang, F., Yu, L., Zhou, Y., Pan, J., Wang, L., Cao, X., & Wang, J. (2011) · Cell Research · doi:10.1038/cr.2011.196 · Cited by 142 · see citing works
Self-citationLü, L., Zhang, X., Wang, Y., Ortiz, L. S., Mao, X., Jiang, Z., Xiao, Z., & Huang, N. (2012) · ACS Applied Materials & Interfaces · doi:10.1021/am302146w · Cited by 135 · see citing works
Self-citationRibas, J., & Lupold, S. E. (2010) · Cell Cycle · doi:10.4161/cc.9.5.10930 · Cited by 120 · see citing works
Expression of Macrophage Antigens by Tumor Cells
Shabo, I., & Svanvik, J. (2011) · Advances in experimental medicine and biology · doi:10.1007/978-94-007-0782-5_7 · Cited by 108 · see citing works
Understanding Living Clathrin-Coated Pits
Rappoport, J. Z., Simon, S. M., & Benmerah, A. (2004) · Traffic · doi:10.1111/j.1398-9219.2004.00187.x · Cited by 86 · see citing works
Staals, R. H. J., & Pruijn, G. J. M. (2010) · Advances in experimental medicine and biology · doi:10.1007/978-1-4419-7841-7_11 · Cited by 68 · see citing works
Late endocytic dysfunction as a putative cause of amyloid fibril formation in Alzheimer’s disease
Yuyama, K., & Yanagisawa, K. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06046.x · Cited by 40 · see citing works
A Novel Strategy for the Invasive Toxin: Hijacking Exosome‐Mediated Intercellular Trafficking
Zhang, F., Sun, S., Feng, D., et al. (2009) · Traffic · doi:10.1111/j.1600-0854.2009.00879.x · Cited by 30 · see citing works
Zhang, W., Smith, A. D., Liu, J., Cheung, N. S., Zhou, S., Liu, K., Li, Q., & Duan, W. (2008) · Cellular Signalling · doi:10.1016/j.cellsig.2008.10.008 · Cited by 24 · see citing works
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- Authors
- Tian, T., Zhu, Y.-L., Zhou, Y.-Y., Liang, G.-F., Wang, Y.-Y., Hu, F.-H., & Xiao, Z.-D.
- Affiliations
- State Key Laboratory of Digital Medical Engineering (CN)
- Corresponding author
- Xiao, Zhong-Dang
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2014-08
- Volume
- 289
- Issue
- 32
- Pages
- 22258-22267
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4139237
- OpenAlex
- W2015994724
- Cited by
- 726
- References
- 41
- Citations by year
- 2026: 50 · 2025: 56 · 2024: 81 · 2023: 71 · 2022: 79 · 2021: 107 · 2020: 75 · 2019: 57 · 2018: 52 · 2017: 39 · 2016: 30 · 2015: 25 · 2014: 1
- FWCI
- 12.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (973 Program, 31371003, 61071047)
- Government of Jiangsu Province
- Natural Science Foundation of Jiangsu Province (BK2012122, BK20130886, No. BK2012122)
- National Key Research and Development Program of China (973 Program: 2013CB932902, 2013CB932902)
- Specialized Research Fund for the Doctoral Program of Higher Education of China (20130092110030)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Keywords
- exosome uptake, clathrin-mediated endocytosis, macropinocytosis, exosomes, PC12 cells, bone marrow-derived mesenchymal stromal cells, TGF-βRII, TPM1, tumor-derived exosomes, intercellular communication, microRNA delivery
- MeSH terms
- Receptor, Transforming Growth Factor-beta Type II, Animals, Biological Transport, Active, Cell Line, Endocytosis, Gene Expression Regulation, Phagocytosis, Pinocytosis, Tropomyosin, PC12 Cells, Protein Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Caveolae, Clathrin Heavy Chains, Dynamin II, MicroRNAs, Caveolin 1, Rats, Exosomes, Gene Knockdown Techniques, Mesenchymal Stem Cells
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