Blebbisomes are large, organelle-rich extracellular vesicles with cell-like properties

Nature Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 21, 2025

Language: Английский

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Therapeutic role of hucMSC-sEV-enriched miR-13896 in cisplatin-induced acute kidney injury through M2 macrophage polarization

Cell Biology and Toxicology, Journal Year: 2025, Volume and Issue: 41(1)

Published: Feb. 24, 2025

Human umbilical cord mesenchymal stem cell-derived small extracellular vesicles (hucMSC-sEV) have recently garnered attention as a potential therapeutic approach for kidney diseases with anti-inflammatory effects. Infiltrated macrophages play an important role in facilitating tissue regeneration. However, the intricate regulatory effects of hucMSC-sEV on during cisplatin-induced acute injury (AKI) remain unknown. In this study, we uncovered that exhibited potent anti-inflammation and effectively inhibited polarization M1 phenotype macrophages. Mechanically, miRNA sequencing analysis qRT-PCR indicated novel miRNA, named miR-13896, was enriched hucMSC-sEV. When transfected miR-13896 mimic, displayed M2 elevated levels Arg1 IL-10, while inhibitor promoted phenotype. Furthermore, firstly established repressed Tradd expression by targeting its 3' untranslated region subsequently NF-κB signaling pathway Additionally, to improve effects, were engineered through electroporation, which resulted promoting macrophages, inhibiting inflammatory factors, enhancing repair. Conclusively, our findings provide insights into mechanisms underlying AKI, also highlighting electroporation promising strategy treating AKI.

Language: Английский

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Leveraging nature’s nanocarriers: Translating insights from extracellular vesicles to biomimetic synthetic vesicles for biomedical applications

Science Advances, Journal Year: 2025, Volume and Issue: 11(9)

Published: Feb. 26, 2025

Naturally occurring extracellular vesicles (EVs) and synthetic nanoparticles like liposomes have revolutionized precision diagnostics medicine. EVs excel in biocompatibility cell targeting, while offer enhanced drug loading capacity scalability. The clinical translation of is hindered by challenges including low yield heterogeneity, whereas face rapid immune clearance limited targeting efficiency. To bridge these gaps, biomimetic (SVs) emerged as innovative platforms, combining the advantageous properties liposomes. This review emphasizes critical aspects EV biology, such mechanisms EV-cell interaction source-dependent functionalities modulation, tissue regeneration, informing SV engineering. We reviewed a broad array SVs, with focus on lipid bilayered functionalized proteins. These include cell-derived nanovesicles, protein-functionalized liposomes, hybrid vesicles. By addressing current highlighting opportunities, this aims to advance SVs for transformative biomedical applications.

Language: Английский

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Diversity in connexin biology

Journal of Biological Chemistry, Journal Year: 2023, Volume and Issue: 299(11), P. 105263 - 105263

Published: Sept. 20, 2023

Over 35 years ago the cell biology community was introduced to connexins as subunit employed assemble semicrystalline clusters of intercellular channels that had been well described morphologically gap junctions. The decade followed would see knowledge unexpectedly large 21-member human connexin family grow reflect unique and overlapping expression patterns in all organ systems. While initially focused on their role constructing highly regulated channels, this destined change discoveries revealed hemichannels at surface novel roles many types, especially when considering pathologies. Acceptance having bifunctional channel properties met with some resistance, which has given way recent premise have multifunctional properties. Depending isoform origin, wide-ranging half-lives vary from a couple hours life expectancy cell. Diversity characteristics molecular were further by X-ray crystallography single-particle cryo-EM. New avenues seen or fragments playing adhesion, tunneling nanotubes, extracellular vesicles, mitochondrial membranes, transcription regulation, other emerging cellular functions. These largely linked Cx43, is prominent most organs. Here, we will review evolution adults more evidence linking diverse array As understood genome project, identification junction (GJ) proteins likely complete 21 members humans (1Sohl G. Willecke K. An update genes nomenclature mouse man.Cell Commun. Adhes. 2003; 10: 173-180Crossref PubMed Google Scholar) (Table 1). Connexin acquired reflects predicted weight (e.g., Cx43 = 43 kD) (2Beyer E.C. Paul D.L. Goodenough D.A. Connexin43: protein rat heart homologous liver.J. Cell Biol. 1987; 105: 2621-2629Crossref Scholar). are found seven chromosomes follow conventional gene system, GJ, Greek letter representing subfamily number reflecting order discovery GJA1, alpha 1, encodes first discovered member subfamily) (3Sohl Gap junctions family.Cardiovasc Res. 2004; 62: 228-232Crossref Scopus (805) Human now classified into five subfamilies based sequence homology denoted GJ-A, GJ-B, GJ-C, GJ-D, GJ-E, alpha, beta, gamma, delta, epsilon subtypes (4Kirichenko E.Y. Skatchkov S.N. Ermakov A.M. Structure functions constituent mammalian CNS.Biochem. (Mosc) Suppl. Ser. A. Membr. 2021; 15: 107-119PubMed Scholar, 5Mikalsen S.O. S I.K. Tausen M. Connexins during 500 Million years-from Cyclostomes Mammals.Int. J. Mol. Sci. 22: 1584Crossref (5) Scholar)(Table Since 1990, there virtual explosion articles focus GJs, connexins, and/or (Fig. depth understanding variable over 50% published reports since 1995 focusing Novel through interrogation commonly extrapolated members. Furthermore, insights nonhuman frequently used deduce information about putative orthologs. approach continues provide systemic entire family, caution needs be exercised each distinguishes it its In fact, unexpected diversity even within individual versus N-terminal truncated Cx43) reveal "same" can remarkably different distinct modes regulation.Table 1Connexin links inherited diseasesConnexinGeneOrgans expressed# Of diseases associated variantsHigh-resolution structure solvedCx43GJA1576108, 109Cx46GJA371101, 102Cx37GJA4181∗—Cx40GJA5273∗—Cx50GJA831101, 102Cx59GJA950—Cx62GJA10100—Cx32GJB1351—Cx26GJB239898–100, 103–106Cx31GJB3103—Cx30.3GJB491—Cx31.1GJB580—Cx30GJB6184—Cx25GJB7100—Cx45GJC1221∗—Cx47GJC253—Cx30.2 (Cx31.3)GJC370107Cx36GJD290110Cx31.9GJD3100—Cx40.1GJD460—Cx23GJE100—A list encoding corresponding names. typically divided A, B, C, D, E, reflective homologies. adult organs where these detected noted systematic analysis available PubMed. Seventy-five assessed, 62 exhibiting for least one connexin. Note Cx26, Cx32 three widely distributed isoforms being numerous vast majority 33 attributed mutations/variants twelve annotated Online Mendelian Inheritance Man database, while others reported elsewhere. Asterisks indicate included identified Genetic Testing Registry search disease-associated variants require patient studies confirm linkage. polymorphisms disease not included. high-resolution six listed along references. Open table new tab A Canonically, capacity GJ forming integral membrane span lipid bilayer four times, oligomerize connexons (commonly referred hemichannels) shortly after cotranslational insertion endoplasmic reticulum (6Laird D.W. proteome relationship disease.Trends 2010; 20: 92-101Abstract Full Text PDF (221) 7Laird Life cycle health disease.Biochem. 2006; 394: 527-543Crossref (663) 8Segretain D. Falk M.M. Regulation biosynthesis, assembly, formation, removal.Biochim. Biophys. Acta. 1662: 3-21Crossref (259) 2, C). exceptions, oligomerization process may delayed until they reach Golgi apparatus (9Musil L.S. Multisubunit assembly an plasma protein, connexin43, occurs exit ER.Cell. 1993; 74: 1065-1077Abstract (410) 10Koval Pathways control oligomerization.Trends 16: 159-166Abstract (111) Transport vesicles actively constitutively carry surface, dock compatible juxtaposed form allow junctional communication (GJIC) (11Koval Molina S.A. Burt J.M. Mix match: investigating heteromeric heterotypic model systems native tissues.FEBS Lett. 2014; 588: 1193-1204Crossref (101) quickly cluster tightly packed arrays historically termed structures interchangeably plaques (12Goodenough Goliger J.A. Connexins, connexons, communication.Annu. Rev. Biochem. 1996; 65: 475-502Crossref 2C). single easily contain hundreds thousands allowing massive site exchange ions potentially metabolome less than 1 kD size (13Veenstra R.D. Wang H.Z. Beblo Chilton M.G. Harris A.L. Beyer et al.Selectivity connexin-specific does correlate conductance.Circ. 1995; 77: 1156-1165Crossref 14Ek-Vitorin J.F. Quantification selectivity.Am. Physiol. 2005; 289: C1535-C1546Crossref (0) 15Ek-Vitorin Structural basis selective permeability made communicating proteins.Biochim. 2013; 1828: 51-68Crossref (55) 16Alexander D.B. Goldberg G.S. Transfer biologically important molecules between cells channels.Curr. Med. Chem. 2045-2058Crossref (196) Scholar)(Fig. A–C). known small pass direct do limited two dozen, including ATP, cAMP, IP3, GSH, nucleotides, ions, amino acids (17Harris cytoplasmic molecules.Prog. 2007; 94: 120-143Crossref (368) 18Harris Electrical coupling channels.J. Gen. 2018; 150: 1606-1639Crossref (18) 3). It unclear transjunctional conduits composed constituents. Given brevity present article, aspect complexity reviewed detail elsewhere 19Leybaert L. Lampe P.D. Dhein S. Kwak B.R. Ferdinandy P. al.Connexins cardiovascular neurovascular disease: pharmacological implications.Pharmacol. 2017; 69: 396-478Crossref (166) GJ-mediated fundamental importance healthy signaling lead pathologies if perturbed loss- gain-of function mutations dysregulation (20Laird Cellular mechanisms connexin-based diseases.Trends 2022; 32: 58-69Abstract 21Laird Therapeutic strategies targeting connexins.Nat. Drug Discov. 17: 905-921Crossref (129) 22Delmar Laird Naus C.C. Nielsen M.S. Verselis V.K. White T.W. disease.Cold Spring Harb. Perspect. 10a029348Crossref (61) Scholar).Figure 3Complexity GJIC. GJIC involve potential passage literally homotypic channels. Selective molecules, metabolites dependent (depicted red/blue subunits) build Identification difficult, so surprising, exists only subset metabolome. Part figure generated using BioRender. For movie animation see: https://www.schulich.uwo.ca/lairdlab/img/cell-animation-small.mp4. GJIC, communication.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Within lined pore proposed second serving (hemichannels) (23Beyer Steinberg T.H. Evidence connexin-43 ATP-induced macrophages.J. 1991; 266: 7971-7974Abstract Early concept considerable resistance transient remained closed proceeded adjacent Opposition acting hemichannel context could also stem evolutionary perspective might considered "step-down" cell–cell conduits. notable addition several transport capable passively moving regulator across ion pannexins, calcium homeostasis modulator) (24Koval Schug W.J. Isakson B.E. Pharmacology pannexin Opin. Pharmacol. 2023; 69102359Crossref (7) 25Syrjanen Michalski Kawate T. Furukawa H. On nature large-pore 433166994Crossref (21) Hemichannel redundancy arguments pointed notion larger (25Syrjanen However, vertebrates, no advantage barring exception acquires rare situations (26Welzel Schuster evolved early chordates lost innexin diversity.Elife. 11e74422Crossref (4) 27Palacios-Prado N. Soto P.A. Lopez X. Choi E.J. Marquez-Miranda V. Rojas al.Endogenous pannexin1 functional cell-cell characteristic voltage-dependent properties.Proc. Natl. Acad. U. 119e2202104119Crossref (12) Nevertheless, overwhelming experimental points key normal chordate physiology, pathology, tissue injury, (28Kiani Targeting treat temporal lobe epilepsy.Nat. Neurol. 19: 1Crossref (1) 29Leybaert De Smet M.A. Lissoni Allewaert R. Roderick H.L. Bultynck al.Connexin candidate targets cardioprotective anti-arrhythmic treatments.J. Clin. Invest. 133e168117Crossref (2) 30Delvaeye Vandenabeele Leybaert Krysko D.V. channels: views challenges.Trends 24: 1036-1053Abstract (59) 31Aasen innexins, pannexins: clinical targets.Biomolecules. 11: 155Crossref opening provides conduit release glutamate, others) cytosol milieu best characterized ATP (32Yang Chen Yang Deng F. Guo toxicity: advances mechanistic insights.Toxicology. 488153488Crossref Hemichannels enable bidirectional diffusion such plethora informative dyes ethidium bromide, YO-PRO) (33Saez J.C. Vargas A.A. Hernandez D.E. Ortiz F.C. Giaume C. Orellana Permeation Astroglial modulated cytokines parameters depending permeant species.Int. 2020; 21: 3970Crossref (9) 34Shahidullah Delamere N.A. Mechanical stretch activates TRPV4 responses Nonpigmented ciliary epithelium.Int. 1673Crossref assessing function, but relevant calcium) (35Nardin Tettey-Matey Donati Marazziti Di Pietro Peres al.A quantitative assay Ca(2+) uptake pathological hemichannels.Int. 23: 7337Crossref When molecule milieu, cognizant microenvironments substantially component compositions necessary ensure local environment survival. our intent here cover breadth supports hemichannels, remiss give examples. lens Cx46 play critical maintaining (36Retamal Altenberg G.A. Role Posttranslational regulation eye lens.Front. 13864948Crossref 37Beyer Berthoud V.M. 5: 20Crossref (68) 38Berthoud Gao Minogue P.J. Jara O. Mathias R.T. mutants compromise circulation cause cataracts Biomineralization.Int. 5822Crossref (27) precise Cx46, Cx50 remains somewhat elusive. models mechanosensitive accommodate steady-state fluid equilibrium pathways influx sodium, efflux potassium (37Beyer required maintenance transparency. Amplified activity, diseased-linked (39Beyer Loss fiber contribute development etiologies.Front. 13989524Crossref Scholar), GSH leaking harboring culminating cytotoxicity cataracts. another example, bone osteocytes, appear remodeling plasticity NAD+, prostaglandin E2 (40Zhao Riquelme Guda Tu Xu Gu anabolic mechanical loading.Elife. 11e74365Crossref expected few open steady state, response changes microenvironment reduction. context, react oxidative stress means protect osteocytes death (41Hua Zhang Jiang J.X. link skeletal physiology pathology.Curr. Osteoporos. Rep. 66-74Crossref (24) 42Kar Werner against stress-induced death.J. Bone Miner. 28: 1611-1621Crossref (72) recognition hyperactive leaky brain, eyes, bone, skin, lens, (43Cocozzelli A.G. increased functionality skin disease.Int. 2019; 6186Crossref (23) 44Retamal Reyes E.P. Garcia I.E. Pinto B. Martinez A.D. Gonzalez Diseases hemichannels.Front. Cell. Neurosci. 2015; 9: 267Crossref viable therapeutics (21Laird 45Mugisho O.O. Green C.R. NLRP3 inflammasome age-related evidence-based therapeutics.Exp. Eye 215108911Crossref (6) 46Peres Sellitto Nardin Putti Orsini al.Antibody transfer treatment drastically improves epidermal pathology keratitis ichthyosis deafness syndrome male mice.EBioMedicine. 89104453Abstract 47Kuang Y. Zorzi Buratto Ziraldo Mazzarda potent antagonist antibody alleviates Clouston symptoms mutant 57102825Abstract 48Mugisho Acosta M.L. Rupenthal I.D. Connexin43 hemichannels: drug target diabetic retinopathy.Drug Today. 1627-1636Crossref note, study newly developed blocker D4 greatly attenuate seizures epilepsy reducing neuroinflammation (49Guo Li Chiu Garcia-Rodriguez Lagos C.F. al.Inhibition hyperexcitability epilepsy.Proc. 119e2213162119Crossref (11) Another preclinical directed Cx26 potently improved (46Peres Preclinical inhibitors continue arise show promise efficacy injury scenarios. broad spectrum effects diseased cells. Complexity formation begins level express isoforms, resulting mixed either homomeric (50Defourny Thiry Recent biogenesis cochlea.Dev. Dyn. 252: 239-246Crossref 2B). co-oligomerize with, thus attenuating connexon 51Abrams C.K. Flores-Obando R.E. Dungan G.D. Cherepanova E. Freidin Investigating oligodendrocyte connexins: interactions wild-type forms Cx47 modulate function.Glia. 1882-1896Crossref (3) 52Moreno A.P. Biophysical heteromultimeric formed cardiac connexins.Cardiovasc. 276-286Crossref 53Ayad W.A. Locke Koreen I.V. Heteromeric, homomeric, selectively permeable inositol phosphates.J. 281: 16727-16739Abstract At docking cell, establishing layer possibilities (54Kim N.K. Santos-Miranda Aoyama Bai Heterotypic compatibility connexin37 vascular connexins.J. Cardiol. 127: 194-203Abstract (8) 55Xin Sun connexin50/connexin50 gating.J. 2012; 590: 5037-5052Crossref 56Nakagawa Gong X.Q. Maeda Dong Misumi Tsukihara al.Asparagine 175 connexin32 residue connexin26.J. 2011; 286: 19672-19681Abstract (37) 57Tong Charge 46th 50 crucial gap-junctional unitary conductance 592: 5187-5202Crossref (19) Finally, GJs progressive stages differentiation epidermis, leading wealth homocellular heterocellular networks (58Sedovy M.W. Leng Leaf M.R. Iqbal Payne L.B. Chappell acro

Language: Английский

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Emergence of Extracellular Vesicles as “Liquid Biopsy” for Neurological Disorders: Boom or Bust

Pharmacological Reviews, Journal Year: 2023, Volume and Issue: 76(2), P. 199 - 227

Published: Dec. 19, 2023

Abstract

Extracellular vesicles (EVs) have emerged as an attractive liquid biopsy approach in the diagnosis and prognosis of multiple diseases disorders. The feasibility enriching specific subpopulations EVs from biofluids based on their unique surface markers has opened novel opportunities to gain molecular insight various tissues organs, including brain. Over past decade, bodily fluids been extensively studied for biomarkers associated with neurological disorders, such Alzheimer9s disease, Parkinson9s schizophrenia, bipolar disorder, major depressive substance use human immunodeficiency virus–associated neurocognitive cancer/treatment-induced neurodegeneration. These studies focused isolation cargo characterization either total or brain cells, neuron-, astrocyte-, microglia-, oligodendrocyte-, pericyte-, endothelial-derived achieve early predict treatment intervention outcomes. findings these demonstrated that could serve a repetitive less invasive source valuable information supplementing existing costly neuroimaging techniques relatively measures, like lumbar puncture. However, initial excitement surrounding blood-based brain-related tempered by challenges, lack central nervous system specificity EV markers, lengthy protocols, absence standardized procedures biological sample collection, isolation, characterization. Nevertheless, rapid advancements field, supported improved methods sensitive assays characterization, cell–derived continue offer unparallel significant translational implications

Significance Statement

present Characterizing holds potential yield information, thereby significantly impacting development This paper reviewed methodology employed isolate extracellular derived cells biofluids, utility enhancing understanding neurodegeneration, challenges this research field.

Language: Английский

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A phosphoinositide switch mediates exocyst recruitment to multivesicular endosomes for exosome secretion

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Oct. 28, 2023

Abstract Exosomes are secreted to the extracellular milieu when multivesicular endosomes (MVEs) dock and fuse with plasma membrane. However, MVEs also known lysosomes for degradation. How directed membrane exosome secretion rather than is unclear. Here we report that a conversion of phosphatidylinositol-3-phosphate (PI(3)P) phosphatidylinositol-4-phosphate (PI(4)P) catalyzed sequentially by Myotubularin 1 (MTM1) phosphatidylinositol 4-kinase type IIα (PI4KIIα) on surface mediates recruitment exocyst complex. The then targets secretion. We further demonstrate disrupting PI(4)P generation or function blocked exosomal Programmed death-ligand (PD-L1), key immune checkpoint protein in tumor cells, led its accumulation lysosomes. Together, our study suggests PI(3)P direct exocytic trafficking

Language: Английский

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The engineering and application of extracellular matrix hydrogels: a review

Biomaterials Science, Journal Year: 2023, Volume and Issue: 11(11), P. 3784 - 3799

Published: Jan. 1, 2023

The engineering and appliccations of ECM hydrogels.

Language: Английский

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Therapeutic potential in rheumatic diseases of extracellular vesicles derived from mesenchymal stromal cells

Nature Reviews Rheumatology, Journal Year: 2023, Volume and Issue: 19(11), P. 682 - 694

Published: Sept. 4, 2023

Language: Английский

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Extracellular vesicles: emerging roles, biomarkers and therapeutic strategies in fibrotic diseases

Journal of Nanobiotechnology, Journal Year: 2023, Volume and Issue: 21(1)

Published: May 24, 2023

Abstract Extracellular vesicles (EVs), a cluster of cell-secreted lipid bilayer nanoscale particles, universally exist in body fluids, as well cell and tissue culture supernatants. Over the past years, increasing attention have been paid to important role EVs effective intercellular communicators fibrotic diseases. Notably, EV cargos, including proteins, lipids, nucleic acids, metabolites, are reported be disease-specific can even contribute fibrosis pathology. Thus, considered biomarkers for disease diagnosis prognosis. Emerging evidence shows that derived from stem/progenitor cells great prospects cell-free therapy various preclinical models diseases engineered improve targeting effectiveness their treatment. In this review, we will focus on biological functions mechanisms diseases, potential novel therapeutic strategies.

Language: Английский

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Host extracellular vesicles confer cytosolic access to systemic LPS licensing non-canonical inflammasome sensing and pyroptosis

Nature Cell Biology, Journal Year: 2023, Volume and Issue: 25(12), P. 1860 - 1872

Published: Nov. 16, 2023

Language: Английский

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