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Palese F, Rakotobe M, Zurzolo C. Transforming the concept of connectivity: unveiling tunneling nanotube biology and their roles in brain development and neurodegeneration. Physiol Rev 2025; 105:1823-1865. [PMID: 40067081 DOI: 10.1152/physrev.00023.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 09/17/2024] [Accepted: 02/03/2025] [Indexed: 05/08/2025] Open
Abstract
Tunneling nanotubes (TNTs) are thin tubular membrane protrusions that connect distant cells, generating a complex cellular network. Over the past few decades, research on TNTs has provided important insights into their biology, including structural composition, formation mechanisms, modulators, and functionality. It has been discovered that TNTs allow cytoplasmic continuity between connected cells, facilitating fast intercellular communication via both passive and active exchange of materials. These features are pivotal in the nervous system, where rapid processing of inputs is physiologically required. TNTs have been implicated in the progression of neurodegenerative diseases and cancer in various in vitro models, and TNT-like structures have also been observed in the developing brain and in vivo. This highlights their significant role in pathophysiological processes. In this comprehensive review we aim to provide an extensive overview of TNTs, starting from key structural features and mechanisms of formation and describing the main experimental techniques used to detect these structures both in vitro and in vivo. We focus primarily on the nervous system, where the discovery of TNTs could prompt a reconsideration of the brain functioning as individual units (the neuronal theory of Cajal) versus neurons being physically connected, as Golgi believed. We illustrate the involvement of TNTs in brain development and neurodegenerative states and highlight the limitations and future research needs in this field.
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Affiliation(s)
- Francesca Palese
- Institut Pasteur, Université Paris Cité, CNRS UMR 3691, Membrane Traffic and Pathogenesis, Paris, France
| | - Malalaniaina Rakotobe
- Institut Pasteur, Université Paris Cité, CNRS UMR 3691, Membrane Traffic and Pathogenesis, Paris, France
| | - Chiara Zurzolo
- Institut Pasteur, Université Paris Cité, CNRS UMR 3691, Membrane Traffic and Pathogenesis, Paris, France
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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2
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Rakotobe M, Zurzolo C. Beyond synapses: cytoplasmic connections in brain function and evolution. Biol Rev Camb Philos Soc 2025. [PMID: 40515735 DOI: 10.1111/brv.70034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 04/27/2025] [Accepted: 04/30/2025] [Indexed: 06/16/2025]
Abstract
Following Ramón y Cajal's groundbreaking contributions to the identification of synapses, research in neuroscience predominantly focused on their pivotal role in neural communication (the neuron doctrine), overlooking an intriguing possibility suggested by Golgi of non-synaptic interactions among neural cells. Recent studies across species have unveiled the existence of direct cellular communication through modalities such as intercellular bridges (IBs) formed during incomplete cytokinesis, de novo tunnelling nanotubes (TNTs), and cytoplasmic connections arising from cell-cell fusion. In this review, we delve into these non-synaptic modes of communication between neural cells, describing their morphological features and functional significance. Notably, we discuss recent in vivo findings in ctenophores and in mice which offer fresh insights into the evolutionary functions of these intercellular connections. These findings underscore the need to consider the roles of cytoplasmic connections in neural cell communication during brain development and in pathophysiological conditions. This review highlights the importance of investigating these non-synaptic communication pathways to improve our understanding of neural communication and evolution in metazoans.
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Affiliation(s)
- Malalaniaina Rakotobe
- Membrane Traffic and Pathogenesis, Institut Pasteur, Université Paris Cité, CNRS UMR 3691, Paris, F-75015, France
| | - Chiara Zurzolo
- Membrane Traffic and Pathogenesis, Institut Pasteur, Université Paris Cité, CNRS UMR 3691, Paris, F-75015, France
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3
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Orange F, Pagnotta S, Pierre O, de Almeida Engler J. Application of array tomography to elucidate nuclear clustering architecture in giant-feeding cells induced by root-knot nematodes. THE NEW PHYTOLOGIST 2025; 246:2346-2369. [PMID: 40186428 DOI: 10.1111/nph.70066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 02/13/2025] [Indexed: 04/07/2025]
Abstract
Plant-parasitic nematodes like root-knot nematodes (RKN; Meloidogyne spp.) cause great losses in agriculture by inducing root swellings, named galls, in host roots disturbing plant growth and development. Previous two-dimensional studies using different microscopy techniques revealed the presence of numerous nuclear clusters in nematode-induced giant cells within galls. Here, we show in three dimensions (3D) that nuclear clustering occurring in giant cells is revealed to be much more complex, illustrating subclusters built of multiple nuclear lobes. These nuclear subclusters are unveiled to be interconnected and likely communicate via nucleotubes, highlighting the potential relevance of this nuclear transfer for disease. In addition, microtubules and microtubule organizing centers are profusely present between the densely packed nuclear lobes, suggesting that the cytoskeleton might be involved in anchoring nuclear clusters in giant cells. This study illustrates that it is possible to apply volume electron microscopy (EM) approaches such as array tomography (AT) to roots infected by nematodes using basic equipment found in most EM facilities. The application of AT was valuable to observe the cellular ultrastructure in 3D, revealing the remarkable nuclear architecture of giant cells in the model host Arabidopsis thaliana. The discovery of nucleotubes, as a unique component of nuclear clusters present in giant cells, can be potentially exploited as a novel strategy to develop alternative approaches for RKN control in crop species.
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Affiliation(s)
- François Orange
- Centre Commun de Microscopie Appliquée (CCMA), Université Côte d'Azur, 06108, Nice, France
| | - Sophie Pagnotta
- Centre Commun de Microscopie Appliquée (CCMA), Université Côte d'Azur, 06108, Nice, France
| | - Olivier Pierre
- INRAE, Université Côte d'Azur, CNRS, ISA, 06903, Sophia Antipolis, France
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Vaamonde-Garcia C, Hermida-Gómez T, Paniagua-Barro S, Burguera EF, Blanco FJ, Fernández-Moreno M. In Vivo and In Vitro Evaluation of the Feasibility and Safety Profiles of Intraarticular Transplantation of Mitochondria for Future Use as a Therapy for Osteoarthritis. Cells 2025; 14:151. [PMID: 39936943 PMCID: PMC11817340 DOI: 10.3390/cells14030151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 01/15/2025] [Accepted: 01/16/2025] [Indexed: 02/13/2025] Open
Abstract
Osteoarthritis (OA) is the most common rheumatologic disease and a major cause of pain and disability in older adults. No efficient treatment is currently available. Mitochondrial dysfunction in chondrocytes drives molecular dysregulation in OA pathogenesis. Recently, mitochondrial transfer to chondrocytes had been described, enabling transplant of mitochondria as a new avenue to modify the OA process, although evidence on its feasibility and safety remains limited.The primary objective of this study was to demonstrate the feasibility and safety of intra-articular mitochondrial transplantation. Mitochondria were isolated from liver using the procedure described by Preble and coworkers combined with magnetic beads coupled to anti-TOM22 antibodies. The organelles obtained were analyzed to determine their purity and viability. The safety and viability of the administration of the isolated mitochondria into articular tissues as well as the integration and distribution of the transplanted mitochondria within joint tissues were analyzed using both in vitro and in vivo models. We established an efficient, reproducible, effective, and rapid protocol for isolating mitochondria from liver. We obtained mitochondria with high viability, yield, and purity. The isolated mitochondria were injected into joint tissue using both in vitro and in vivo models. Functional mitochondria were detected in the extracellular matrix of the cartilage, menisci and synovium. Our results establish a safe and viable protocol for mitochondrial isolation and intra-articular injection. The methodology and findings presented here pave the way for future studies in osteoarthritis models to validate mitochondrial transplantation as a potentially effective treatment for OA.
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Affiliation(s)
- Carlos Vaamonde-Garcia
- Grupo de Investigación en Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), 15005 Sergas, Spain; (C.V.-G.); (T.H.-G.); (S.P.-B.); (E.F.B.)
- Grupo de Investigación en Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Universidade de A Coruña (UDC), 15006 A Coruña, Spain
- Grupo de Investigación en Reumatología y Salud (GIR-S), Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Facultad de Fisioterapia, Centro Interdisciplinar de Química y Biología (CICA), INIBIC-Sergas, Universidade de A Coruña (UDC), Campus de Oza, 15006 A Coruña, Spain
| | - Tamara Hermida-Gómez
- Grupo de Investigación en Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), 15005 Sergas, Spain; (C.V.-G.); (T.H.-G.); (S.P.-B.); (E.F.B.)
- Grupo de Investigación en Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Universidade de A Coruña (UDC), 15006 A Coruña, Spain
- Centro de Investigación Biomédica en Red, Bioingenieria, Biomateriales y Nanomedicina (CIBER-BBN), 28029 Madrid, Spain
| | - Sara Paniagua-Barro
- Grupo de Investigación en Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), 15005 Sergas, Spain; (C.V.-G.); (T.H.-G.); (S.P.-B.); (E.F.B.)
- Grupo de Investigación en Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Universidade de A Coruña (UDC), 15006 A Coruña, Spain
| | - Elena F. Burguera
- Grupo de Investigación en Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), 15005 Sergas, Spain; (C.V.-G.); (T.H.-G.); (S.P.-B.); (E.F.B.)
- Grupo de Investigación en Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Universidade de A Coruña (UDC), 15006 A Coruña, Spain
| | - Francisco J. Blanco
- Grupo de Investigación en Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), 15005 Sergas, Spain; (C.V.-G.); (T.H.-G.); (S.P.-B.); (E.F.B.)
- Grupo de Investigación en Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Universidade de A Coruña (UDC), 15006 A Coruña, Spain
- Grupo de Investigación en Reumatología y Salud (GIR-S), Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Facultad de Fisioterapia, Centro Interdisciplinar de Química y Biología (CICA), INIBIC-Sergas, Universidade de A Coruña (UDC), Campus de Oza, 15006 A Coruña, Spain
| | - Mercedes Fernández-Moreno
- Grupo de Investigación en Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), 15005 Sergas, Spain; (C.V.-G.); (T.H.-G.); (S.P.-B.); (E.F.B.)
- Grupo de Investigación en Reumatología (GIR), Instituto de Investigación Biomédica de A Coruña (INIBIC), Complexo Hospitalario Universitario de A Coruña (CHUAC), Universidade de A Coruña (UDC), 15006 A Coruña, Spain
- Grupo de Investigación en Reumatología y Salud (GIR-S), Departamento de Fisioterapia, Medicina y Ciencias Biomédicas, Facultad de Fisioterapia, Centro Interdisciplinar de Química y Biología (CICA), INIBIC-Sergas, Universidade de A Coruña (UDC), Campus de Oza, 15006 A Coruña, Spain
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5
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Keller KE, Kaech Petrie S. Nanotubules and Cellular Communication in Trabecular Meshwork Cells. Methods Mol Biol 2025; 2858:49-62. [PMID: 39433666 DOI: 10.1007/978-1-0716-4140-8_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2024]
Abstract
Glaucoma causes dysfunction to tissues located in the anterior and posterior eye. In the anterior eye, the trabecular meshwork (TM) is the site of pathogenesis, where decreased TM cell numbers and alterations to the amount and composition of extracellular matrix hinder outflow of aqueous humor fluid from the anterior chamber. This causes intraocular pressure (IOP) elevation. Elevated IOP, a main risk factor for primary open-angle glaucoma, damages the axons of retinal ganglion cells in the posterior eye, which ultimately leads to blindness. Thus, clinical treatment paradigms for glaucoma are focused on reducing IOP. Normotensive IOPs are established by balancing the production of aqueous fluid from the ciliary body with drainage through the TM to Schlemm's canal. When IOP becomes elevated, TM cells coordinate a homeostatic response to lower IOP, which requires effective and efficient cellular communication. Tunneling nanotubes (TNTs) are transient specialized structures that allow cells to communicate with one another. Actin-rich tubes allow direct transmission of signals and cargoes between cells. This is important to overcome limitations of diffusion-based signaling in aqueous environments such as the anterior eye. Here, we describe a live-cell imaging method for monitoring TNTs in primary TM cells.
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Affiliation(s)
- Kate E Keller
- Department of Ophthalmology, Oregon Health & Science University, Portland, OR, USA.
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Heatlie JK, Lazniewska J, Moore CR, Johnson IRD, Nturubika BD, Williams R, Ward MP, O’Leary JJ, Butler LM, Brooks DA. Extracellular Vesicles and Tunnelling Nanotubes as Mediators of Prostate Cancer Intercellular Communication. Biomolecules 2024; 15:23. [PMID: 39858418 PMCID: PMC11762852 DOI: 10.3390/biom15010023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 12/04/2024] [Accepted: 12/05/2024] [Indexed: 01/27/2025] Open
Abstract
Prostate cancer (PCa) pathogenesis relies on intercellular communication, which can involve tunnelling nanotubes (TNTs) and extracellular vesicles (EVs). TNTs and EVs have been reported to transfer critical cargo involved in cellular functions and signalling, prompting us to investigate the extent of organelle and protein transfer in PCa cells and the potential involvement of the androgen receptor. Using live cell imaging microscopy, we observed extensive formation of TNTs and EVs operating between PCa, non-malignant, and immune cells. PCa cells were capable of transferring lysosomes, mitochondria, lipids, and endoplasmic reticulum, as well as syndecan-1, sortilin, Glut1, and Glut4. In mechanistic studies, androgen-sensitive PCa cells exhibited changes in cell morphology when stimulated by R1881 treatment. Overexpression assays of a newly designed androgen receptor (AR) plasmid revealed its novel localization in PCa cellular vesicles, which were also transferred to neighbouring cells. Selected molecular machinery, thought to be involved in intercellular communication, was investigated by knockdown studies and Western blotting/immunofluorescence/scanning electron microscopy (SEM). PCa TNTs and EVs transported proteins and organelles, which may contain specialist signalling, programming, and energy requirements that support cancer growth and progression. This makes these important intercellular communication systems ideal potential targets for therapeutic intervention.
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Affiliation(s)
- Jessica K. Heatlie
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
| | - Joanna Lazniewska
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
| | - Courtney R. Moore
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
| | - Ian R. D. Johnson
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
| | - Bukuru D. Nturubika
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
| | - Ruth Williams
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
| | - Mark P. Ward
- Department of Histopathology, Trinity College Dublin, D02 PN40 Dublin, Ireland
| | - John J. O’Leary
- Department of Histopathology, Trinity College Dublin, D02 PN40 Dublin, Ireland
| | - Lisa M. Butler
- South Australian ImmunoGENomics Cancer Institute and Freemasons Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, SA 5005, Australia
- Solid Tumour Program, Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia
| | - Doug A. Brooks
- Clinical and Health Sciences, University of South Australia, Adelaide, SA 5000, Australia
- Department of Histopathology, Trinity College Dublin, D02 PN40 Dublin, Ireland
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7
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Rakotobe M, Zurzolo C. [Tunneling nanotubes (TNTs): An essential yet overlooked modality of inter-cellular communication]. Med Sci (Paris) 2024; 40:829-836. [PMID: 39656980 DOI: 10.1051/medsci/2024152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2024] Open
Abstract
Tunneling nanotubes (TNTs) are open membranous protrusions that allow direct communication between distant cells. Recent research has revealed their significant biological roles, prompting a reassessment of many physiological and pathological processes, especially in the nervous system where TNT properties could play a key physiological role. TNT-like connections have been observed in the developing brain and are implicated in neurodegenerative diseases, brain cancers, as well as in other diseases, underscoring their importance in pathophysiological events. This review covers the key features of TNTs, including their structural properties, formation mechanisms, and detection challenges. We also explore their functions, focusing on the nervous system. The discovery of TNTs may lead to a reconsideration of brain function as a physically connected neuronal network, as proposed by Golgi, complementing Cajal's theory of neurons as separate entities.
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Affiliation(s)
- Malalaniaina Rakotobe
- Trafic membranaire et pathogénèse, Institut Pasteur, Université Paris Cité, CNRS UMR 3691, Paris, France
| | - Chiara Zurzolo
- Trafic membranaire et pathogénèse, Institut Pasteur, Université Paris Cité, CNRS UMR 3691, Paris, France
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8
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Zhao Y, Gao R, Ma J, Cui Y, Li J, Lin H. Characteristics of tunneling nanotube-like structures formed by human dermal microvascular pericytes in vitro. Tissue Cell 2024; 89:102431. [PMID: 38870572 DOI: 10.1016/j.tice.2024.102431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 05/16/2024] [Accepted: 06/03/2024] [Indexed: 06/15/2024]
Abstract
Tunneling nanotubes (TNTs) represent an innovative way for cells to communicate with one another, as they act as long conduits between cells. However, their roles in human dermal microvascular pericytes (HDMPCs) interaction remain elusive in vitro. In this work, we identified and characterized the TNT-like structures that connected two or more pericytes in two-dimensional cultures and formed a functional network in the human dermis. Immunofluorescence assay indicated that the F-actin was an essential element to form inter-pericyte TNT-like structures, as it decreased in actin polymer inhibitor-cytochalasin B treated groups, and microtubules were present in almost half of the TNT-like structures. Most importantly, we only found the presence of mitochondrial in TNT-like structures containing α-tubulin, and the application of microtubule assembly inhibitor-Nocodazole significantly reduced the percentage of TNT-like structures that contain α-tubulin, resulting in a sudden decrease in the positive rate of cytochrome c oxidase subunit 4 isoform 1 (COX IV, a marker of mitochondria) in TNT-like structures. In summary, we described a novel intercellular communication-TNT-like structures-between HDMPCs in vitro, and this work allows us to properly understand the cellular mechanisms of spreading materials between HDMPCs, shedding light on the role of HDMPCs.
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Affiliation(s)
- Yinhua Zhao
- Plastic and Reconstructive Surgery, Beijing Anzhen Hospital, Capital Medical University, 2 Anzhen road, Chaoyang district, Beijing 100029, China
| | - Ridong Gao
- Plastic and Reconstructive Surgery, Beijing Anzhen Hospital, Capital Medical University, 2 Anzhen road, Chaoyang district, Beijing 100029, China
| | - Jiaxing Ma
- Plastic and Reconstructive Surgery, Beijing Anzhen Hospital, Capital Medical University, 2 Anzhen road, Chaoyang district, Beijing 100029, China
| | - Yue Cui
- Plastic and Reconstructive Surgery, Beijing Anzhen Hospital, Capital Medical University, 2 Anzhen road, Chaoyang district, Beijing 100029, China
| | - Jiaxi Li
- Plastic and Reconstructive Surgery, Beijing Anzhen Hospital, Capital Medical University, 2 Anzhen road, Chaoyang district, Beijing 100029, China
| | - Huang Lin
- Plastic and Reconstructive Surgery, Beijing Anzhen Hospital, Capital Medical University, 2 Anzhen road, Chaoyang district, Beijing 100029, China.
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Hu HT, Nishimura T, Kawana H, Dante RAS, D’Angelo G, Suetsugu S. The cellular protrusions for inter-cellular material transfer: similarities between filopodia, cytonemes, tunneling nanotubes, viruses, and extracellular vesicles. Front Cell Dev Biol 2024; 12:1422227. [PMID: 39035026 PMCID: PMC11257967 DOI: 10.3389/fcell.2024.1422227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 06/17/2024] [Indexed: 07/23/2024] Open
Abstract
Extracellular vesicles (EVs) are crucial for transferring bioactive materials between cells and play vital roles in both health and diseases. Cellular protrusions, including filopodia and microvilli, are generated by the bending of the plasma membrane and are considered to be rigid structures facilitating various cellular functions, such as cell migration, adhesion, and environment sensing. Compelling evidence suggests that these protrusions are dynamic and flexible structures that can serve as sources of a new class of EVs, highlighting the unique role they play in intercellular material transfer. Cytonemes are specialized filopodia protrusions that make direct contact with neighboring cells, mediating the transfer of bioactive materials between cells through their tips. In some cases, these tips fuse with the plasma membrane of neighboring cells, creating tunneling nanotubes that directly connect the cytosols of the adjacent cells. Additionally, virus particles can be released from infected cells through small bud-like of plasma membrane protrusions. These different types of protrusions, which can transfer bioactive materials, share common protein components, including I-BAR domain-containing proteins, actin cytoskeleton, and their regulatory proteins. The dynamic and flexible nature of these protrusions highlights their importance in cellular communication and material transfer within the body, including development, cancer progression, and other diseases.
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Affiliation(s)
- Hooi Ting Hu
- Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara, Japan
| | - Tamako Nishimura
- Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara, Japan
| | - Hiroki Kawana
- Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara, Japan
| | - Rachelle Anne So Dante
- Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara, Japan
| | - Gisela D’Angelo
- Institut Curie, PSL Research University, Centre national de la recherche scientifique (CNRS), Paris, France
| | - Shiro Suetsugu
- Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Nara, Japan
- Data Science Center, Nara Institute of Science and Technology, Nara, Japan
- Center for Digital Green-innovation, Nara Institute of Science and Technology, Nara, Japan
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10
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Nguyen DLB, Okolicsanyi RK, Haupt LM. Heparan sulfate proteoglycans: Mediators of cellular and molecular Alzheimer's disease pathogenic factors via tunnelling nanotubes? Mol Cell Neurosci 2024; 129:103936. [PMID: 38750678 DOI: 10.1016/j.mcn.2024.103936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 04/14/2024] [Accepted: 05/01/2024] [Indexed: 05/19/2024] Open
Abstract
Neurological disorders impact around one billion individuals globally (15 % approx.), with significant implications for disability and mortality with their impact in Australia currently amounts to 6.8 million deaths annually. Heparan sulfate proteoglycans (HSPGs) are complex extracellular molecules implicated in promoting Tau fibril formation resulting in Tau tangles, a hallmark of Alzheimer's disease (AD). HSPG-Tau protein interactions contribute to various AD stages via aggregation, toxicity, and clearance, largely via interactions with the glypican 1 and syndecan 3 core proteins. The tunnelling nanotubes (TNTs) pathway is emerging as a facilitator of intercellular molecule transport, including Tau and Amyloid β proteins, across extensive distances. While current TNT-associated evidence primarily stems from cancer models, their role in Tau propagation and its effects on recipient cells remain unclear. This review explores the interplay of TNTs, HSPGs, and AD-related factors and proposes that HSPGs influence TNT formation in neurodegenerative conditions such as AD.
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Affiliation(s)
- Duy L B Nguyen
- Stem Cell and Neurogenesis Group, Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology (QUT), 60 Musk Ave., Kelvin Grove, Queensland 4059, Australia
| | - Rachel K Okolicsanyi
- Stem Cell and Neurogenesis Group, Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology (QUT), 60 Musk Ave., Kelvin Grove, Queensland 4059, Australia; ARC Training Centre for Cell and Tissue Engineering Technologies, Queensland University of Technology (QUT), Australia
| | - Larisa M Haupt
- Stem Cell and Neurogenesis Group, Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology (QUT), 60 Musk Ave., Kelvin Grove, Queensland 4059, Australia; Centre for Biomedical Technologies, Queensland University of Technology (QUT), 60 Musk Ave., Kelvin Grove, QLD 4059, Australia; ARC Training Centre for Cell and Tissue Engineering Technologies, Queensland University of Technology (QUT), Australia; Max Planck Queensland Centre for the Materials Sciences of Extracellular Matrices, Queensland University of Technology (QUT), Australia.
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11
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Needs HI, Glover E, Pereira GC, Witt A, Hübner W, Dodding MP, Henley JM, Collinson I. Rescue of mitochondrial import failure by intercellular organellar transfer. Nat Commun 2024; 15:988. [PMID: 38307874 PMCID: PMC10837123 DOI: 10.1038/s41467-024-45283-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Accepted: 01/19/2024] [Indexed: 02/04/2024] Open
Abstract
Mitochondria are the powerhouses of eukaryotic cells, composed mostly of nuclear-encoded proteins imported from the cytosol. Thus, problems with the import machinery will disrupt their regenerative capacity and the cell's energy supplies - particularly troublesome for energy-demanding cells of nervous tissue and muscle. Unsurprisingly then, import breakdown is implicated in disease. Here, we explore the consequences of import failure in mammalian cells; wherein, blocking the import machinery impacts mitochondrial ultra-structure and dynamics, but, surprisingly, does not affect import. Our data are consistent with a response involving intercellular mitochondrial transport via tunnelling nanotubes to import healthy mitochondria and jettison those with blocked import sites. These observations support the existence of a widespread mechanism for the rescue of mitochondrial dysfunction.
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Affiliation(s)
- Hope I Needs
- School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK
| | - Emily Glover
- School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK
| | - Gonçalo C Pereira
- School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK
- Nanna Therapeutics, Merrifield Centre, Rosemary Lane, Cambridge, CB1 3LQ, UK
| | - Alina Witt
- Fakultät für Physik, Universität Bielefeld, Bielefeld, Postfach 100131 D-33501, Germany
| | - Wolfgang Hübner
- Fakultät für Physik, Universität Bielefeld, Bielefeld, Postfach 100131 D-33501, Germany
| | - Mark P Dodding
- School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK
| | - Jeremy M Henley
- School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK.
| | - Ian Collinson
- School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK.
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12
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Dagar S, Subramaniam S. Tunneling Nanotube: An Enticing Cell-Cell Communication in the Nervous System. BIOLOGY 2023; 12:1288. [PMID: 37886998 PMCID: PMC10604474 DOI: 10.3390/biology12101288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 09/22/2023] [Accepted: 09/25/2023] [Indexed: 10/28/2023]
Abstract
The field of neuroscience is rapidly progressing, continuously uncovering new insights and discoveries. Among the areas that have shown immense potential in research, tunneling nanotubes (TNTs) have emerged as a promising subject of study. These minute structures act as conduits for the transfer of cellular materials between cells, representing a mechanism of communication that holds great significance. In particular, the interplay facilitated by TNTs among various cell types within the brain, including neurons, astrocytes, oligodendrocytes, glial cells, and microglia, can be essential for the normal development and optimal functioning of this complex organ. The involvement of TNTs in neurodegenerative disorders, such as Alzheimer's disease, Huntington's disease, and Parkinson's disease, has attracted significant attention. These disorders are characterized by the progressive degeneration of neurons and the subsequent decline in brain function. Studies have predicted that TNTs likely play critical roles in the propagation and spread of pathological factors, contributing to the advancement of these diseases. Thus, there is a growing interest in understanding the precise functions and mechanisms of TNTs within the nervous system. This review article, based on our recent work on Rhes-mediated TNTs, aims to explore the functions of TNTs within the brain and investigate their implications for neurodegenerative diseases. Using the knowledge gained from studying TNTs could offer novel opportunities for designing targeted treatments that can stop the progression of neurodegenerative disorders.
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Affiliation(s)
- Sunayana Dagar
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL 33458, USA
| | - Srinivasa Subramaniam
- Department of Neuroscience, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL 33458, USA
- The Scripps Research Institute, La Jolla, CA 92037, USA
- Norman Fixel Institute for Neurological Diseases, 130 Scripps Way, C323, Jupiter, FL 33458, USA
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13
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Nikoo A, Roudkenar MH, Sato T, Kuwahara Y, Tomita K, Pourmohammadi-Bejarpasi Z, Najafi-Ghalehlou N, Roushandeh AM. Mitochondrial transfer in PC-3 cells fingerprinted in ferroptosis sensitivity: a brand new approach targeting cancer metabolism. Hum Cell 2023; 36:1441-1450. [PMID: 36961656 DOI: 10.1007/s13577-023-00896-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 03/10/2023] [Indexed: 03/25/2023]
Abstract
Despite recent therapeutic advancements, cancer remains one of the leading causes of death worldwide, with mitochondrial dysfunction being associated with cancer initiation and progression, along with chemotherapeutic resistance and ferroptotic cell death failure; however, the significance of mitochondria in various cancer types remains a matter of debate for the moment. The aim of this study is to ascertain the outcome of transferring healthy mitochondria into the aggressive and rapidly proliferating prostate cancer (PC-3) cells and afterwards evaluate the efficacy of combination therapy with or without the ferroptosis inducer erastin. In this sense, normal mitochondria were first isolated from human umbilical cord-derived mesenchymal stem cells, human umbilical vein endothelial cells, and human embryonic kidney cells and were later transferred into PC-3 cells and rhodamine 6G-treated PC-3 cells exhibiting mitochondrial dysfunction. Next, cell proliferation and sensitivity to cisplatin were measured using Cell Counting Kit-8 and the Malondialdehyde Assay Lipid Peroxidation Kit, respectively, along with ferroptotic damage. Transferring the healthy mitochondria into PC-3 cells was observed to increase cell proliferation and rescue the cisplatin-induced cell death, but not the erastin-induced ferroptosis, as in mitochondrial transfer effectively enhanced erastin-mediated ferroptosis in PC-3 cells. Hence, the introduction of healthy mitochondria into the highly aggressive and proliferating cancer cells would be deemed a brand new therapeutic strategy for a variety of cancers.
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Affiliation(s)
- Amirsadegh Nikoo
- Department of Medical Biotechnology, Faculty of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Mehryar Habibi Roudkenar
- Burn and Regenerative Medicine Research Center, Velayat Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Tomoaki Sato
- Department of Applied Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Yoshikazu Kuwahara
- Division of Radiation Biology and Medicine, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
| | - Kazuo Tomita
- Department of Applied Pharmacology, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Zahra Pourmohammadi-Bejarpasi
- Burn and Regenerative Medicine Research Center, Velayat Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Nima Najafi-Ghalehlou
- Department of Medical Laboratory Sciences, Faculty of Paramedicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amaneh Mohammadi Roushandeh
- Burn and Regenerative Medicine Research Center, Velayat Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.
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14
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García-Sánchez D, González-González A, Alfonso-Fernández A, Del Dujo-Gutiérrez M, Pérez-Campo FM. Communication between bone marrow mesenchymal stem cells and multiple myeloma cells: Impact on disease progression. World J Stem Cells 2023; 15:421-437. [PMID: 37342223 PMCID: PMC10277973 DOI: 10.4252/wjsc.v15.i5.421] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Revised: 02/27/2023] [Accepted: 04/17/2023] [Indexed: 05/26/2023] Open
Abstract
Multiple myeloma (MM) is a hematological malignancy characterized by the accumulation of immunoglobulin-secreting clonal plasma cells at the bone marrow (BM). The interaction between MM cells and the BM microenvironment, and specifically BM mesenchymal stem cells (BM-MSCs), has a key role in the pathophysiology of this disease. Multiple data support the idea that BM-MSCs not only enhance the proliferation and survival of MM cells but are also involved in the resistance of MM cells to certain drugs, aiding the progression of this hematological tumor. The relation of MM cells with the resident BM-MSCs is a two-way interaction. MM modulate the behavior of BM-MSCs altering their expression profile, proliferation rate, osteogenic potential, and expression of senescence markers. In turn, modified BM-MSCs can produce a set of cytokines that would modulate the BM microenvironment to favor disease progression. The interaction between MM cells and BM-MSCs can be mediated by the secretion of a variety of soluble factors and extracellular vesicles carrying microRNAs, long non-coding RNAs or other molecules. However, the communication between these two types of cells could also involve a direct physical interaction through adhesion molecules or tunneling nanotubes. Thus, understanding the way this communication works and developing strategies to interfere in the process, would preclude the expansion of the MM cells and might offer alternative treatments for this incurable disease.
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Affiliation(s)
- Daniel García-Sánchez
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain
| | - Alberto González-González
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain
| | - Ana Alfonso-Fernández
- Servicio de Traumatología y Cirugía Ortopédica, Hospital Universitario Marqués de Valdecilla, Instituto de Investigación Sanitaria Valdecilla (IDIVAL), Facultad de Medicina, Universidad de Cantabria, Santander 39008, Cantabria, Spain
| | - Mónica Del Dujo-Gutiérrez
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain
| | - Flor M Pérez-Campo
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain.
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15
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Turkel I, Ozerklig B, Yılmaz M, Ulger O, Kubat GB, Tuncer M. Mitochondrial transplantation as a possible therapeutic option for sarcopenia. J Mol Med (Berl) 2023:10.1007/s00109-023-02326-3. [PMID: 37209146 DOI: 10.1007/s00109-023-02326-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 04/09/2023] [Accepted: 04/20/2023] [Indexed: 05/22/2023]
Abstract
With advancing age, the skeletal muscle phenotype is characterized by a progressive loss of mass, strength, and quality. This phenomenon, known as sarcopenia, has a negative impact on quality of life and increases the risk of morbidity and mortality in older adults. Accumulating evidence suggests that damaged and dysfunctional mitochondria play a critical role in the pathogenesis of sarcopenia. Lifestyle modifications, such as physical activity, exercise, and nutrition, as well as medical interventions with therapeutic agents, are effective in the management of sarcopenia and offer solutions to maintain and improve skeletal muscle health. Although a great deal of effort has been devoted to the identification of the best treatment option, these strategies are not sufficient to overcome sarcopenia. Recently, it has been reported that mitochondrial transplantation may be a possible therapeutic approach for the treatment of mitochondria-related pathological conditions such as ischemia, liver toxicity, kidney injury, cancer, and non-alcoholic fatty liver disease. Given the role of mitochondria in the function and metabolism of skeletal muscle, mitochondrial transplantation may be a possible option for the treatment of sarcopenia. In this review, we summarize the definition and characteristics of sarcopenia and molecular mechanisms associated with mitochondria that are known to contribute to sarcopenia. We also discuss mitochondrial transplantation as a possible option. Despite the progress made in the field of mitochondrial transplantation, further studies are needed to elucidate the role of mitochondrial transplantation in sarcopenia. KEY MESSAGES: Sarcopenia is the progressive loss of skeletal muscle mass, strength, and quality. Although the specific mechanisms that lead to sarcopenia are not fully understood, mitochondria have been identified as a key factor in the development of sarcopenia. Damaged and dysfunctional mitochondria initiate various cellular mediators and signaling pathways, which largely contribute to the age-related loss of skeletal muscle mass and strength. Mitochondrial transplantation has been reported to be a possible option for the treatment/prevention of several diseases. Mitochondrial transplantation may be a possible therapeutic option for improving skeletal muscle health and treating sarcopenia. Mitochondrial transplantation as a possible treatment option for sarcopenia.
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Affiliation(s)
- Ibrahim Turkel
- Department of Exercise and Sport Sciences, Faculty of Sport Sciences, Hacettepe University, Ankara, Turkey
- Division of Sport Sciences and Technology, Institute of Health Sciences, Hacettepe University, Ankara, Turkey
| | - Berkay Ozerklig
- Department of Exercise and Sport Sciences, Faculty of Sport Sciences, Hacettepe University, Ankara, Turkey
- Division of Sport Sciences and Technology, Institute of Health Sciences, Hacettepe University, Ankara, Turkey
| | - Merve Yılmaz
- Department of Medical Biochemistry, Faculty of Medicine, Hacettepe University, Ankara, Turkey
| | - Oner Ulger
- Department of Mitochondria and Cellular Research, Health Sciences Institute, Health Sciences University, Ankara, Turkey
| | - Gokhan Burcin Kubat
- Division of Sport Sciences and Technology, Institute of Health Sciences, Hacettepe University, Ankara, Turkey.
- Department of Mitochondria and Cellular Research, Health Sciences Institute, Health Sciences University, Ankara, Turkey.
| | - Meltem Tuncer
- Department of Physiology, Faculty of Medicine, Hacettepe University, Ankara, Turkey
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16
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Nieland L, Mahjoum S, Grandell E, Breyne K, Breakefield XO. Engineered EVs designed to target diseases of the CNS. J Control Release 2023; 356:493-506. [PMID: 36907561 DOI: 10.1016/j.jconrel.2023.03.009] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 01/28/2023] [Accepted: 03/06/2023] [Indexed: 03/14/2023]
Abstract
Diseases of the central nervous system (CNS) are challenging to treat, mainly due to the blood-brain barrier (BBB), which restricts drugs in circulation from entering target regions in the brain. To address this issue extracellular vesicles (EVs) have gained increasing scientific interest as carriers able to cross the BBB with multiplex cargos. EVs are secreted by virtually every cell, and their escorted biomolecules are part of an intercellular information gateway between cells within the brain and with other organs. Scientists have undertaken efforts to safeguard the inherent features of EVs as therapeutic delivery vehicles, such as protecting and transferring functional cargo, as well as loading them with therapeutic small molecules, proteins, and oligonucleotides and targeting them to specific cell types for the treatment of CNS diseases. Here, we review current emerging approaches that engineer the EV surface and cargo to improve targeting and functional responses in the brain. We summarize existing applications of engineered EVs as a therapeutic delivery platform for brain diseases, some of which have been evaluated clinically.
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Affiliation(s)
- Lisa Nieland
- Department of Neurology, Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA; Department of Neurosurgery, Leiden University Medical Center, Leiden 2300 RC, the Netherlands.
| | - Shadi Mahjoum
- Department of Neurology, Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Emily Grandell
- Department of Neurology, Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA; Department of Bioengineering, Northeastern University, Boston, MA 02115, USA
| | - Koen Breyne
- Department of Neurology, Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Xandra O Breakefield
- Department of Neurology, Molecular Neurogenetics Unit, Massachusetts General Hospital, Boston, MA 02129, USA; Harvard Medical School, Boston, MA 02115, USA
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17
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Dong LF, Rohlena J, Zobalova R, Nahacka Z, Rodriguez AM, Berridge MV, Neuzil J. Mitochondria on the move: Horizontal mitochondrial transfer in disease and health. J Cell Biol 2023; 222:213873. [PMID: 36795453 PMCID: PMC9960264 DOI: 10.1083/jcb.202211044] [Citation(s) in RCA: 49] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Revised: 01/12/2023] [Accepted: 02/01/2023] [Indexed: 02/17/2023] Open
Abstract
Mammalian genes were long thought to be constrained within somatic cells in most cell types. This concept was challenged recently when cellular organelles including mitochondria were shown to move between mammalian cells in culture via cytoplasmic bridges. Recent research in animals indicates transfer of mitochondria in cancer and during lung injury in vivo, with considerable functional consequences. Since these pioneering discoveries, many studies have confirmed horizontal mitochondrial transfer (HMT) in vivo, and its functional characteristics and consequences have been described. Additional support for this phenomenon has come from phylogenetic studies. Apparently, mitochondrial trafficking between cells occurs more frequently than previously thought and contributes to diverse processes including bioenergetic crosstalk and homeostasis, disease treatment and recovery, and development of resistance to cancer therapy. Here we highlight current knowledge of HMT between cells, focusing primarily on in vivo systems, and contend that this process is not only (patho)physiologically relevant, but also can be exploited for the design of novel therapeutic approaches.
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Affiliation(s)
- Lan-Feng Dong
- https://ror.org/02sc3r913School of Pharmacy and Medical Sciences, Griffith University, Southport, Australia,Lan-Feng Dong:
| | - Jakub Rohlena
- https://ror.org/00wzqmx94Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague-West, Czech Republic
| | - Renata Zobalova
- https://ror.org/00wzqmx94Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague-West, Czech Republic
| | - Zuzana Nahacka
- https://ror.org/00wzqmx94Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague-West, Czech Republic
| | | | | | - Jiri Neuzil
- https://ror.org/02sc3r913School of Pharmacy and Medical Sciences, Griffith University, Southport, Australia,https://ror.org/00wzqmx94Institute of Biotechnology, Academy of Sciences of the Czech Republic, Prague-West, Czech Republic,Faculty of Science, Charles University, Prague, Czech Republic,First Faculty of Medicine, Charles University, Prague, Czech Republic,Correspondence to Jiri Neuzil: ,
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18
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Protasoni M, Serrano M. Targeting Mitochondria to Control Ageing and Senescence. Pharmaceutics 2023; 15:352. [PMID: 36839673 PMCID: PMC9960816 DOI: 10.3390/pharmaceutics15020352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 12/22/2022] [Accepted: 12/26/2022] [Indexed: 01/24/2023] Open
Abstract
Ageing is accompanied by a progressive impairment of cellular function and a systemic deterioration of tissues and organs, resulting in increased vulnerability to multiple diseases. Here, we review the interplay between two hallmarks of ageing, namely, mitochondrial dysfunction and cellular senescence. The targeting of specific mitochondrial features in senescent cells has the potential of delaying or even reverting the ageing process. A deeper and more comprehensive understanding of mitochondrial biology in senescent cells is necessary to effectively face this challenge. Here, we discuss the main alterations in mitochondrial functions and structure in both ageing and cellular senescence, highlighting the differences and similarities between the two processes. Moreover, we describe the treatments available to target these pathways and speculate on possible future directions of anti-ageing and anti-senescence therapies targeting mitochondria.
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Affiliation(s)
- Margherita Protasoni
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain
| | - Manuel Serrano
- Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain
- Catalan Institution for Research and Advanced Studies (ICREA), 08010 Barcelona, Spain
- Cambridge Institute of Science, Altos Labs, Granta Park, Cambridge CB21 6GP, UK
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19
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Yi S, Wang L, Wang H, Ho MS, Zhang S. Pathogenesis of α-Synuclein in Parkinson's Disease: From a Neuron-Glia Crosstalk Perspective. Int J Mol Sci 2022; 23:14753. [PMID: 36499080 PMCID: PMC9739123 DOI: 10.3390/ijms232314753] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 11/21/2022] [Accepted: 11/22/2022] [Indexed: 11/29/2022] Open
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder. The classical behavioral defects of PD patients involve motor symptoms such as bradykinesia, tremor, and rigidity, as well as non-motor symptoms such as anosmia, depression, and cognitive impairment. Pathologically, the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN) and the accumulation of α-synuclein (α-syn)-composed Lewy bodies (LBs) and Lewy neurites (LNs) are key hallmarks. Glia are more than mere bystanders that simply support neurons, they actively contribute to almost every aspect of neuronal development and function; glial dysregulation has been implicated in a series of neurodegenerative diseases including PD. Importantly, amounting evidence has added glial activation and neuroinflammation as new features of PD onset and progression. Thus, gaining a better understanding of glia, especially neuron-glia crosstalk, will not only provide insight into brain physiology events but also advance our knowledge of PD pathologies. This review addresses the current understanding of α-syn pathogenesis in PD, with a focus on neuron-glia crosstalk. Particularly, the transmission of α-syn between neurons and glia, α-syn-induced glial activation, and feedbacks of glial activation on DA neuron degeneration are thoroughly discussed. In addition, α-syn aggregation, iron deposition, and glial activation in regulating DA neuron ferroptosis in PD are covered. Lastly, we summarize the preclinical and clinical therapies, especially targeting glia, in PD treatments.
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Affiliation(s)
| | | | | | - Margaret S. Ho
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
| | - Shiping Zhang
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
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20
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Han M, Woottum M, Mascarau R, Vahlas Z, Verollet C, Benichou S. Mechanisms of HIV-1 cell-to-cell transfer to myeloid cells. J Leukoc Biol 2022; 112:1261-1271. [PMID: 35355323 DOI: 10.1002/jlb.4mr0322-737r] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/09/2022] [Indexed: 12/24/2022] Open
Abstract
In addition to CD4+ T lymphocytes, cells of the myeloid lineage such as macrophages, dendritic cells (DCs), and osteoclasts (OCs) are emerging as important target cells for HIV-1, as they likely participate in all steps of pathogenesis, including sexual transmission and early virus dissemination in both lymphoid and nonlymphoid tissues where they can constitute persistent virus reservoirs. At least in vitro, these myeloid cells are poorly infected by cell-free viral particles. In contrast, intercellular virus transmission through direct cell-to-cell contacts may be a predominant mode of virus propagation in vivo leading to productive infection of these myeloid target cells. HIV-1 cell-to-cell transfer between CD4+ T cells mainly through the formation of the virologic synapse, or from infected macrophages or dendritic cells to CD4+ T cell targets, have been extensively described in vitro. Recent reports demonstrate that myeloid cells can be also productively infected through virus homotypic or heterotypic cell-to-cell transfer between macrophages or from virus-donor-infected CD4+ T cells, respectively. These modes of infection of myeloid target cells lead to very efficient spreading in these poorly susceptible cell types. Thus, the goal of this review is to give an overview of the different mechanisms reported in the literature for cell-to-cell transfer and spreading of HIV-1 in myeloid cells.
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Affiliation(s)
- Mingyu Han
- Institut Cochin, Inserm U1016, Paris, France.,Centre National de la Recherche Scientifique CNRS UMR8104, Paris, France.,Faculty of Health, University of Paris Cité, Paris, France
| | - Marie Woottum
- Institut Cochin, Inserm U1016, Paris, France.,Centre National de la Recherche Scientifique CNRS UMR8104, Paris, France.,Faculty of Health, University of Paris Cité, Paris, France
| | - Rémi Mascarau
- Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, CNRS, Toulouse, France.,International Research Project (IRP) CNRS, Toulouse, France.,International Research Project (IRP), CNRS, Buenos Aires, Argentina
| | - Zoï Vahlas
- Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, CNRS, Toulouse, France.,International Research Project (IRP) CNRS, Toulouse, France.,International Research Project (IRP), CNRS, Buenos Aires, Argentina
| | - Christel Verollet
- Institut de Pharmacologie et Biologie Structurale, IPBS, Université de Toulouse, CNRS, Toulouse, France.,International Research Project (IRP) CNRS, Toulouse, France.,International Research Project (IRP), CNRS, Buenos Aires, Argentina
| | - Serge Benichou
- Institut Cochin, Inserm U1016, Paris, France.,Centre National de la Recherche Scientifique CNRS UMR8104, Paris, France.,Faculty of Health, University of Paris Cité, Paris, France
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21
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Tozzi A, Mariniello L. Unusual Mathematical Approaches Untangle Nervous Dynamics. Biomedicines 2022; 10:biomedicines10102581. [PMID: 36289843 PMCID: PMC9599563 DOI: 10.3390/biomedicines10102581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 10/10/2022] [Accepted: 10/10/2022] [Indexed: 11/16/2022] Open
Abstract
The massive amount of available neurodata suggests the existence of a mathematical backbone underlying neuronal oscillatory activities. For example, geometric constraints are powerful enough to define cellular distribution and drive the embryonal development of the central nervous system. We aim to elucidate whether underrated notions from geometry, topology, group theory and category theory can assess neuronal issues and provide experimentally testable hypotheses. The Monge’s theorem might contribute to our visual ability of depth perception and the brain connectome can be tackled in terms of tunnelling nanotubes. The multisynaptic ascending fibers connecting the peripheral receptors to the neocortical areas can be assessed in terms of knot theory/braid groups. Presheaves from category theory permit the tackling of nervous phase spaces in terms of the theory of infinity categories, highlighting an approach based on equivalence rather than equality. Further, the physical concepts of soft-matter polymers and nematic colloids might shed new light on neurulation in mammalian embryos. Hidden, unexpected multidisciplinary relationships can be found when mathematics copes with neural phenomena, leading to novel answers for everlasting neuroscientific questions. For instance, our framework leads to the conjecture that the development of the nervous system might be correlated with the occurrence of local thermal changes in embryo–fetal tissues.
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Affiliation(s)
- Arturo Tozzi
- Center for Nonlinear Science, University of North Texas, Denton, TX 76203-5017, USA
- Correspondence:
| | - Lucio Mariniello
- Department of Pediatrics, University Federico II, 80131 Naples, Italy
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22
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Mentor S, Fisher D. Exosomes form tunneling nanotubes (TUNTs) in the blood-brain barrier: a nano-anatomical perspective of barrier genesis. Front Mol Neurosci 2022; 15:938315. [PMID: 36204136 PMCID: PMC9531021 DOI: 10.3389/fnmol.2022.938315] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 07/04/2022] [Indexed: 11/25/2022] Open
Abstract
The blood-brain barrier (BBB) is a robust interface between the blood and the central nervous system. Barrier type endothelium is able to limit paracellular (PC) movement, relegating molecular flux to the transendothelial pathways of brain endothelial cells (BECs). It is, therefore, apparent that any leakage via the PC shunts would effectively nullify the regulation of molecular flux across the transcellular pathways. The application of higher-resolution scanning electron microscopy (HR-SEM) illuminates the heterogenous, morphological profile that exists on the surface of BEC membranes and the relationship between these ultrastructures during the molecular construction of the PC space between adjacent BECs. In this study developing BEC monolayers were grown on mixed, cellulose esters insert membranes in a bicameral system. BEC monolayers were fixed in 2.5% glutaraldehyde, hydrated, critically dried, and sputter-coated, for imaging utilizing HR-SEM. This study, for the first time, showed membrane-bound exosomes were attached to the plasma membrane surfaces of the BECs. The exosomes were characterized as small membrane-bound, nano-sized exosomes (30–300 nm). Based on their membrane morphology and anatomical structure, exosomes appear to possess two distinct functions, namely: paracrine secretion and nanotube construction between adjacent BECs, during in vitro barrier genesis. The HR-SEM micrographs in conjunction with the Tipifarnib inhibition of exosome formation, suggests that brain capillary endothelial exosomes play a prominent role in the bilateral signaling, which contribute to the regulation of the permeability of the BBB. Given that blood-brain barrier permeability has been implicated in the progression of many neurodegenerative pathologies, the role of these exosomes and TUNTs posits the capacity of these structures to exacerbate neuropathologies that implicate BBB permeability. These findings could lead to the development of novel treatment interventions and moreover, the characterization of BBB exosomes may be a reliable target for identifying therapeutic biomarkers in neurodegenerative disease. Conversely, the presence of BBB exosomes raises a critical enterprise to target the exosome-induced nanotubes as a vehicle for transferring therapeutic treatments across the BBB.
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Affiliation(s)
- Shireen Mentor
- Neurobiology Research Group, Department of Medical Biosciences, University of the Western Cape, Cape Town, South Africa
| | - David Fisher
- Neurobiology Research Group, Department of Medical Biosciences, University of the Western Cape, Cape Town, South Africa
- School of Health Professions, University of Missouri, Columbia, MO, United States
- *Correspondence: David Fisher
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Lagalwar S. Mechanisms of tunneling nanotube-based propagation of neurodegenerative disease proteins. Front Mol Neurosci 2022; 15:957067. [PMID: 35909452 PMCID: PMC9336677 DOI: 10.3389/fnmol.2022.957067] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 06/27/2022] [Indexed: 11/13/2022] Open
Abstract
Tunneling nanotubes (TNTs), intercellular connections enriched with F-actin, were first identified as a viable means of cellular communication and organelle transport in animal cells at the early part of this century. Within the last 10 years, these microscopic and highly dynamic protrusions have been implicated in neurodegenerative disease propagation and pathogenesis. A host of aggregation-prone protein inclusions, including those containing alpha-synuclein, tau, prions and others, hijack this communication mechanism in both neurons and astrocytes. The exact cellular mechanisms underlying TNT-based propagation remain largely unknown, however, common practices can be identified. First, selective expression of the aggregation-prone form of proteins increases TNT density; next, endo-lysosomal pathways appear to support the loading and unloading of protein onto the TNT; and finally, TNT assembly results in the spontaneous formation of aggregation-prone protein inclusions in “acceptor” cells, indicating that TNTs are involved in not only the transport of inclusions but also in the seeding of new inclusions in naïve cells. These observations have implications for the spreading of neurodegenerative disease in the central nervous system and the consequent progression of symptoms. Here, I will summarize the empirical evidence of TNT-based aggregation-prone protein propagation to date, and propose an inclusive model of aggregate inclusion propagation along TNTs.
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Rubio-Casillas A, Redwan EM, Uversky VN. SARS-CoV-2: A Master of Immune Evasion. Biomedicines 2022; 10:1339. [PMID: 35740361 PMCID: PMC9220273 DOI: 10.3390/biomedicines10061339] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/03/2022] [Accepted: 06/04/2022] [Indexed: 02/07/2023] Open
Abstract
Viruses and their hosts have coevolved for a long time. This coevolution places both the pathogen and the human immune system under selective pressure; on the one hand, the immune system has evolved to combat viruses and virally infected cells, while viruses have developed sophisticated mechanisms to escape recognition and destruction by the immune system. SARS-CoV-2, the pathogen that is causing the current COVID-19 pandemic, has shown a remarkable ability to escape antibody neutralization, putting vaccine efficacy at risk. One of the virus's immune evasion strategies is mitochondrial sabotage: by causing reactive oxygen species (ROS) production, mitochondrial physiology is impaired, and the interferon antiviral response is suppressed. Seminal studies have identified an intra-cytoplasmatic pathway for viral infection, which occurs through the construction of tunneling nanotubes (TNTs), hence enhancing infection and avoiding immune surveillance. Another method of evading immune monitoring is the disruption of the antigen presentation. In this scenario, SARS-CoV-2 infection reduces MHC-I molecule expression: SARS-CoV-2's open reading frames (ORF 6 and ORF 8) produce viral proteins that specifically downregulate MHC-I molecules. All of these strategies are also exploited by other viruses to elude immune detection and should be studied in depth to improve the effectiveness of future antiviral treatments. Compared to the Wuhan strain or the Delta variant, Omicron has developed mutations that have impaired its ability to generate syncytia, thus reducing its pathogenicity. Conversely, other mutations have allowed it to escape antibody neutralization and preventing cellular immune recognition, making it the most contagious and evasive variant to date.
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Affiliation(s)
- Alberto Rubio-Casillas
- Biology Laboratory, Autlán Regional Preparatory School, University of Guadalajara, Autlán 48900, Jalisco, Mexico
| | - Elrashdy M. Redwan
- Biological Science Department, Faculty of Science, King Abdulaziz University, P.O. Box 80203, Jeddah 21589, Saudi Arabia;
- Therapeutic and Protective Proteins Laboratory, Protein Research Department, Genetic Engineering and Biotechnology Research Institute, City for Scientific Research and Technology Applications, New Borg EL-Arab, Alexandria 21934, Egypt
| | - Vladimir N. Uversky
- Department of Molecular Medicine and USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
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Eugenin E, Camporesi E, Peracchia C. Direct Cell-Cell Communication via Membrane Pores, Gap Junction Channels, and Tunneling Nanotubes: Medical Relevance of Mitochondrial Exchange. Int J Mol Sci 2022; 23:6133. [PMID: 35682809 PMCID: PMC9181466 DOI: 10.3390/ijms23116133] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 05/28/2022] [Accepted: 05/28/2022] [Indexed: 02/07/2023] Open
Abstract
The history of direct cell-cell communication has evolved in several small steps. First discovered in the 1930s in invertebrate nervous systems, it was thought at first to be an exception to the "cell theory", restricted to invertebrates. Surprisingly, however, in the 1950s, electrical cell-cell communication was also reported in vertebrates. Once more, it was thought to be an exception restricted to excitable cells. In contrast, in the mid-1960s, two startling publications proved that virtually all cells freely exchange small neutral and charged molecules. Soon after, cell-cell communication by gap junction channels was reported. While gap junctions are the major means of cell-cell communication, in the early 1980s, evidence surfaced that some cells might also communicate via membrane pores. Questions were raised about the possible artifactual nature of the pores. However, early in this century, we learned that communication via membrane pores exists and plays a major role in medicine, as the structures involved, "tunneling nanotubes", can rescue diseased cells by directly transferring healthy mitochondria into compromised cells and tissues. On the other hand, pathogens/cancer could also use these communication systems to amplify pathogenesis. Here, we describe the evolution of the discovery of these new communication systems and the potential therapeutic impact on several uncurable diseases.
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Affiliation(s)
- Eliseo Eugenin
- Department of Neuroscience, Cell Biology, and Anatomy, University of Texas Medical Branch (UTMB), 105 11th Street, Galveston, TX 77555, USA
| | - Enrico Camporesi
- Department of Surgery and TEAM Health Anesthesia, University of South Florida, 2 Tampa General Circle, Tampa, FL 33606, USA;
| | - Camillo Peracchia
- Department of Pharmacology and Physiology, School of Medicine and Dentistry, University Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA;
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Couteaudier M, Montange T, Njouom R, Bilounga-Ndongo C, Gessain A, Buseyne F. Plasma antibodies from humans infected with zoonotic simian foamy virus do not inhibit cell-to-cell transmission of the virus despite binding to the surface of infected cells. PLoS Pathog 2022; 18:e1010470. [PMID: 35605011 PMCID: PMC9166401 DOI: 10.1371/journal.ppat.1010470] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 06/03/2022] [Accepted: 03/25/2022] [Indexed: 01/23/2023] Open
Abstract
Zoonotic simian foamy viruses (SFV) establish lifelong infection in their human hosts. Despite repeated transmission of SFV from nonhuman primates to humans, neither transmission between human hosts nor severe clinical manifestations have been reported. We aim to study the immune responses elicited by chronic infection with this retrovirus and previously reported that SFV-infected individuals generate potent neutralizing antibodies that block cell infection by viral particles. Here, we assessed whether human plasma antibodies block SFV cell-to-cell transmission and present the first description of cell-to-cell spreading of zoonotic gorilla SFV. We set-up a microtitration assay to quantify the ability of plasma samples from 20 Central African individuals infected with gorilla SFV and 9 uninfected controls to block cell-associated transmission of zoonotic gorilla SFV strains. We used flow-based cell cytometry and fluorescence microscopy to study envelope protein (Env) localization and the capacity of plasma antibodies to bind to infected cells. We visualized the cell-to-cell spread of SFV by real-time live imaging of a GFP-expressing prototype foamy virus (CI-PFV) strain. None of the samples neutralized cell-associated SFV infection, despite the inhibition of cell-free virus. We detected gorilla SFV Env in the perinuclear region, cytoplasmic vesicles and at the cell surface. We found that plasma antibodies bind to Env located at the surface of cells infected with primary gorilla SFV strains. Extracellular labeling of SFV proteins by human plasma samples showed patchy staining at the base of the cell and dense continuous staining at the cell apex, as well as staining in the intercellular connections that formed when previously connected cells separated from each other. In conclusion, SFV-specific antibodies from infected humans do not block cell-to-cell transmission, at least in vitro, despite their capacity to bind to the surface of infected cells. Trial registration: Clinical trial registration: www.clinicaltrials.gov, https://clinicaltrials.gov/ct2/show/NCT03225794/. Foamy viruses are the oldest known retroviruses and have been mostly described to be nonpathogenic in their natural animal hosts. Simian foamy viruses (SFVs) can be transmitted to humans, in whom they establish persistent infection, as have the simian viruses that led to the emergence of two major human pathogens, human immunodeficiency virus type 1 (HIV-1) and human T lymphotropic virus type 1 (HTLV-1). Such cross-species transmission of SFV is ongoing in many parts of the world where humans have contact with nonhuman primates. We previously showed high titers of neutralizing antibodies in the plasma of most SFV-infected individuals. These antiviral antibodies can inhibit cell-free virus entry. However, SFV efficiently spread from one cell to another. Here, we demonstrate that plasma antibodies do not block such cell-to-cell transmission, despite their capacity to bind to the surface of infected cells. In addition, we document for the first time the cell-to-cell spread of primary zoonotic gorilla SFV.
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Affiliation(s)
- Mathilde Couteaudier
- Institut Pasteur, Université Paris Cité, CNRS UMR3569, Unité d’Epidémiologie et Physiopathologie des Virus Oncogènes, Paris, France
| | - Thomas Montange
- Institut Pasteur, Université Paris Cité, CNRS UMR3569, Unité d’Epidémiologie et Physiopathologie des Virus Oncogènes, Paris, France
| | | | | | - Antoine Gessain
- Institut Pasteur, Université Paris Cité, CNRS UMR3569, Unité d’Epidémiologie et Physiopathologie des Virus Oncogènes, Paris, France
| | - Florence Buseyne
- Institut Pasteur, Université Paris Cité, CNRS UMR3569, Unité d’Epidémiologie et Physiopathologie des Virus Oncogènes, Paris, France
- * E-mail:
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Driscoll J, Gondaliya P, Patel T. Tunneling Nanotube-Mediated Communication: A Mechanism of Intercellular Nucleic Acid Transfer. Int J Mol Sci 2022; 23:5487. [PMID: 35628298 PMCID: PMC9143920 DOI: 10.3390/ijms23105487] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 05/09/2022] [Accepted: 05/12/2022] [Indexed: 12/19/2022] Open
Abstract
Tunneling nanotubes (TNTs) are thin, F-actin-based membranous protrusions that connect distant cells and can provide e a novel mechanism for intercellular communication. By establishing cytoplasmic continuity between interconnected cells, TNTs enable the bidirectional transfer of nuclear and cytoplasmic cargo, including organelles, nucleic acids, drugs, and pathogenic molecules. TNT-mediated nucleic acid transfer provides a unique opportunity for donor cells to directly alter the genome, transcriptome, and metabolome of recipient cells. TNTs have been reported to transport DNA, mitochondrial DNA, mRNA, viral RNA, and non-coding RNAs, such as miRNA and siRNA. This mechanism of transfer is observed in physiological as well as pathological conditions, and has been implicated in the progression of disease. Herein, we provide a concise overview of TNTs' structure, mechanisms of biogenesis, and the functional effects of TNT-mediated intercellular transfer of nucleic acid cargo. Furthermore, we highlight the potential translational applications of TNT-mediated nucleic acid transfer in cancer, immunity, and neurological diseases.
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Affiliation(s)
| | | | - Tushar Patel
- Departments of Transplantation and Cancer Biology, Mayo Clinic, Jacksonville, FL 32224, USA; (J.D.); (P.G.)
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28
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Tunneling Nanotubes between Cells Migrating in ECM Mimicking Fibrous Environments. Cancers (Basel) 2022; 14:cancers14081989. [PMID: 35454893 PMCID: PMC9030013 DOI: 10.3390/cancers14081989] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 04/04/2022] [Indexed: 12/28/2022] Open
Abstract
Simple Summary Tumor cells grow, spread, and invade in a three-dimensional manner, but most experimental approaches in cancer cell biology focus on the behavior of cells in two-dimensional spaces. Patterns of cell invasion and spread in 2D may not accurately depict cell behavior in 3D tumors. We cultivated and investigated malignant mesothelioma cells on a 3D scaffold composed of nanofibers positioned in parallel and crosshatched network configurations to overcome this barrier. We focused on studying long extensions called tunneling nanotubes (TNTs) protruding from cells and connecting with other cells, which have been shown to transmit signals from cell to cell and extend into the tumor microenvironments in a 3D manner. This manuscript describes the biophysics of the formation and function of cancer cell TNTs. These findings will impact the research community by accurately assessing how TNTs affect cancer cell invasion and migration in their natural 3D microenvironment using a novel bioengineered platform. Abstract Tunneling nanotubes (TNTs) comprise a unique class of actin-rich nanoscale membranous protrusions. They enable long-distance intercellular communication and may play an integral role in tumor formation, progression, and drug resistance. TNTs are three-dimensional, but nearly all studies have investigated them using two-dimensional cell culture models. Here, we applied a unique 3D culture platform consisting of crosshatched and aligned fibers to fabricate synthetic suspended scaffolds that mimic the native fibrillar architecture of tumoral extracellular matrix (ECM) to characterize TNT formation and function in its native state. TNTs are upregulated in malignant mesothelioma; we used this model to analyze the biophysical properties of TNTs in this 3D setting, including cell migration in relation to TNT dynamics, rate of TNT-mediated intercellular transport of cargo, and conformation of TNT-forming cells. We found that highly migratory elongated cells on aligned fibers formed significantly longer but fewer TNTs than uniformly spread cells on crossing fibers. We developed new quantitative metrics for the classification of TNT morphologies based on shape and cytoskeletal content using confocal microscopy. In sum, our strategy for culturing cells in ECM-mimicking bioengineered scaffolds provides a new approach for accurate biophysical and biologic assessment of TNT formation and structure in native fibrous microenvironments.
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Merolli A, Kasaei L, Ramasamy S, Kolloli A, Kumar R, Subbian S, Feldman LC. An intra-cytoplasmic route for SARS-CoV-2 transmission unveiled by Helium-ion microscopy. Sci Rep 2022; 12:3794. [PMID: 35260703 PMCID: PMC8904465 DOI: 10.1038/s41598-022-07867-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 02/23/2022] [Indexed: 12/11/2022] Open
Abstract
SARS-CoV-2 virions enter the host cells by docking their spike glycoproteins to the membrane-bound Angiotensin Converting Enzyme 2. After intracellular assembly, the newly formed virions are released from the infected cells to propagate the infection, using the extra-cytoplasmic ACE2 docking mechanism. However, the molecular events underpinning SARS-CoV-2 transmission between host cells are not fully understood. Here, we report the findings of a scanning Helium-ion microscopy study performed on Vero E6 cells infected with mNeonGreen-expressing SARS-CoV-2. Our data reveal, with unprecedented resolution, the presence of: (1) long tunneling nanotubes that connect two or more host cells over submillimeter distances; (2) large scale multiple cell fusion events (syncytia); and (3) abundant extracellular vesicles of various sizes. Taken together, these ultrastructural features describe a novel intra-cytoplasmic connection among SARS-CoV-2 infected cells that may act as an alternative route of viral transmission, disengaged from the well-known extra-cytoplasmic ACE2 docking mechanism. Such route may explain the elusiveness of SARS-CoV-2 to survive from the immune surveillance of the infected host.
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Affiliation(s)
- Antonio Merolli
- Department of Physics and Astronomy, School of Arts and Sciences, Rutgers University, 136 Frelinghuysen Road, Piscataway, NJ, 08854, USA. .,Department Physics and Astronomy, Rutgers University, DLS Building, 145 Bevier Road, Room 108, Piscataway, NJ, 08854, USA.
| | - Leila Kasaei
- Department of Physics and Astronomy, School of Arts and Sciences, Rutgers University, 136 Frelinghuysen Road, Piscataway, NJ, 08854, USA
| | - Santhamani Ramasamy
- Public Health Research Institute (PHRI), New Jersey Medical School, Rutgers University, 225 Warren Street, Newark, NJ, 07103, USA
| | - Afsal Kolloli
- Public Health Research Institute (PHRI), New Jersey Medical School, Rutgers University, 225 Warren Street, Newark, NJ, 07103, USA
| | - Ranjeet Kumar
- Public Health Research Institute (PHRI), New Jersey Medical School, Rutgers University, 225 Warren Street, Newark, NJ, 07103, USA
| | - Selvakumar Subbian
- Public Health Research Institute (PHRI), New Jersey Medical School, Rutgers University, 225 Warren Street, Newark, NJ, 07103, USA
| | - Leonard C Feldman
- Department of Physics and Astronomy, School of Arts and Sciences, Rutgers University, 136 Frelinghuysen Road, Piscataway, NJ, 08854, USA
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30
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Mentor S, Fisher D. The Ism between Endothelial Cilia and Endothelial Nanotubules Is an Evolving Concept in the Genesis of the BBB. Int J Mol Sci 2022; 23:ijms23052457. [PMID: 35269595 PMCID: PMC8910322 DOI: 10.3390/ijms23052457] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 02/15/2022] [Accepted: 02/17/2022] [Indexed: 02/06/2023] Open
Abstract
The blood–brain barrier (BBB) is fundamental in maintaining central nervous system (CNS) homeostasis by regulating the chemical environment of the underlying brain parenchyma. Brain endothelial cells (BECs) constitute the anatomical and functional basis of the BBB. Communication between adjacent BECs is critical for establishing BBB integrity, and knowledge of its nanoscopic landscape will contribute to our understanding of how juxtaposed zones of tight-junction protein interactions between BECs are aligned. The review discusses and critiques types of nanostructures contributing to the process of BBB genesis. We further critically evaluate earlier findings in light of novel high-resolution electron microscopy descriptions of nanoscopic tubules. One such phenotypic structure is BEC cytoplasmic projections, which, early in the literature, is postulated as brain capillary endothelial cilia, and is evaluated and compared to the recently discovered nanotubules (NTs) formed in the paracellular spaces between BECs during barrier-genesis. The review attempts to elucidate a myriad of unique topographical ultrastructures that have been reported to be associated with the development of the BBB, viz., structures ranging from cilia to BEC tunneling nanotubules (TUNTs) and BEC tethering nanotubules (TENTs).
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Affiliation(s)
- Shireen Mentor
- Neurobiology Research Group, Department of Medical Biosciences, University of the Western Cape, Bellville, Cape Town 7535, South Africa;
| | - David Fisher
- Neurobiology Research Group, Department of Medical Biosciences, University of the Western Cape, Bellville, Cape Town 7535, South Africa;
- School of Health Professions, University of Missouri, Columbia, MO 65211, USA
- Correspondence:
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31
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Mentor S, Makhathini KB, Fisher D. The Role of Cytoskeletal Proteins in the Formation of a Functional In Vitro Blood-Brain Barrier Model. Int J Mol Sci 2022; 23:ijms23020742. [PMID: 35054928 PMCID: PMC8775705 DOI: 10.3390/ijms23020742] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 12/27/2021] [Accepted: 01/07/2022] [Indexed: 02/05/2023] Open
Abstract
The brain capillary endothelium is highly regulatory, maintaining the chemical stability of the brain’s microenvironment. The role of cytoskeletal proteins in tethering nanotubules (TENTs) during barrier-genesis was investigated using the established immortalized mouse brain endothelial cell line (bEnd5) as an in vitro blood-brain barrier (BBB) model. The morphology of bEnd5 cells was evaluated using both high-resolution scanning electron microscopy and immunofluorescence to evaluate treatment with depolymerizing agents Cytochalasin D for F-actin filaments and Nocodazole for α-tubulin microtubules. The effects of the depolymerizing agents were investigated on bEnd5 monolayer permeability by measuring the transendothelial electrical resistance (TEER). The data endorsed that during barrier-genesis, F-actin and α-tubulin play a cytoarchitectural role in providing both cell shape dynamics and cytoskeletal structure to TENTs forming across the paracellular space to provide cell-cell engagement. Western blot analysis of the treatments suggested a reduced expression of both proteins, coinciding with a reduction in the rates of cellular proliferation and decreased TEER. The findings endorsed that TENTs provide alignment of the paracellular (PC) spaces and tight junction (TJ) zones to occlude bEnd5 PC spaces. The identification of specific cytoskeletal structures in TENTs endorsed the postulate of their indispensable role in barrier-genesis and the maintenance of regulatory permeability across the BBB.
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Affiliation(s)
- Shireen Mentor
- Neurobiology Research Group, Department of Medical Biosciences, University of the Western Cape, Cape Town 7535, South Africa; (S.M.); (K.B.M.)
| | - Khayelihle Brian Makhathini
- Neurobiology Research Group, Department of Medical Biosciences, University of the Western Cape, Cape Town 7535, South Africa; (S.M.); (K.B.M.)
| | - David Fisher
- Neurobiology Research Group, Department of Medical Biosciences, University of the Western Cape, Cape Town 7535, South Africa; (S.M.); (K.B.M.)
- School of Health Professions, University of Missouri, Columbia, MO 65211, USA
- Correspondence: ; Tel.: +27-21-959-2185
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32
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Tunneling nanotubes and related structures: molecular mechanisms of formation and function. Biochem J 2021; 478:3977-3998. [PMID: 34813650 DOI: 10.1042/bcj20210077] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 10/12/2021] [Accepted: 11/01/2021] [Indexed: 12/13/2022]
Abstract
Tunneling nanotubes (TNTs) are F-actin-based, membrane-enclosed tubular connections between animal cells that transport a variety of cellular cargo. Over the last 15 years since their discovery, TNTs have come to be recognized as key players in normal cell communication and organism development, and are also exploited for the spread of various microbial pathogens and major diseases like cancer and neurodegenerative disorders. TNTs have also been proposed as modalities for disseminating therapeutic drugs between cells. Despite the rapidly expanding and wide-ranging relevance of these structures in both health and disease, there is a glaring dearth of molecular mechanistic knowledge regarding the formation and function of these important but enigmatic structures. A series of fundamental steps are essential for the formation of functional nanotubes. The spatiotemporally controlled and directed modulation of cortical actin dynamics would be required to ensure outward F-actin polymerization. Local plasma membrane deformation to impart negative curvature and membrane addition at a rate commensurate with F-actin polymerization would enable outward TNT elongation. Extrinsic tactic cues, along with cognate intrinsic signaling, would be required to guide and stabilize the elongating TNT towards its intended target, followed by membrane fusion to create a functional TNT. Selected cargoes must be transported between connected cells through the action of molecular motors, before the TNT is retracted or destroyed. This review summarizes the current understanding of the molecular mechanisms regulating these steps, also highlighting areas that deserve future attention.
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Huang H, Toker N, Burr E, Okoro J, Moog M, Hearing C, Lagalwar S. Intercellular Propagation and Aggregate Seeding of Mutant Ataxin-1. J Mol Neurosci 2021; 72:708-718. [PMID: 34826062 PMCID: PMC8986690 DOI: 10.1007/s12031-021-01944-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Accepted: 11/06/2021] [Indexed: 01/07/2023]
Abstract
Intercellular propagation of aggregated protein inclusions along actin-based tunneling nanotubes (TNTs) has been reported as a means of pathogenic spread in Alzheimer’s, Parkinson’s, and Huntington’s diseases. Propagation of oligomeric-structured polyglutamine-expanded ataxin-1 (Atxn1[154Q]) has been reported in the cerebellum of a Spinocerebellar ataxia type 1 (SCA1) knock-in mouse to correlate with disease propagation. In this study, we investigated whether a physiologically relevant polyglutamine-expanded ATXN1 protein (ATXN1[82Q]) could propagate intercellularly. Using a cerebellar-derived live cell model, we observed ATXN1 aggregates form in the nucleus, subsequently form in the cytoplasm, and finally, propagate to neighboring cells along actin-based intercellular connections. Additionally, we observed the facilitation of aggregate-resistant proteins into aggregates given the presence of aggregation-prone proteins within cells. Taken together, our results support a pathogenic role of intercellular propagation of polyglutamine-expanded ATXN1 inclusions.
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Affiliation(s)
- Haoyang Huang
- Neuroscience Program, Skidmore College, Saratoga Springs, NY, USA
| | - Nicholas Toker
- Neuroscience Program, Skidmore College, Saratoga Springs, NY, USA
| | - Eliza Burr
- Neuroscience Program, Skidmore College, Saratoga Springs, NY, USA
| | - Jeff Okoro
- Neuroscience Program, Skidmore College, Saratoga Springs, NY, USA
| | - Maia Moog
- Neuroscience Program, Skidmore College, Saratoga Springs, NY, USA
| | - Casey Hearing
- Neuroscience Program, Skidmore College, Saratoga Springs, NY, USA
| | - Sarita Lagalwar
- Neuroscience Program, Skidmore College, Saratoga Springs, NY, USA.
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Terceiro LEL, Edechi CA, Ikeogu NM, Nickel BE, Hombach-Klonisch S, Sharif T, Leygue E, Myal Y. The Breast Tumor Microenvironment: A Key Player in Metastatic Spread. Cancers (Basel) 2021; 13:4798. [PMID: 34638283 PMCID: PMC8507966 DOI: 10.3390/cancers13194798] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/12/2021] [Accepted: 09/20/2021] [Indexed: 12/12/2022] Open
Abstract
The tumor microenvironment plays a pivotal role in the tumorigenesis, progression, and metastatic spread of many cancers including breast. There is now increasing evidence to support the observations that a bidirectional interplay between breast cancer cells and stromal cells exists within the tumor and the tumor microenvironment both at the primary tumor site and at the metastatic site. This interaction occurs through direct cell to cell contact, or by the release of autocrine or paracrine factors which can activate pro-tumor signaling pathways and modulate tumor behavior. In this review, we will highlight recent advances in our current knowledge about the multiple interactions between breast cancer cells and neighboring cells (fibroblasts, endothelial cells, adipocytes, innate and adaptive immune cells) in the tumor microenvironment that coordinate to regulate metastasis. We also highlight the role of exosomes and circulating tumor cells in facilitating breast cancer metastasis. We discuss some key markers associated with stromal cells in the breast tumor environment and their potential to predict patient survival and guide treatment. Finally, we will provide some brief perspectives on how current technologies may lead to the development of more effective therapies for the clinical management of breast cancer patients.
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Affiliation(s)
- Lucas E. L. Terceiro
- Department of Pathology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 3P5, Canada; (L.E.L.T.); (C.A.E.); (T.S.)
| | - Chidalu A. Edechi
- Department of Pathology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 3P5, Canada; (L.E.L.T.); (C.A.E.); (T.S.)
| | - Nnamdi M. Ikeogu
- Department of Immunology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0T5, Canada;
| | - Barbara E. Nickel
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada;
| | - Sabine Hombach-Klonisch
- Department of Human Anatomy and Cell Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada;
| | - Tanveer Sharif
- Department of Pathology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 3P5, Canada; (L.E.L.T.); (C.A.E.); (T.S.)
| | - Etienne Leygue
- Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0T5, Canada;
| | - Yvonne Myal
- Department of Pathology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 3P5, Canada; (L.E.L.T.); (C.A.E.); (T.S.)
- Senior Scientist, CancerCare Manitoba Research Institute, Winnipeg, MB R3E 0V9, Canada
- Department of Physiology and Pathophysiology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
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35
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Lachaize V, Peña B, Ciubotaru C, Cojoc D, Chen SN, Taylor MRG, Mestroni L, Sbaizero O. Compromised Biomechanical Properties, Cell-Cell Adhesion and Nanotubes Communication in Cardiac Fibroblasts Carrying the Lamin A/C D192G Mutation. Int J Mol Sci 2021; 22:9193. [PMID: 34502098 PMCID: PMC8431729 DOI: 10.3390/ijms22179193] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Revised: 08/03/2021] [Accepted: 08/05/2021] [Indexed: 11/16/2022] Open
Abstract
Clinical effects induced by arrhythmogenic cardiomyopathy (ACM) originate from a large spectrum of genetic variations, including the missense mutation of the lamin A/C gene (LMNA), LMNA D192G. The aim of our study was to investigate the biophysical and biomechanical impact of the LMNA D192G mutation on neonatal rat ventricular fibroblasts (NRVF). The main findings in mutated NRVFs were: (i) cytoskeleton disorganization (actin and intermediate filaments); (ii) decreased elasticity of NRVFs; (iii) altered cell-cell adhesion properties, that highlighted a strong effect on cellular communication, in particular on tunneling nanotubes (TNTs). In mutant-expressing fibroblasts, these nanotubes were weakened with altered mechanical properties as shown by atomic force microscopy (AFM) and optical tweezers. These outcomes complement prior investigations on LMNA mutant cardiomyocytes and suggest that the LMNA D192G mutation impacts the biomechanical properties of both cardiomyocytes and cardiac fibroblasts. These observations could explain how this mutation influences cardiac biomechanical pathology and the severity of ACM in LMNA-cardiomyopathy.
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Affiliation(s)
- Veronique Lachaize
- Department of Engineering and Architecture, University of Trieste, Via Valerio 10, 34127 Trieste, Italy;
| | - Brisa Peña
- CU-Cardiovascular Institute, University of Colorado Anschutz Medical Campus, 12700 E. 19th Ave., Aurora, CO 80045, USA; (B.P.); (S.N.C.); (M.R.G.T.); (L.M.)
- Consortium for Fibrosis Research & Translation, Anschutz Medical Campus, University of Colorado, 12700 E. 19th Ave., Aurora, CO 80045, USA
- Bioengineering Department, University of Colorado Denver Anschutz Medical Campus, Bioscience 2 1270 E. Montview Ave., Suite 100, Aurora, CO 80045, USA
| | - Catalin Ciubotaru
- Institute of Materials, National Research Council of Italy (CNR_IOM), Area Science Park Basovizza, 34149 Trieste, Italy; (C.C.); (D.C.)
| | - Dan Cojoc
- Institute of Materials, National Research Council of Italy (CNR_IOM), Area Science Park Basovizza, 34149 Trieste, Italy; (C.C.); (D.C.)
| | - Suet Nee Chen
- CU-Cardiovascular Institute, University of Colorado Anschutz Medical Campus, 12700 E. 19th Ave., Aurora, CO 80045, USA; (B.P.); (S.N.C.); (M.R.G.T.); (L.M.)
| | - Matthew R. G. Taylor
- CU-Cardiovascular Institute, University of Colorado Anschutz Medical Campus, 12700 E. 19th Ave., Aurora, CO 80045, USA; (B.P.); (S.N.C.); (M.R.G.T.); (L.M.)
| | - Luisa Mestroni
- CU-Cardiovascular Institute, University of Colorado Anschutz Medical Campus, 12700 E. 19th Ave., Aurora, CO 80045, USA; (B.P.); (S.N.C.); (M.R.G.T.); (L.M.)
| | - Orfeo Sbaizero
- Department of Engineering and Architecture, University of Trieste, Via Valerio 10, 34127 Trieste, Italy;
- CU-Cardiovascular Institute, University of Colorado Anschutz Medical Campus, 12700 E. 19th Ave., Aurora, CO 80045, USA; (B.P.); (S.N.C.); (M.R.G.T.); (L.M.)
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The 3.0 Cell Communication: New Insights in the Usefulness of Tunneling Nanotubes for Glioblastoma Treatment. Cancers (Basel) 2021; 13:cancers13164001. [PMID: 34439156 PMCID: PMC8392307 DOI: 10.3390/cancers13164001] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 07/05/2021] [Accepted: 08/03/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Communication between cells helps tumors acquire resistance to chemotherapy and makes the struggle against cancer more challenging. Tunneling nanotubes (TNTs) are long channels able to connect both nearby and distant cells, contributing to a more malignant phenotype. This finding might be useful in designing novel strategies of drug delivery exploiting these systems of connection. This would be particularly important to reach tumor niches, where glioblastoma stem cells proliferate and provoke immune escape, thereby increasing metastatic potential and tumor recurrence a few months after surgical resection of the primary mass. Along with the direct inhibition of TNT formation, TNT analysis, and targeting strategies might be useful in providing innovative tools for the treatment of this tumor. Abstract Glioblastoma (GBM) is a particularly challenging brain tumor characterized by a heterogeneous, complex, and multicellular microenvironment, which represents a strategic network for treatment escape. Furthermore, the presence of GBM stem cells (GSCs) seems to contribute to GBM recurrence after surgery, and chemo- and/or radiotherapy. In this context, intercellular communication modalities play key roles in driving GBM therapy resistance. The presence of tunneling nanotubes (TNTs), long membranous open-ended channels connecting distant cells, has been observed in several types of cancer, where they emerge to steer a more malignant phenotype. Here, we discuss the current knowledge about the formation of TNTs between different cellular types in the GBM microenvironment and their potential role in tumor progression and recurrence. Particularly, we highlight two prospective strategies targeting TNTs as possible therapeutics: (i) the inhibition of TNT formation and (ii) a boost in drug delivery between cells through these channels. The latter may require future studies to design drug delivery systems that are exchangeable through TNTs, thus allowing for access to distant tumor niches that are involved in tumor immune escape, maintenance of GSC plasticity, and increases in metastatic potential.
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Mentor S, Fisher D. High-Resolution Insights Into the in vitro Developing Blood-Brain Barrier: Novel Morphological Features of Endothelial Nanotube Function. Front Neuroanat 2021; 15:661065. [PMID: 34248507 PMCID: PMC8267063 DOI: 10.3389/fnana.2021.661065] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 04/21/2021] [Indexed: 12/28/2022] Open
Abstract
High-resolution electron microscopy (HREM) imaging of the in vitro blood-brain barrier (BBB), is a promising modality for investigating the dynamic morphological interplay underpinning BBB development. The successful establishment of BBB integrity is grounded in the brain endothelial cells (BEC’s) ability to occlude its paracellular spaces of brain capillaries through the expression of the intercellular tight junction (TJ) proteins. The impermeability of these paracellular spaces are crucial in the regulation of transcellular transport systems to achieve homeostasis of the central nervous system. To-date research describing morphologically, the dynamics by which TJ interaction is orchestrated to successfully construct a specialized barrier remains undescribed. In this study, the application of HREM illuminates the novel, dynamic and highly restrictive BEC paracellular pathway which is founded based on lateral membrane alignment which is the functional imperative for the mechanical juxtapositioning of TJ zones that underpin molecular bonding and sealing of the paracellular space. For the first time, we report on the secretion of a basement membrane in vitro, which allow BECs to orientate themselves into distinct basolateral and apicolateral domains and establish a 3-dimensional BEC construct. We report for the first time, on the expression of nanovesicles bound to the plasma membrane surfaces of the BECs. These membrane-bound vesicles are reported to possess an array of DNA/RNA constituents and chemotaxic properties affecting the formation of nanotubes that span the paracellular space between BECs, facilitating BBB construction, alluding to a functional role in mediating cell-to-cell communication. This study suggests that novel, ultrathin nanotubular (NT) structures are involved in functional roles in bringing into alignment the paracellular space of BECs. Immortalized mouse BECs (b.End3, b.End5) and primary rat cardiac microvascular ECs were used to further validate the in vitro BBB model by profiling variances in peripheral EC monolayer development. These cardiac capillary ECs presented with an opposite topographical profile: large fenestra and intercellular spaces, devoid of morphological ultrastructures. This comparative study alludes to the role of NT facilitation in TJ-induced hemifusion of apicolateral BEC membranes, as a structural event forming the basis for establishing a polarized BBB.
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Affiliation(s)
- Shireen Mentor
- Neurobiology Research Group, Department of Medical Biosciences, Faculty of Natural Sciences, University of the Western Cape, Cape Town, South Africa
| | - David Fisher
- Neurobiology Research Group, Department of Medical Biosciences, Faculty of Natural Sciences, University of the Western Cape, Cape Town, South Africa.,Adjunct Professor in School of Health Professions, University of Missouri, Columbia, MO, United States
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Nahacka Z, Zobalova R, Dubisova M, Rohlena J, Neuzil J. Miro proteins connect mitochondrial function and intercellular transport. Crit Rev Biochem Mol Biol 2021; 56:401-425. [PMID: 34139898 DOI: 10.1080/10409238.2021.1925216] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Mitochondria are organelles present in most eukaryotic cells, where they play major and multifaceted roles. The classical notion of the main mitochondrial function as the powerhouse of the cell per se has been complemented by recent discoveries pointing to mitochondria as organelles affecting a number of other auxiliary processes. They go beyond the classical energy provision via acting as a relay point of many catabolic and anabolic processes, to signaling pathways critically affecting cell growth by their implication in de novo pyrimidine synthesis. These additional roles further underscore the importance of mitochondrial homeostasis in various tissues, where its deregulation promotes a number of pathologies. While it has long been known that mitochondria can move within a cell to sites where they are needed, recent research has uncovered that mitochondria can also move between cells. While this intriguing field of research is only emerging, it is clear that mobilization of mitochondria requires a complex apparatus that critically involves mitochondrial proteins of the Miro family, whose role goes beyond the mitochondrial transfer, as will be covered in this review.
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Affiliation(s)
- Zuzana Nahacka
- Institute of Biotechnology, Czech Academy of Sciences, Prague-West, Czech Republic
| | - Renata Zobalova
- Institute of Biotechnology, Czech Academy of Sciences, Prague-West, Czech Republic
| | - Maria Dubisova
- Institute of Biotechnology, Czech Academy of Sciences, Prague-West, Czech Republic.,Faculty of Science, Charles University, Prague, Czech Republic
| | - Jakub Rohlena
- Institute of Biotechnology, Czech Academy of Sciences, Prague-West, Czech Republic
| | - Jiri Neuzil
- Institute of Biotechnology, Czech Academy of Sciences, Prague-West, Czech Republic.,School of Medical Science, Griffith University, Southport, Australia
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Cicardi ME, Marrone L, Azzouz M, Trotti D. Proteostatic imbalance and protein spreading in amyotrophic lateral sclerosis. EMBO J 2021; 40:e106389. [PMID: 33792056 PMCID: PMC8126909 DOI: 10.15252/embj.2020106389] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 11/18/2020] [Accepted: 02/25/2021] [Indexed: 12/11/2022] Open
Abstract
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder whose exact causative mechanisms are still under intense investigation. Several lines of evidence suggest that the anatomical and temporal propagation of pathological protein species along the neural axis could be among the main driving mechanisms for the fast and irreversible progression of ALS pathology. Many ALS-associated proteins form intracellular aggregates as a result of their intrinsic prion-like properties and/or following impairment of the protein quality control systems. During the disease course, these mutated proteins and aberrant peptides are released in the extracellular milieu as soluble or aggregated forms through a variety of mechanisms. Internalization by recipient cells may seed further aggregation and amplify existing proteostatic imbalances, thus triggering a vicious cycle that propagates pathology in vulnerable cells, such as motor neurons and other susceptible neuronal subtypes. Here, we provide an in-depth review of ALS pathology with a particular focus on the disease mechanisms of seeding and transmission of the most common ALS-associated proteins, including SOD1, FUS, TDP-43, and C9orf72-linked dipeptide repeats. For each of these proteins, we report historical, biochemical, and pathological evidence of their behaviors in ALS. We further discuss the possibility to harness pathological proteins as biomarkers and reflect on the implications of these findings for future research.
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Affiliation(s)
- Maria Elena Cicardi
- Department of NeuroscienceWeinberg ALS CenterVickie and Jack Farber Institute for NeuroscienceThomas Jefferson UniversityPhiladelphiaPAUSA
| | - Lara Marrone
- Department of NeuroscienceSheffield Institute for Translational Neuroscience (SITraN)University of SheffieldSheffieldUK
| | - Mimoun Azzouz
- Department of NeuroscienceSheffield Institute for Translational Neuroscience (SITraN)University of SheffieldSheffieldUK
| | - Davide Trotti
- Department of NeuroscienceWeinberg ALS CenterVickie and Jack Farber Institute for NeuroscienceThomas Jefferson UniversityPhiladelphiaPAUSA
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40
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Cordero Cervantes D, Zurzolo C. Peering into tunneling nanotubes-The path forward. EMBO J 2021; 40:e105789. [PMID: 33646572 PMCID: PMC8047439 DOI: 10.15252/embj.2020105789] [Citation(s) in RCA: 87] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 10/21/2020] [Accepted: 01/15/2021] [Indexed: 12/19/2022] Open
Abstract
The identification of Tunneling Nanotubes (TNTs) and TNT-like structures signified a critical turning point in the field of cell-cell communication. With hypothesized roles in development and disease progression, TNTs' ability to transport biological cargo between distant cells has elevated these structures to a unique and privileged position among other mechanisms of intercellular communication. However, the field faces numerous challenges-some of the most pressing issues being the demonstration of TNTs in vivo and understanding how they form and function. Another stumbling block is represented by the vast disparity in structures classified as TNTs. In order to address this ambiguity, we propose a clear nomenclature and provide a comprehensive overview of the existing knowledge concerning TNTs. We also discuss their structure, formation-related pathways, biological function, as well as their proposed role in disease. Furthermore, we pinpoint gaps and dichotomies found across the field and highlight unexplored research avenues. Lastly, we review the methods employed to date and suggest the application of new technologies to better understand these elusive biological structures.
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Affiliation(s)
| | - Chiara Zurzolo
- Institut PasteurMembrane Traffic and PathogenesisParisFrance
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41
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Wang S, Li Y, Zhao Y, Lin F, Qu J, Liu L. Investigating tunneling nanotubes in ovarian cancer based on two-photon excitation FLIM-FRET. BIOMEDICAL OPTICS EXPRESS 2021; 12:1962-1973. [PMID: 33996210 PMCID: PMC8086450 DOI: 10.1364/boe.418778] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/25/2021] [Accepted: 02/25/2021] [Indexed: 05/13/2023]
Abstract
Precise and efficient cell-to-cell communication is critical to the growth and differentiation of organisms, the formation of various organism, the maintenance of tissue function and the coordination of their various physiological activities, especially to the growth and invasion of cancer cells. Tunneling nanotubes (TNTs) were discovered as a new method of cell-to-cell communication in many cell lines. In this paper, we investigated TNTs-like structures in ovarian cancer cells and proved their elements by fluorescent staining, which showed that TNTs are comprised of natural lipid bilayers with microtubules as the skeleton that can transmit ions and organelles between adjacent cells. We then used fluorescence resonance energy transfer (FRET) based on two-photon excitation fluorescence lifetime imaging microscopy (FLIM) (TP-FLIM-FRET) to detect material transport in TNTs. The experimental results showed that the number of TNTs have an impact on the drug treatment of cancer cells, which provided a new perspective for TNTs involvement in cancer treatment. Our results also showed that TP-FLIM-FRET would potentially become a new optical method for TNTs study.
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42
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Zhu C, Shi Y, You J. Immune Cell Connection by Tunneling Nanotubes: The Impact of Intercellular Cross-Talk on the Immune Response and Its Therapeutic Applications. Mol Pharm 2021; 18:772-786. [PMID: 33529022 DOI: 10.1021/acs.molpharmaceut.0c01248] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Direct intercellular communication is an important prerequisite for the development of multicellular organisms, the regeneration of tissue, and the maintenance of various physiological activities. Tunnel nanotubes (TNTs), which have diameters of approximately 50-1500 nm and lengths of up to several cell diameters, can connect cells over long distances and have emerged as one of the most important recently discovered types of efficient communication between cells. Moreover, TNTs can also directly transfer organelles, vehicles, proteins, genetic material, ions, and small molecules from one cell to adjacent and even distant cells. However, the mechanism of intercellular communication between various immune cells within the complex immune system has not been fully elucidated. Studies in the past decades have confirmed the existence of TNTs in many types of cells, especially in various kinds of immune cells. TNTs display different structural and functional characteristics between and within different immunocytes, playing a major role in the transmission of signals across various kinds of immune cells. In this review, we introduce the discovery and structure of TNTs, as well as their different functional properties within different immune cells. We also discuss the roles of TNTs in potentiating the immune response and their potential therapeutic applications.
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Affiliation(s)
- Chunqi Zhu
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, People's Republic of China
| | - Yingying Shi
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, People's Republic of China
| | - Jian You
- College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, People's Republic of China
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43
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Mohammadalipour A, Dumbali SP, Wenzel PL. Mitochondrial Transfer and Regulators of Mesenchymal Stromal Cell Function and Therapeutic Efficacy. Front Cell Dev Biol 2020; 8:603292. [PMID: 33365311 PMCID: PMC7750467 DOI: 10.3389/fcell.2020.603292] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 11/16/2020] [Indexed: 12/16/2022] Open
Abstract
Mesenchymal stromal cell (MSC) metabolism plays a crucial role in the surrounding microenvironment in both normal physiology and pathological conditions. While MSCs predominantly utilize glycolysis in their native hypoxic niche within the bone marrow, new evidence reveals the importance of upregulation in mitochondrial activity in MSC function and differentiation. Mitochondria and mitochondrial regulators such as sirtuins play key roles in MSC homeostasis and differentiation into mature lineages of the bone and hematopoietic niche, including osteoblasts and adipocytes. The metabolic state of MSCs represents a fine balance between the intrinsic needs of the cellular state and constraints imposed by extrinsic conditions. In the context of injury and inflammation, MSCs respond to reactive oxygen species (ROS) and damage-associated molecular patterns (DAMPs), such as damaged mitochondria and mitochondrial products, by donation of their mitochondria to injured cells. Through intercellular mitochondria trafficking, modulation of ROS, and modification of nutrient utilization, endogenous MSCs and MSC therapies are believed to exert protective effects by regulation of cellular metabolism in injured tissues. Similarly, these same mechanisms can be hijacked in malignancy whereby transfer of mitochondria and/or mitochondrial DNA (mtDNA) to cancer cells increases mitochondrial content and enhances oxidative phosphorylation (OXPHOS) to favor proliferation and invasion. The role of MSCs in tumor initiation, growth, and resistance to treatment is debated, but their ability to modify cancer cell metabolism and the metabolic environment suggests that MSCs are centrally poised to alter malignancy. In this review, we describe emerging evidence for adaptations in MSC bioenergetics that orchestrate developmental fate decisions and contribute to cancer progression. We discuss evidence and potential strategies for therapeutic targeting of MSC mitochondria in regenerative medicine and tissue repair. Lastly, we highlight recent progress in understanding the contribution of MSCs to metabolic reprogramming of malignancies and how these alterations can promote immunosuppression and chemoresistance. Better understanding the role of metabolic reprogramming by MSCs in tissue repair and cancer progression promises to broaden treatment options in regenerative medicine and clinical oncology.
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Affiliation(s)
- Amina Mohammadalipour
- Department of Integrative Biology & Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Sandeep P Dumbali
- Department of Integrative Biology & Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Pamela L Wenzel
- Department of Integrative Biology & Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States.,Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, United States.,Immunology Program, MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, United States
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44
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Subramaniam MD, Iyer M, Nair AP, Venkatesan D, Mathavan S, Eruppakotte N, Kizhakkillach S, Chandran MK, Roy A, Gopalakrishnan AV, Vellingiri B. Oxidative stress and mitochondrial transfer: A new dimension towards ocular diseases. Genes Dis 2020; 9:610-637. [PMID: 35782976 PMCID: PMC9243399 DOI: 10.1016/j.gendis.2020.11.020] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 09/18/2020] [Accepted: 11/27/2020] [Indexed: 12/12/2022] Open
Abstract
Ocular cells like, retinal pigment epithelium (RPE) is a highly specialized pigmented monolayer of post-mitotic cells, which is located in the posterior segment of the eye between neuro sensory retina and vascular choroid. It functions as a selective barrier and nourishes retinal visual cells. As a result of high-level oxygen consumption of retinal cells, RPE cells are vulnerable to chronic oxidative stress and an increased level of reactive oxygen species (ROS) generated from mitochondria. These oxidative stress and ROS generation in retinal cells lead to RPE degeneration. Various sources including mtDNA damage could be an important factor of oxidative stress in RPE. Gene therapy and mitochondrial transfer studies are emerging fields in ocular disease research. For retinal degenerative diseases stem cell-based transplantation methods are developed from basic research to preclinical and clinical trials. Translational research contributions of gene and cell therapy would be a new strategy to prevent, treat and cure various ocular diseases. This review focuses on the effect of oxidative stress in ocular cell degeneration and recent translational researches on retinal degenerative diseases to cure blindness.
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Affiliation(s)
- Mohana Devi Subramaniam
- SN ONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai 600006, Tamil Nadu, India
- Corresponding author.
| | - Mahalaxmi Iyer
- SN ONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai 600006, Tamil Nadu, India
- Department of Zoology, Avinashilingam Institute for Home Science and Higher Education for Women, Coimbatore 641 043, Tamil Nadu, India
| | - Aswathy P. Nair
- SN ONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai 600006, Tamil Nadu, India
| | - Dhivya Venkatesan
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641046, Tamil Nadu, India
| | - Sinnakaruppan Mathavan
- SN ONGC Department of Genetics and Molecular Biology, Vision Research Foundation, Chennai 600006, Tamil Nadu, India
| | - Nimmisha Eruppakotte
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641046, Tamil Nadu, India
| | - Soumya Kizhakkillach
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641046, Tamil Nadu, India
| | - Manoj kumar Chandran
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641046, Tamil Nadu, India
| | - Ayan Roy
- Department of Biotechnology, Lovely Professional University, Punjab 144411, India
| | - Abilash Valsala Gopalakrishnan
- Department of Biomedical Sciences, School of Bio Sciences and Technology (SBST), Vellore Institute of Technology (VIT), Vellore 600127, India
| | - Balachandar Vellingiri
- Human Molecular Cytogenetics and Stem Cell Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641046, Tamil Nadu, India
- Corresponding author. Human Molecular Cytogenetics and Stem Cell, Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore 641 046, Tamil Nadu, India.Fax: +91 422 2422387.
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Nieland L, Morsett LM, Broekman MLD, Breakefield XO, Abels ER. Extracellular Vesicle-Mediated Bilateral Communication between Glioblastoma and Astrocytes. Trends Neurosci 2020; 44:215-226. [PMID: 33234347 DOI: 10.1016/j.tins.2020.10.014] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/09/2020] [Accepted: 10/27/2020] [Indexed: 02/07/2023]
Abstract
Glioblastoma the most aggressive form of brain cancer, comprises a complex mixture of tumor cells and nonmalignant stromal cells, including neurons, astrocytes, microglia, infiltrating monocytes/macrophages, lymphocytes, and other cell types. All nonmalignant cells within and surrounding the tumor are affected by the presence of glioblastoma. Astrocytes use multiple modes of communication to interact with neighboring cells. Extracellular vesicle-directed intercellular communication has been found to be an important component of signaling between astrocytes and glioblastoma in tumor progression. In this review, we focus on recent findings on extracellular vesicle-mediated bilateral crosstalk, between glioblastoma cells and astrocytes, highlighting the protumor and antitumor roles of astrocytes in glioblastoma development.
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Affiliation(s)
- Lisa Nieland
- Departments of Neurology and Radiology, Massachusetts General Hospital, and NeuroDiscovery Center, Harvard Medical School, Boston, MA, 02129, USA
| | - Liza M Morsett
- Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, 02129, USA
| | - Marike L D Broekman
- Departments of Neurology and Radiology, Massachusetts General Hospital, and NeuroDiscovery Center, Harvard Medical School, Boston, MA, 02129, USA; Department of Neurosurgery, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands; Department of Neurosurgery, Haaglanden Medical Center, 2512 VA, The Hague, The Netherlands
| | - Xandra O Breakefield
- Departments of Neurology and Radiology, Massachusetts General Hospital, and NeuroDiscovery Center, Harvard Medical School, Boston, MA, 02129, USA
| | - Erik R Abels
- Departments of Neurology and Radiology, Massachusetts General Hospital, and NeuroDiscovery Center, Harvard Medical School, Boston, MA, 02129, USA; Department of Neurosurgery, Leiden University Medical Center, 2300 RC, Leiden, The Netherlands.
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46
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Tunneling Nanotubes: The Fuel of Tumor Progression? Trends Cancer 2020; 6:874-888. [DOI: 10.1016/j.trecan.2020.04.012] [Citation(s) in RCA: 44] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 04/29/2020] [Accepted: 04/30/2020] [Indexed: 12/26/2022]
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47
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Tunneling Nanotubes and the Eye: Intercellular Communication and Implications for Ocular Health and Disease. BIOMED RESEARCH INTERNATIONAL 2020; 2020:7246785. [PMID: 32352005 PMCID: PMC7171654 DOI: 10.1155/2020/7246785] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 03/10/2020] [Indexed: 12/31/2022]
Abstract
Cellular communication is an essential process for the development and maintenance of all tissues including the eye. Recently, a new method of cellular communication has been described, which relies on formation of tubules, called tunneling nanotubes (TNTs). These structures connect the cytoplasm of adjacent cells and allow the direct transport of cellular cargo between cells without the need for secretion into the extracellular milieu. TNTs may be an important mechanism for signaling between cells that reside long distances from each other or for cells in aqueous environments, where diffusion-based signaling is challenging. Given the wide range of cargoes transported, such as lysosomes, endosomes, mitochondria, viruses, and miRNAs, TNTs may play a role in normal homeostatic processes in the eye as well as function in ocular disease. This review will describe TNT cellular communication in ocular cell cultures and the mammalian eye in vivo, the role of TNTs in mitochondrial transport with an emphasis on mitochondrial eye diseases, and molecules involved in TNT biogenesis and their function in eyes, and finally, we will describe TNT formation in inflammation, cancer, and stem cells, focusing on pathological processes of particular interest to vision scientists.
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Matejka N, Reindl J. Perspectives of cellular communication through tunneling nanotubes in cancer cells and the connection to radiation effects. Radiat Oncol 2019; 14:218. [PMID: 31796110 PMCID: PMC6889217 DOI: 10.1186/s13014-019-1416-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Accepted: 11/05/2019] [Indexed: 02/07/2023] Open
Abstract
Direct cell-to-cell communication is crucial for the survival of cells in stressful situations such as during or after radiation exposure. This communication can lead to non-targeted effects, where non-treated or non-infected cells show effects induced by signal transduction from non-healthy cells or vice versa. In the last 15 years, tunneling nanotubes (TNTs) were identified as membrane connections between cells which facilitate the transfer of several cargoes and signals. TNTs were identified in various cell types and serve as promoter of treatment resistance e.g. in chemotherapy treatment of cancer. Here, we discuss our current understanding of how to differentiate tunneling nanotubes from other direct cellular connections and their role in the stress reaction of cellular networks. We also provide a perspective on how the capability of cells to form such networks is related to the ability to surpass stress and how this can be used to study radioresistance of cancer cells.
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Affiliation(s)
- Nicole Matejka
- Institut für angewandte Physik und Messtechnik, Universität der Bundeswehr München, Werner-Heisenberg-Weg 39, 85577 Neubiberg, Germany
| | - Judith Reindl
- Institut für angewandte Physik und Messtechnik, Universität der Bundeswehr München, Werner-Heisenberg-Weg 39, 85577 Neubiberg, Germany
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Furnon W, Fender P, Confort MP, Desloire S, Nangola S, Kitidee K, Leroux C, Ratinier M, Arnaud F, Lecollinet S, Boulanger P, Hong SS. Remodeling of the Actin Network Associated with the Non-Structural Protein 1 (NS1) of West Nile Virus and Formation of NS1-Containing Tunneling Nanotubes. Viruses 2019; 11:v11100901. [PMID: 31569658 PMCID: PMC6832617 DOI: 10.3390/v11100901] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 09/24/2019] [Accepted: 09/24/2019] [Indexed: 12/14/2022] Open
Abstract
The cellular response to the recombinant NS1 protein of West Nile virus (NS1WNV) was studied using three different cell types: Vero E6 simian epithelial cells, SH-SY5Y human neuroblastoma cells, and U-87MG human astrocytoma cells. Cells were exposed to two different forms of NS1WNV: (i) the exogenous secreted form, sNS1WNV, added to the extracellular milieu; and (ii) the endogenous NS1WNV, the intracellular form expressed in plasmid-transfected cells. The cell attachment and uptake of sNS1WNV varied with the cell type and were only detectable in Vero E6 and SH-SY5Y cells. Addition of sNS1WNV to the cell culture medium resulted in significant remodeling of the actin filament network in Vero E6 cells. This effect was not observed in SH-SY5Y and U-87MG cells, implying that the cellular uptake of sNS1WNV and actin network remodeling were dependent on cell type. In the three cell types, NS1WNV-expressing cells formed filamentous projections reminiscent of tunneling nanotubes (TNTs). These TNT-like projections were found to contain actin and NS1WNV proteins. Interestingly, similar actin-rich, TNT-like filaments containing NS1WNV and the viral envelope glycoprotein EWNV were also observed in WNV-infected Vero E6 cells.
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Affiliation(s)
- Wilhelm Furnon
- Université de Lyon, University Claude Bernard Lyon 1, INRA, EPHE, IVPC, UMR754, Viral Infections & Comparative Pathology, Cedex 07, 69366 Lyon, France.
| | - Pascal Fender
- Institut de Biologie Structurale, CNRS UMR 5075, 38042 Grenoble, France.
| | - Marie-Pierre Confort
- Université de Lyon, University Claude Bernard Lyon 1, INRA, EPHE, IVPC, UMR754, Viral Infections & Comparative Pathology, Cedex 07, 69366 Lyon, France.
| | - Sophie Desloire
- Université de Lyon, University Claude Bernard Lyon 1, INRA, EPHE, IVPC, UMR754, Viral Infections & Comparative Pathology, Cedex 07, 69366 Lyon, France.
| | - Sawitree Nangola
- Department of Medical Technology, School of Allied Health Sciences, University of Phayao, Phayao 56000, Thailand.
| | - Kuntida Kitidee
- Center for Research & Innovation, Faculty of Medical Technology, Mahidol University, Nakhon Pathom 73170, Thailand.
| | - Caroline Leroux
- Université de Lyon, University Claude Bernard Lyon 1, INRA, EPHE, IVPC, UMR754, Viral Infections & Comparative Pathology, Cedex 07, 69366 Lyon, France.
| | - Maxime Ratinier
- Université de Lyon, University Claude Bernard Lyon 1, INRA, EPHE, IVPC, UMR754, Viral Infections & Comparative Pathology, Cedex 07, 69366 Lyon, France.
- EPHE, PSL Research University, INRA, Université de Lyon, University Claude Bernard Lyon 1, UMR754, IVPC, Cedex 07, 69366 Lyon, France.
| | - Frédérick Arnaud
- Université de Lyon, University Claude Bernard Lyon 1, INRA, EPHE, IVPC, UMR754, Viral Infections & Comparative Pathology, Cedex 07, 69366 Lyon, France.
- EPHE, PSL Research University, INRA, Université de Lyon, University Claude Bernard Lyon 1, UMR754, IVPC, Cedex 07, 69366 Lyon, France.
| | - Sylvie Lecollinet
- UMR-1161 Virology, ANSES, INRA, Ecole Nationale Vétérinaire d'Alfort, ANSES Animal Health Laboratory, EURL on Equine Diseases, 94704 Maisons-Alfort, France.
| | - Pierre Boulanger
- Université de Lyon, University Claude Bernard Lyon 1, INRA, EPHE, IVPC, UMR754, Viral Infections & Comparative Pathology, Cedex 07, 69366 Lyon, France.
| | - Saw-See Hong
- Université de Lyon, University Claude Bernard Lyon 1, INRA, EPHE, IVPC, UMR754, Viral Infections & Comparative Pathology, Cedex 07, 69366 Lyon, France.
- Institut National de la Santé et de la Recherche Médicale, 101, rue de Tolbiac, Cedex 13, 75654 Paris, France.
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In focus in HCB. Histochem Cell Biol 2019; 152:249-251. [PMID: 31555899 DOI: 10.1007/s00418-019-01816-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
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