Pericyte-to-Endothelial Cell Communication via Tunneling Nanotubes Is Disrupted by a Diol of Docosahexaenoic Acid
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animals
2.2. Cell Culture
2.3. Endothelial Cell Pericyte Co-Culture
2.4. TNT Formation
2.5. Detection of Mitochondria and Mitochondrial Exchange
2.6. Mitochondria Depletion
2.7. Immunohistochemistry
2.8. Immunoblotting
2.9. Measurement of Mitochondrial Oxidation by MitoSOX
2.10. Proteomics
2.11. Metabolomics
2.12. Statistical Analyses
3. Results
3.1. Tunneling Nanotubes and Migrating Pericytes in the Retina
3.2. Tunneling Nanotubes Transport Mitochondria between Pericytes and Endothelial Cells
3.3. Impact of Pericyte-Derived Mitochondria on EtBr-Treated Endothelial Cells
3.4. 19,20-DHDP Antagonizes the Rescue of Endothelial Cell Metabolism by Pericytes
3.5. Effect of 19,20-DHDP on Pericyte-Endothelial Cell Junction Proteins
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Wu, Y.; Fu, J.; Huang, Y.; Duan, R.; Zhang, W.; Wang, C.; Wang, S.; Hu, X.; Zhao, H.; Wang, L.; et al. Biology and function of pericytes in the vascular microcirculation. Anim. Model Exp. Med. 2023, 6, 337–345. [Google Scholar] [CrossRef] [PubMed]
- Davies, P.F.; Civelek, M.; Fang, Y.; Fleming, I. The atherosusceptible endothelium: Endothelial phenotypes in complex haemodynamic shear stress regions in vivo. Cardiovasc. Res. 2013, 99, 315–327. [Google Scholar] [CrossRef]
- Siragusa, M.; Fleming, I. The eNOS signalosome and its link to endothelial dysfunction. Pflug. Arch. Eur. J. Physiol. 2016, 468, 1125–1137. [Google Scholar] [CrossRef] [PubMed]
- Hammes, H.-P.; Lin, J.; Renner, O.; Shani, M.; Lundqvist, A.; Betsholtz, C.; Brownlee, M.; Deutsch, U. Pericytes and the pathogenesis of diabetic retinopathy. Diabetes 2002, 51, 3107–3112. [Google Scholar] [CrossRef] [PubMed]
- Simmonds, S.J.; Grootaert, M.O.J.; Cuijpers, I.; Carai, P.; Geuens, N.; Herwig, M.; Baatsen, P.; Hamdani, N.; Luttun, A.; Heymans, S.; et al. Pericyte loss initiates microvascular dysfunction in the development of diastolic dysfunction. Eur. Heart J. Open 2024, 4, oead129. [Google Scholar] [CrossRef]
- Hinkel, R.; Howe, A.; Renner, S.; Ng, J.; Lee, S.; Klett, K.; Kaczmarek, V.; Moretti, A.; Laugwitz, K.-L.; Skroblin, P.; et al. Diabetes mellitus-induced microvascular destabilization in the myocardium. J. Am. Coll. Cardiol. 2017, 69, 131–143. [Google Scholar] [CrossRef]
- Onfelt, B.; Nedvetzki, S.; Yanagi, K.; Davis, D.M. Cutting edge: Membrane nanotubes connect immune cells. J. Immunol. 2004, 173, 1511–1513. [Google Scholar] [CrossRef]
- Rustom, A.; Saffrich, R.; Markovic, I.; Walther, P.; Gerdes, H.-H. Nanotubular highways for intercellular organelle transport. Science 2004, 303, 1007–1010. [Google Scholar] [CrossRef]
- Abounit, S.; Zurzolo, C. Wiring through tunneling nanotubes--from electrical signals to organelle transfer. J. Cell Sci. 2012, 125, 1089–1098. [Google Scholar] [CrossRef]
- Climent, M.; Quintavalle, M.; Miragoli, M.; Chen, J.; Condorelli, G.; Elia, L. TGFβ triggers miR-143/145 transfer from smooth muscle cells to endothelial cells, thereby modulating vessel stabilization. Circ. Res. 2015, 116, 1753–1764. [Google Scholar] [CrossRef]
- Dieriks, B.V.; Park, T.I.-H.; Fourie, C.; Faull, R.L.M.; Dragunow, M.; Curtis, M.A. α-synuclein transfer through tunneling nanotubes occurs in SH-SY5Y cells and primary brain pericytes from Parkinson’s disease patients. Sci. Rep. 2017, 7, 42984. [Google Scholar] [CrossRef] [PubMed]
- Abounit, S.; Bousset, L.; Loria, F.; Zhu, S.; de Chaumont, F.; Pieri, L.; Olivo-Marin, J.-C.; Melki, R.; Zurzolo, C. Tunneling nanotubes spread fibrillar α-synuclein by intercellular trafficking of lysosomes. EMBO J. 2016, 35, 2120–2138. [Google Scholar] [CrossRef]
- Campana, S.; de Pasquale, C.; Carrega, P.; Ferlazzo, G.; Bonaccorsi, I. Cross-dressing: An alternative mechanism for antigen presentation. Immunol. Lett. 2015, 168, 349–354. [Google Scholar] [CrossRef]
- Rogers, R.S.; Bhattacharya, J. When cells become organelle donors. Physiology 2013, 28, 414–422. [Google Scholar] [CrossRef] [PubMed]
- Torralba, D.; Baixauli, F.; Sánchez-Madrid, F. Mitochondria know no boundaries: Mechanisms and functions of intercellular mitochondrial transfer. Front. Cell Dev. Biol. 2016, 4, 107. [Google Scholar] [CrossRef] [PubMed]
- Jackson, M.V.; Morrison, T.J.; Doherty, D.F.; McAuley, D.F.; Matthay, M.A.; Kissenpfennig, A.; O’Kane, C.M.; Krasnodembskaya, A.D. Mitochondrial transfer via tunneling nanotubes is an important mechanism by which mesenchymal stem cells enhance macrophage phagocytosis in the in vitro and in vivo models of ARDS. Stem Cells 2016, 34, 2210–2223. [Google Scholar] [CrossRef]
- Agnati, L.F.; Guidolin, D.; Baluska, F.; Leo, G.; Barlow, P.W.; Carone, C.; Genedani, S. A new hypothesis of pathogenesis based on the divorce between mitochondria and their host cells: Possible relevance for Alzheimer’s disease. Curr. Alzheimer Res. 2010, 7, 307–322. [Google Scholar] [CrossRef]
- Burt, R.; Dey, A.; Aref, S.; Aguiar, M.; Akarca, A.; Bailey, K.; Day, W.; Hooper, S.; Kirkwood, A.; Kirschner, K.; et al. Activated stromal cells transfer mitochondria to rescue acute lymphoblastic leukemia cells from oxidative stress. Blood 2019, 134, 1415–1429. [Google Scholar] [CrossRef]
- Hu, J.; Dziumbla, S.; Lin, J.; Bibli, S.-I.; Zukunft, S.; de Mos, J.; Awwad, K.; Frömel, T.; Jungmann, A.; Devraj, K.; et al. Inhibition of soluble epoxide hydrolase prevents diabetic retinopathy. Nature 2017, 552, 248–252. [Google Scholar] [CrossRef]
- Barber, A.J.; Antonetti, D.A.; Kern, T.S.; Reiter, C.E.N.; Soans, R.S.; Krady, J.K.; Levison, S.W.; Gardner, T.W.; Bronson, S.K. The Ins2Akita mouse as a model of early retinal complications in diabetes. Investig. Ophthalmol. Vis. Sci. 2005, 46, 2210–2218. [Google Scholar] [CrossRef]
- Busse, R.; Lamontagne, D. Endothelium-derived bradykinin is responsible for the increase in calcium produced by angiotensin-converting enzyme inhibitors in human endothelial cells. Naunyn-Schmiedeberg’s Arch. Pharmacol. 1991, 344, 126–129. [Google Scholar] [CrossRef] [PubMed]
- King, M.P.; Attardi, G. Human cells lacking mtDNA: Repopulation with exogenous mitochondria by complementation. Science 1989, 246, 500–503. [Google Scholar] [CrossRef] [PubMed]
- Khozhukhar, N.; Spadafora, D.; Rodriguez, Y.; Alexeyev, M. Elimination of mitochondrial DNA from mammalian cells. Curr. Protoc. Cell Biol. 2018, 78, 20.11.1–20.11.14. [Google Scholar] [CrossRef]
- Fleming, I.; Fisslthaler, B.; Dixit, M.; Busse, R. Role of PECAM-1 in the shear-stress-induced activation of Akt and the endothelial nitric oxide synthase (eNOS) in endothelial cells. J. Cell Sci. 2005, 118, 4103–4111. [Google Scholar] [CrossRef] [PubMed]
- Yang, Y.; Zhang, G.; Yang, T.; Gan, J.; Xu, L.; Yang, H. A flow-cytometry-based protocol for detection of mitochondrial ROS production under hypoxia. STAR Protoc. 2021, 2, 100466. [Google Scholar] [CrossRef]
- Perez-Riverol, Y.; Bai, J.; Bandla, C.; García-Seisdedos, D.; Hewapathirana, S.; Kamatchinathan, S.; Kundu, D.J.; Prakash, A.; Frericks-Zipper, A.; Eisenacher, M.; et al. The PRIDE database resources in 2022: A hub for mass spectrometry-based proteomics evidences. Nucleic. Acids Res. 2022, 50, D543–D552. [Google Scholar] [CrossRef]
- Tyanova, S.; Temu, T.; Sinitcyn, P.; Carlson, A.; Hein, M.Y.; Geiger, T.; Mann, M.; Cox, J. The Perseus computational platform for comprehensive analysis of (prote)omics data. Nat. Methods 2016, 13, 731–740. [Google Scholar] [CrossRef]
- Errede, M.; Mangieri, D.; Longo, G.; Girolamo, F.; de Trizio, I.; Vimercati, A.; Serio, G.; Frei, K.; Perris, R.; Virgintino, D. Tunneling nanotubes evoke pericyte/endothelial communication during normal and tumoral angiogenesis. Fluids Barriers CNS 2018, 15, 28. [Google Scholar] [CrossRef]
- Alarcon-Martinez, L.; Villafranca-Baughman, D.; Quintero, H.; Kacerovsky, J.B.; Dotigny, F.; Murai, K.K.; Prat, A.; Drapeau, P.; Di Polo, A. Interpericyte tunnelling nanotubes regulate neurovascular coupling. Nature 2020, 585, 91–95. [Google Scholar] [CrossRef]
- Islam, M.N.; Das, S.R.; Emin, M.T.; Wei, M.; Sun, L.; Westphalen, K.; Rowlands, D.J.; Quadri, S.K.; Bhattacharya, S.; Bhattacharya, J. Mitochondrial transfer from bone-marrow-derived stromal cells to pulmonary alveoli protects against acute lung injury. Nat. Med. 2012, 18, 759–765. [Google Scholar] [CrossRef]
- He, K.; Shi, X.; Zhang, X.; Dang, S.; Ma, X.; Liu, F.; Xu, M.; Lv, Z.; Han, D.; Fang, X.; et al. Long-distance intercellular connectivity between cardiomyocytes and cardiofibroblasts mediated by membrane nanotubes. Cardiovasc. Res. 2011, 92, 39–47. [Google Scholar] [CrossRef] [PubMed]
- Ahmad, T.; Mukherjee, S.; Pattnaik, B.; Kumar, M.; Singh, S.; Rehman, R.; Tiwari, B.K.; Jha, K.A.; Barhanpurkar, A.P.; Wani, M.R.; et al. Miro1 regulates intercellular mitochondrial transport & enhances mesenchymal stem cell rescue efficacy. EMBO J. 2014, 33, 994–1010. [Google Scholar] [CrossRef]
- Abad, E.; Lyakhovich, A. Movement of mitochondria with mutant DNA through extracellular vesicles helps cancer cells acquire chemoresistance. ChemMedChem 2022, 17, e202100642. [Google Scholar] [CrossRef] [PubMed]
- Bukoreshtliev, N.V.; Wang, X.; Hodneland, E.; Gurke, S.; Barroso, J.F.V.; Gerdes, H.-H. Selective block of tunneling nanotube (TNT) formation inhibits intercellular organelle transfer between PC12 cells. FEBS Lett. 2009, 583, 1481–1488. [Google Scholar] [CrossRef] [PubMed]
- Nacarelli, T.; Azar, A.; Sell, C. Inhibition of mTOR prevents ROS production initiated by ethidium bromide-induced mitochondrial DNA depletion. Front. Endocrinol. 2014, 5, 122. [Google Scholar] [CrossRef]
- Correia-Melo, C.; Ichim, G.; Tait, S.W.G.; Passos, J.F. Depletion of mitochondria in mammalian cells through enforced mitophagy. Nat. Protoc. 2017, 12, 183–194. [Google Scholar] [CrossRef]
- Kemp, S.S.; Lin, P.K.; Sun, Z.; Castaño, M.A.; Yrigoin, K.; Penn, M.R.; Davis, G.E. Molecular basis for pericyte-induced capillary tube network assembly and maturation. Front. Cell Dev. Biol. 2022, 10, 943533. [Google Scholar] [CrossRef]
- Abramsson, A.; Lindblom, P.; Betsholtz, C. Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors. J. Clin. Investig. 2003, 112, 1142–1151. [Google Scholar] [CrossRef]
- Hu, J.; Popp, R.; Frömel, T.; Ehling, M.; Awwad, K.; Adams, R.H.; Hammes, H.-P.; Fleming, I. Müller glia cells regulate Notch signaling and retinal angiogenesis via the generation of 19,20-dihydroxydocosapentaenoic acid. J. Exp. Med. 2014, 211, 281–295. [Google Scholar] [CrossRef]
- Alarcon-Martinez, L.; Shiga, Y.; Villafranca-Baughman, D.; Cueva Vargas, J.L.; Vidal Paredes, I.A.; Quintero, H.; Fortune, B.; Danesh-Meyer, H.; Di Polo, A. Neurovascular dysfunction in glaucoma. Prog. Retin. Eye Res. 2023, 97, 101217. [Google Scholar] [CrossRef]
- Longden, T.A.; Zhao, G.; Hariharan, A.; Lederer, W.J. Pericytes and the control of blood flow in brain and heart. Ann. Rev. Physiol. 2023, 85, 137–164. [Google Scholar] [CrossRef] [PubMed]
- Hariharan, A.; Robertson, C.D.; Garcia, D.C.G.; Longden, T.A. Brain capillary pericytes are metabolic sentinels that control blood flow through a KATP channel-dependent energy switch. Cell Rep. 2022, 41, 111872. [Google Scholar] [CrossRef] [PubMed]
- Dagar, S.; Subramaniam, S. Tunneling nanotube: An enticing cell-cell communication in the nervous system. Biology 2023, 12, 1288. [Google Scholar] [CrossRef]
- Alarcon-Martinez, L.; Shiga, Y.; Villafranca-Baughman, D.; Belforte, N.; Quintero, H.; Dotigny, F.; Cueva Vargas, J.L.; Di Polo, A. Pericyte dysfunction and loss of interpericyte tunneling nanotubes promote neurovascular deficits in glaucoma. Proc. Natl. Acad. Sci. USA 2022, 119, e2110329119. [Google Scholar] [CrossRef] [PubMed]
- Selhorst, S.; Nakisli, S.; Kandalai, S.; Adhicary, S.; Nielsen, C.M. Pathological pericyte expansion and impaired endothelial cell-pericyte communication in endothelial Rbpj deficient brain arteriovenous malformation. Front. Hum. Neurosci. 2022, 16, 974033. [Google Scholar] [CrossRef]
- Wang, Y.; Cui, J.; Sun, X.; Zhang, Y. Tunneling-nanotube development in astrocytes depends on p53 activation. Cell Death Differ. 2011, 18, 732–742. [Google Scholar] [CrossRef]
- Lv, W.; Li, Z.; Wang, S.; He, J.; Zhang, L. A role for tunneling nanotubes in virus spread. Front. Microbiol. 2024, 15, 1356415. [Google Scholar] [CrossRef]
- Charreau, B. Secretome and tunneling nanotubes: A multilevel network for long range intercellular communication between endothelial cells and distant cells. Int. J. Mol. Sci. 2021, 22, 7971. [Google Scholar] [CrossRef]
- Jiang, D.; Xu, W.; Peng, F.; Sun, Y.; Pan, C.; Yu, J.; Zheng, Q.; Chen, W. Tunneling nanotubes-based intercellular mitochondrial trafficking as a novel therapeutic target in dry eye. Exp. Eye Res. 2023, 232, 109497. [Google Scholar] [CrossRef]
- Dagar, S.; Pathak, D.; Oza, H.V.; Mylavarapu, S.V.S. Tunneling nanotubes and related structures: Molecular mechanisms of formation and function. Biochem. J. 2021, 478, 3977–3998. [Google Scholar] [CrossRef]
- Chernomordik, L.V.; Kozlov, M.M. Protein-lipid interplay in fusion and fission of biological membranes. Ann. Rev. Biochem. 2003, 72, 175–207. [Google Scholar] [CrossRef] [PubMed]
- Delage, E.; Zurzolo, C. Exploring the role of lipids in intercellular conduits: Breakthroughs in the pipeline. Front. Plant Sci. 2013, 4, 504. [Google Scholar] [CrossRef] [PubMed]
- Lokar, M.; Kabaso, D.; Resnik, N.; Sepčić, K.; Kralj-Iglič, V.; Veranič, P.; Zorec, R.; Iglič, A. The role of cholesterol-sphingomyelin membrane nanodomains in the stability of intercellular membrane nanotubes. Int. J. Nanomed. 2012, 7, 1891–1902. [Google Scholar] [CrossRef]
- Fifadara, N.H.; Beer, F.; Ono, S.; Ono, S.J. Interaction between activated chemokine receptor 1 and FcepsilonRI at membrane rafts promotes communication and F-actin-rich cytoneme extensions between mast cells. Int. Immunol. 2010, 22, 113–128. [Google Scholar] [CrossRef] [PubMed]
- Hu, J.; Bibli, S.-I.; Wittig, J.; Zukunft, S.; Lin, J.; Hammes, H.-P.; Popp, R.; Fleming, I. Soluble epoxide hydrolase promotes astrocyte survival in retinopathy of prematurity. J. Clin. Investig. 2019, 129, 5204–5218. [Google Scholar] [CrossRef]
- World Medical Association. Declaration of Helsinki: Ethical principles for medical research involving human subjects. JAMA 2013, 310, 2191–2194. [Google Scholar] [CrossRef]
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Kempf, S.; Popp, R.; Naeem, Z.; Frömel, T.; Wittig, I.; Klatt, S.; Fleming, I. Pericyte-to-Endothelial Cell Communication via Tunneling Nanotubes Is Disrupted by a Diol of Docosahexaenoic Acid. Cells 2024, 13, 1429. https://doi.org/10.3390/cells13171429
Kempf S, Popp R, Naeem Z, Frömel T, Wittig I, Klatt S, Fleming I. Pericyte-to-Endothelial Cell Communication via Tunneling Nanotubes Is Disrupted by a Diol of Docosahexaenoic Acid. Cells. 2024; 13(17):1429. https://doi.org/10.3390/cells13171429
Chicago/Turabian StyleKempf, Sebastian, Rüdiger Popp, Zumer Naeem, Timo Frömel, Ilka Wittig, Stephan Klatt, and Ingrid Fleming. 2024. "Pericyte-to-Endothelial Cell Communication via Tunneling Nanotubes Is Disrupted by a Diol of Docosahexaenoic Acid" Cells 13, no. 17: 1429. https://doi.org/10.3390/cells13171429