Mitochondria Transfer from Mesenchymal Stem Cells Confers Chemoresistance to Glioblastoma Stem Cells through Metabolic Rewiring

Cancer Research Communications, Journal Year: 2023, Volume and Issue: 3(6), P. 1041 - 1056

Published: May 25, 2023

Glioblastomas (GBM) are heterogeneous tumors with high metabolic plasticity. Their poor prognosis is linked to the presence of glioblastoma stem cells (GSC), which support resistance therapy, notably temozolomide (TMZ). Mesenchymal (MSC) recruitment GBM contributes GSC chemoresistance, by mechanisms still poorly understood. Here, we provide evidence that MSCs transfer mitochondria GSCs through tunneling nanotubes, enhances TMZ. More precisely, our metabolomics analyses reveal MSC induce reprograming, a nutrient shift from glucose glutamine, rewiring tricarboxylic acid cycle glutaminolysis reductive carboxylation and increase in orotate turnover as well pyrimidine purine synthesis. Metabolomics analysis patient tissues at relapse after TMZ treatment documents increased concentrations AMP, CMP, GMP, UMP nucleotides thus corroborate vitro analyses. Finally, mechanism whereby mitochondrial demonstrating inhibition production Brequinar (BRQ) restores sensitivity acquired mitochondria. Altogether, these results identify for dependency chemoresistant following acquisition exogenous mitochondria, opens therapeutic perspectives based on synthetic lethality between BRQ. Significance: Mitochondria enhance chemoresistance GBMs. The discovery they also generate vulnerability paves way novel approaches.

Language: Английский

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The Therapeutic Mechanisms of Mesenchymal Stem Cells in MS—A Review Focusing on Neuroprotective Properties

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(3), P. 1365 - 1365

Published: Jan. 23, 2024

In multiple sclerosis (MS), there is a great need for treatment with the ability to suppress compartmentalized inflammation within central nervous system (CNS) and promote remyelination regeneration. Mesenchymal stem cells (MSCs) represent promising therapeutic option, as they have been shown migrate site of CNS injury exert neuroprotective properties, including immunomodulation, neurotrophic factor secretion, endogenous neural cell stimulation. This review summarizes current understanding underlying mechanisms discusses translation MSC transplantation their derivatives from pre-clinical demyelinating models clinical trials MS patients.

Language: Английский

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Exercise-Intervened Endothelial Progenitor Cell Exosomes Protect N2a Cells by Improving Mitochondrial Function

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 1148 - 1148

Published: Jan. 17, 2024

We have recently demonstrated that exosomal communication between endothelial progenitor cells (EPCs) and brain is compromised in hypertensive conditions, which might contribute to the poor outcomes of stroke subjects with hypertension. The present study investigated whether exercise intervention can regulate EPC–exosome (EPC-EX) functions conditions. Bone marrow EPCs from sedentary exercised transgenic mice were used for generating EPC-EXs, denoted as R-EPC-EXs R-EPC-EXET. microRNA profile was analyzed, EX determined a co-culture system N2a challenged by angiotensin II (Ang II) plus hypoxia. EX-uptake efficiency, cellular survival ability, reactive oxygen species (ROS) production, mitochondrial membrane potential, expressions cytochrome c superoxide-generating enzyme (Nox4) assessed. found (1) improves uptake efficiency EPC-EXs cells. (2) restores miR-27a levels R-EPC-EXs. (3) R-EPC-EXET improved ability reduced ROS overproduction Ang (4) potential decreased Nox4 hypoxia-injured All these effects significantly inhibitor. Together, data exercise-intervened function be ascribed their carried miR-27a.

Language: Английский

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Tunneling nanotubes: The transport highway for astrocyte-neuron communication in the central nervous system

Brain Research Bulletin, Journal Year: 2024, Volume and Issue: 209, P. 110921 - 110921

Published: March 4, 2024

Tunneling nanotubes (TNTs) have emerged as pivotal structures for intercellular communication, enabling the transfer of cellular components across distant cells. Their involvement in neurological disorders has attracted considerable scientific interest. This review delineates functions TNTs within central nervous system, examining their role transmission bioenergetic substrates, and signaling molecules, multifaceted impact on both physiological pathological processes, with an emphasis neurodegenerative diseases. The highlights selectivity specificity dedicated pathways cargo delivery, particularly under stress conditions that provoke increased TNT formation. potential therapeutic targets is explored depth. We pay particular attention to interactions between astrocytes neurons mediated by TNTs, which are fundamental brain architecture function. Dysfunctions these implicated spread protein aggregates mitochondrial anomalies, contributing pathogenesis culminates a synthesis current understanding biology identifies research gaps, advocating intensified exploration into promising frontier.

Language: Английский

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Autophagy modulation effect on homotypic transfer of intracellular components via tunneling nanotubes in mesenchymal stem cells

Stem Cell Research & Therapy, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 2, 2024

Abstract Background Recent studies have proved the role of autophagy in mesenchymal stem cell (MSCs) function and regenerative properties. How by which mechanism modulation can affect juxtacrine interaction MSCs should be addressed. Here, was investigated formation tunneling nanotubes (TNTs) homotypic mitochondrial donation. Methods were incubated with 15 µM Metformin (Met) and/or 3 3-methyladenine (3-MA) for 48 h. The TNTs assessed using bright-field SEM images. mitochondria density ΔΨ values monitored flow cytometry analysis. Using RT-PCR protein array, close shared mediators between autophagy, apoptosis, Wnt signaling pathways also monitored. total fatty acid profile gas chromatography. Result Data indicated increase TNT length number, along other projections after induction while these features blunted 3-MA-treated ( p < 0.05). Western blotting revealed significant reduction Rab8 p-FAK 0.05), indicating inhibition assembly vesicle transport. Likewise, stimulation increased autophagic flux membrane integrity compared to MSCs. Despite findings, levels Miro1 2 unchanged inhibition/stimulation > We found that protein, transcription several related apoptosis involved different bioactivities. confirmed profound mono polyunsaturated/saturated ratio exposed stimulator. Conclusions In summary, could is required Thus, creates a promising perspective efficiency cell-based therapies.

Language: Английский

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Novel strategies in Parkinson’s disease treatment: a review

Frontiers in Molecular Neuroscience, Journal Year: 2024, Volume and Issue: 17

Published: Aug. 9, 2024

An unprecedented extension of life expectancy observed during the past century drastically increased number patients diagnosed with Parkinson’s diseases (PD) worldwide. Estimated costs PD alone reached $52 billion per year, making effective neuroprotective treatments an urgent and unmet need. Current both AD focus on mitigating symptoms associated these pathologies are not neuroprotective. In this review, we discuss most advanced therapeutic strategies that can be used to treat PD. We also critically review shift paradigm from a small molecule-based inhibition protein aggregation utilization natural degradation pathways immune cells capable degrading toxic amyloid deposits in brain patients.

Language: Английский

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Miro proteins and their role in mitochondrial transfer in cancer and beyond

Frontiers in Cell and Developmental Biology, Journal Year: 2022, Volume and Issue: 10

Published: July 25, 2022

Mitochondria are organelles essential for tumor cell proliferation and metastasis. Although their main cellular function, generation of energy in the form ATP is dispensable cancer cells, capability to drive adaptation stress originating from microenvironment makes them a plausible therapeutic target. Recent research has revealed that cells with damaged oxidative phosphorylation import healthy (functional) mitochondria surrounding stromal pyrimidine synthesis proliferation. Furthermore, it been shown energetically competent fundamental migration, invasion The spatial positioning transport involves Miro proteins subfamily small GTPases, localized outer mitochondrial membrane. involved structure MICOS complex, connecting inner-mitochondrial membrane; mitochondria-ER communication; Ca 2+ metabolism; recycling via mitophagy. most important role regulation movement distribution within (and between) acting as an adaptor linking cytoskeleton-associated motor proteins. In this review, we discuss function various modes intercellular transfer, emphasizing dynamics tunneling nanotubes, common transfer modality. We summarize evidence propose possible roles nanotube-mediated well migration metastasis, both processes being tightly connected cytoskeleton-driven positioning.

Language: Английский

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Extracellular communication between brain cells through functional transfer of Cre mRNA mediated by extracellular vesicles

Molecular Therapy, Journal Year: 2023, Volume and Issue: 31(7), P. 2220 - 2239

Published: May 16, 2023

In the central nervous system (CNS), crosstalk between neural cells is mediated by extracellular mechanisms, including brain-derived vesicles (bdEVs). To study endogenous communication across brain and periphery, we explored Cre-mediated DNA recombination to permanently record functional uptake of bdEVs cargo over time. elucidate transfer within at physiological levels, promoted continuous secretion levels containing Cre mRNA from a localized region in situ lentiviral transduction striatum Flox-tdTomato Ai9 mice reporter activity. Our approach efficiently detected vivo events throughout brain. Remarkably, spatial gradient persistent tdTomato expression was observed along whole brain, exhibiting an increment more than 10-fold 4 months. Moreover, were bloodstream extracted tissue further confirm their delivery novel highly sensitive Nanoluc system. Overall, report method track bdEV which will shed light on role beyond.

Language: Английский

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High-Resolution Microscopic Characterization of Tunneling Nanotubes in Living U87 MG and LN229 Glioblastoma Cells

Cells, Journal Year: 2024, Volume and Issue: 13(5), P. 464 - 464

Published: March 6, 2024

Tunneling nanotubes (TNTs) are fine, nanometer-sized membrane connections between distant cells that provide an efficient communication tool for cellular organization. TNTs thought to play a critical role in behavior, particularly cancer cells. The treatment of aggressive cancers such as glioblastoma remains challenging due their high potential developing therapy resistance, infiltration rates, uncontrolled cell growth, and other features. A better understanding the organization via through could help find new therapeutic approaches. In this study, we investigate properties two lines, U87 MG LN229, including measurements diameter by high-resolution live-cell stimulated emission depletion (STED) microscopy analysis length, morphology, lifetime, formation confocal microscopy. addition, discuss how these fine compounds can ideally be studied microscopically. particular, show which membrane-labeling method is suitable studying demonstrate studies should preferred explore behavior. Our observations on TNT suggest involved migration serve guidance.

Language: Английский

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The Synucleins and the Astrocyte

Biology, Journal Year: 2023, Volume and Issue: 12(2), P. 155 - 155

Published: Jan. 19, 2023

Synucleins consist of three proteins exclusively expressed in vertebrates. α-Synuclein (αS) has been identified as the main proteinaceous aggregate Lewy bodies, a pathological hallmark many neurodegenerative diseases. Less is understood about β-synuclein (βS) and γ-synuclein (γS), although it known βS can interact with αS vivo to inhibit aggregation. Likewise, both γS αS’s propensity vitro. In central nervous system, αS, lesser extent γS, are highly neural presynaptic terminal, they not strictly located there, emerging data have shown more complex expression profile. Synapse loss astrocyte atrophy early aspects degenerative diseases brain correlate disease progression. appear be involved synaptic transmission, astrocytes coordinate organize function, excess degraded by microglia adjacent synapse. also observed may provide beneficial roles. The astrocytic responsibility for degradation well evidence on possible functions warrant closer inspection astrocyte–synuclein interactions at

Language: Английский

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