Hypoxic extracellular vesicles from hiPSCs protect cardiomyocytes from oxidative damage by transferring antioxidant proteins and enhancing Akt/Erk/NRF2 signaling.
Myocytes, Cardiac
/ metabolism
Extracellular Vesicles
/ metabolism
NF-E2-Related Factor 2
/ metabolism
Humans
Proto-Oncogene Proteins c-akt
/ metabolism
Induced Pluripotent Stem Cells
/ metabolism
Signal Transduction
/ drug effects
Antioxidants
/ pharmacology
Oxidative Stress
/ drug effects
Cell Hypoxia
/ drug effects
Apoptosis
/ drug effects
Extracellular Signal-Regulated MAP Kinases
/ metabolism
Animals
Antioxidant response
Cardiomyocyte
Cardiovascular disease
Cell survival
Extracellular vesicles
Heart regeneration
Hypoxia
Induced pluripotent stem cells
NRF2
Journal
Cell communication and signaling : CCS
ISSN: 1478-811X
Titre abrégé: Cell Commun Signal
Pays: England
ID NLM: 101170464
Informations de publication
Date de publication:
09 Jul 2024
09 Jul 2024
Historique:
received:
25
02
2024
accepted:
21
06
2024
medline:
10
7
2024
pubmed:
10
7
2024
entrez:
9
7
2024
Statut:
epublish
Résumé
Stem cell-derived extracellular vesicles (EVs) are an emerging class of therapeutics with excellent biocompatibility, bioactivity and pro-regenerative capacity. One of the potential targets for EV-based medicines are cardiovascular diseases (CVD). In this work we used EVs derived from human induced pluripotent stem cells (hiPSCs; hiPS-EVs) cultured under different oxygen concentrations (21, 5 and 3% O EVs were isolated by ultrafiltration combined with size exclusion chromatography (UF + SEC), followed by characterization by nanoparticle tracking analysis, atomic force microscopy (AFM) and Western blot methods. Liquid chromatography and tandem mass spectrometry coupled with bioinformatic analyses were used to identify differentially enriched proteins in various oxygen conditions. We directly compared the cardioprotective effects of these EVs in an oxygen-glucose deprivation/reoxygenation (OGD/R) model of cardiomyocyte (CM) injury. Using advanced molecular biology, fluorescence microscopy, atomic force spectroscopy and bioinformatics techniques, we investigated intracellular signaling pathways involved in the regulation of cell survival, apoptosis and antioxidant response. The direct effect of EVs on NRF2-regulated signaling was evaluated in CMs following NRF2 inhibition with ML385. We demonstrate that hiPS-EVs derived from physiological hypoxia at 5% O In this work, we demonstrate a superior cardioprotective function of EV-H5 compared to EV-N and EV-H3. Such EVs were most effective in restoring redox balance in stressed CMs, preserving their contractile function and preventing cell death. Our data support the potential use of hiPS-EVs derived from physiological hypoxia, as cell-free therapeutics with regenerative properties for the treatment of cardiac diseases.
Sections du résumé
BACKGROUND
BACKGROUND
Stem cell-derived extracellular vesicles (EVs) are an emerging class of therapeutics with excellent biocompatibility, bioactivity and pro-regenerative capacity. One of the potential targets for EV-based medicines are cardiovascular diseases (CVD). In this work we used EVs derived from human induced pluripotent stem cells (hiPSCs; hiPS-EVs) cultured under different oxygen concentrations (21, 5 and 3% O
METHODS
METHODS
EVs were isolated by ultrafiltration combined with size exclusion chromatography (UF + SEC), followed by characterization by nanoparticle tracking analysis, atomic force microscopy (AFM) and Western blot methods. Liquid chromatography and tandem mass spectrometry coupled with bioinformatic analyses were used to identify differentially enriched proteins in various oxygen conditions. We directly compared the cardioprotective effects of these EVs in an oxygen-glucose deprivation/reoxygenation (OGD/R) model of cardiomyocyte (CM) injury. Using advanced molecular biology, fluorescence microscopy, atomic force spectroscopy and bioinformatics techniques, we investigated intracellular signaling pathways involved in the regulation of cell survival, apoptosis and antioxidant response. The direct effect of EVs on NRF2-regulated signaling was evaluated in CMs following NRF2 inhibition with ML385.
RESULTS
RESULTS
We demonstrate that hiPS-EVs derived from physiological hypoxia at 5% O
CONCLUSIONS
CONCLUSIONS
In this work, we demonstrate a superior cardioprotective function of EV-H5 compared to EV-N and EV-H3. Such EVs were most effective in restoring redox balance in stressed CMs, preserving their contractile function and preventing cell death. Our data support the potential use of hiPS-EVs derived from physiological hypoxia, as cell-free therapeutics with regenerative properties for the treatment of cardiac diseases.
Identifiants
pubmed: 38982464
doi: 10.1186/s12964-024-01722-7
pii: 10.1186/s12964-024-01722-7
doi:
Substances chimiques
NF-E2-Related Factor 2
0
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Antioxidants
0
NFE2L2 protein, human
0
Extracellular Signal-Regulated MAP Kinases
EC 2.7.11.24
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
356Subventions
Organisme : Narodowe Centrum Nauki
ID : UMO-2016/23/D/NZ3/01310
Informations de copyright
© 2024. The Author(s).
Références
Vaduganathan M, Mensah GA, Turco JV, Fuster V, Roth GA. The global burden of cardiovascular diseases and risk: a compass for future health. J Am Coll Cardiol. 2022;80:2361–71. https://doi.org/10.1016/j.jacc.2022.11.005 .
doi: 10.1016/j.jacc.2022.11.005
pubmed: 36368511
Litviňuková M, Talavera-López C, Maatz H, Reichart D, Worth CL, Lindberg EL, Kanda M, Polanski K, Heinig M, Lee M, Nadelmann ER, Roberts K, Tuck L, Fasouli ES, DeLaughter DM, McDonough B, Wakimoto H, Gorham JM, Samari S, Mahbubani KT, Saeb-Parsy K, Patone G, Boyle JJ, Zhang H, Zhang H, Viveiros A, Oudit GY, Bayraktar OA, Seidman JG, Seidman CE, Noseda M, Hubner N, Teichmann SA. Cells of the adult human heart. Nature. 2020;588:466–72. https://doi.org/10.1038/s41586-020-2797-4 .
doi: 10.1038/s41586-020-2797-4
pubmed: 32971526
pmcid: 7681775
Chiong M, Wang ZV, Pedrozo Z, Cao DJ, Troncoso R, Ibacache M, Criollo A, Nemchenko A, Hill JA, Lavandero S. Cardiomyocyte death: mechanisms and translational implications. Cell Death Dis. 2011;2:e244. https://doi.org/10.1038/cddis.2011.130 .
doi: 10.1038/cddis.2011.130
pubmed: 22190003
pmcid: 3252742
Prabhu SD, Frangogiannis NG. The Biological basis for Cardiac Repair after myocardial infarction: from inflammation to Fibrosis. Circ Res. 2016;119:91–112. https://doi.org/10.1161/CIRCRESAHA.116.303577 .
doi: 10.1161/CIRCRESAHA.116.303577
pubmed: 27340270
pmcid: 4922528
van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19:213–28. https://doi.org/10.1038/nrm.2017.125 .
doi: 10.1038/nrm.2017.125
pubmed: 29339798
Théry C, Witwer KW, Aikawa E, Alcaraz MJ, Anderson JD, Andriantsitohaina R, Antoniou A, Arab T, Archer F, Atkin-Smith GK, Ayre DC, Bach JM, Bachurski D, et al. Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the international society for extracellular vesicles and update of the MISEV2014 guidelines. J Extracell Vesicles. 2018;7:1535750. https://doi.org/10.1080/20013078.2018.1535750 .
doi: 10.1080/20013078.2018.1535750
pubmed: 30637094
pmcid: 6322352
Mathieu M, Martin-Jaular L, Lavieu G, Théry C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat Cell Biol. 2019;21:9–17. https://doi.org/10.1038/s41556-018-0250-9 .
doi: 10.1038/s41556-018-0250-9
pubmed: 30602770
de Abreu RC, Fernandes H, da Costa Martins PA, Sahoo S, Emanueli C, Ferreira L. Native and bioengineered extracellular vesicles for cardiovascular therapeutics. Nat Rev Cardiol. 2020;17:685–97. https://doi.org/10.1038/s41569-020-0389-5 .
doi: 10.1038/s41569-020-0389-5
pubmed: 32483304
pmcid: 7874903
Han C, Yang J, Sun J, Qin G. Extracellular vesicles in cardiovascular disease: biological functions and therapeutic implications. Pharmacol Ther. 2022;233:108025. https://doi.org/10.1016/j.pharmthera.2021.108025 .
doi: 10.1016/j.pharmthera.2021.108025
pubmed: 34687770
Khan M, Nickoloff E, Abramova T, Johnson J, Verma SK, Krishnamurthy P, Mackie AR, Vaughan E, Garikipati VN, Benedict C, Ramirez V, Lambers E, Ito A, Gao E, Misener S, Luongo T, Elrod J, Qin G, Houser SR, Koch WJ, Kishore R. Embryonic stem cell-derived exosomes promote endogenous repair mechanisms and enhance cardiac function following myocardial infarction. Circ Res. 2015;117:52–64. https://doi.org/10.1161/CIRCRESAHA.117.305990 .
doi: 10.1161/CIRCRESAHA.117.305990
pubmed: 25904597
pmcid: 4482130
Bobis-Wozowicz S, Kmiotek K, Sekula M, Kedracka-Krok S, Kamycka E, Adamiak M, Jankowska U, Madetko-Talowska A, Sarna M, Bik-Multanowski M, Kolcz J, Boruczkowski D, Madeja Z, Dawn B, Zuba-Surma EK. Human Induced Pluripotent Stem cell-derived microvesicles transmit RNAs and proteins to recipient mature heart cells modulating cell fate and behavior. Stem Cells. 2015;33:2748–61. https://doi.org/10.1002/stem.2078 .
doi: 10.1002/stem.2078
pubmed: 26031404
Adamiak M, Cheng G, Bobis-Wozowicz S, Zhao L, Kedracka-Krok S, Samanta A, Karnas E, Xuan YT, Skupien-Rabian B, Chen X, Jankowska U, Girgis M, Sekula M, Davani A, Lasota S, Vincent RJ, Sarna M, Newell KL, Wang OL, Dudley N, Madeja Z, Dawn B, Zuba-Surma EK. Induced Pluripotent Stem cell (iPSC)-Derived extracellular vesicles are Safer and more effective for Cardiac Repair Than iPSCs. Circ Res. 2018;122:296–309. https://doi.org/10.1161/CIRCRESAHA.117.311769 .
doi: 10.1161/CIRCRESAHA.117.311769
pubmed: 29118058
Louro AF, Paiva MA, Oliveira MR, Kasper KA, Alves PM, Gomes-Alves P, Serra M. Bioactivity and miRNome profiling of native extracellular vesicles in human induced pluripotent stem cell-cardiomyocyte differentiation. Adv Sci (Weinh). 2022;9:e2104296. https://doi.org/10.1002/advs.202104296 .
doi: 10.1002/advs.202104296
pubmed: 35322574
Lozano J, Rai A, Lees JG, Fang H, Claridge B, Lim SY, Greening DW. Scalable generation of Nanovesicles from human-induced pluripotent stem cells for cardiac repair. Int J Mol Sci. 2022;23:14334. https://doi.org/10.3390/ijms232214334 .
doi: 10.3390/ijms232214334
pubmed: 36430812
pmcid: 9696585
Nit K, Tyszka-Czochara M, Bobis-Wozowicz S. Oxygen as a master regulator of human pluripotent stem cell function and metabolism. J Pers Med. 2021;11:905.
doi: 10.3390/jpm11090905
pubmed: 34575682
pmcid: 8466012
Bister N, Pistono C, Huremagic B, Jolkkonen J, Giugno R, Malm T. Hypoxia and extracellular vesicles: a review on methods, vesicular cargo and functions. J Extracell Vesicles. 2020;10:e12002. https://doi.org/10.1002/jev2.12002 .
doi: 10.1002/jev2.12002
pubmed: 33304471
pmcid: 7710128
Yaghoubi S, Najminejad H, Dabaghian M, Karimi MH, Abdollahpour-Alitappeh M, Rad F, Mahi-Birjand M, Mohammadi S, Mohseni F, Sobhani Lari M, Teymouri GH, Rigi Yousofabadi E, Salmani A, Bagheri N. How hypoxia regulate exosomes in ischemic diseases and cancer microenvironment? IUBMB Life. 2020;72:1286–305. https://doi.org/10.1002/iub.2275 .
doi: 10.1002/iub.2275
pubmed: 32196941
Andrade AC, Wolf M, Binder HM, Gomes FG, Manstein F, Ebner-Peking P, Poupardin R, Zweigerdt R, Schallmoser K, Strunk D. Hypoxic conditions promote the angiogenic potential of human induced pluripotent stem cell-derived extracellular vesicles. Int J Mol Sci. 2021;22:3890. https://doi.org/10.3390/ijms22083890 .
doi: 10.3390/ijms22083890
pubmed: 33918735
pmcid: 8070165
Wu Q, Wang J, Tan WLW, Jiang Y, Wang S, Li Q, Yu X, Tan J, Liu S, Zhang P, Tiang Z, Chen Z, Foo RS, Yang HT. Extracellular vesicles from human embryonic stem cell-derived cardiovascular progenitor cells promote cardiac infarct healing through reducing cardiomyocyte death and promoting angiogenesis. Cell Death Dis. 2020;11:354. https://doi.org/10.1038/s41419-020-2508-y .
doi: 10.1038/s41419-020-2508-y
pubmed: 32393784
pmcid: 7214429
Li Q, Xu Y, Lv K, Wang Y, Zhong Z, Xiao C, Zhu K, Ni C, Wang K, Kong M, Li X, Fan Y, Zhang F, Chen Q, Li Y, Li Q, Liu C, Zhu J, Zhong S, Wang J, Chen Y, Zhao J, Zhu D, Wu R, Chen J, Zhu W, Yu H, Ardehali R, Zhang JJ, Wang J, Hu X. Small extracellular vesicles containing mir-486-5p promote angiogenesis after myocardial infarction in mice and nonhuman primates. Sci Transl Med. 2021;13:eabb0202. https://doi.org/10.1126/scitranslmed.abb0202 .
doi: 10.1126/scitranslmed.abb0202
pubmed: 33692129
Balbi C, Lodder K, Costa A, Moimas S, Moccia F, van Herwaarden T, Rosti V, Campagnoli F, Palmeri A, De Biasio P, Santini F, Giacca M, Goumans MJ, Barile L, Smits AM, Bollini S. Reactivating endogenous mechanisms of cardiac regeneration via paracrine boosting using the human amniotic fluid stem cell secretome. Int J Cardiol. 2019;287:87–95. https://doi.org/10.1016/j.ijcard.2019.04.011 .
doi: 10.1016/j.ijcard.2019.04.011
pubmed: 30987834
Paw M, Kusiak AA, Nit K, Litewka JJ, Piejko M, Wnuk D, Sarna M, Fic K, Stopa KB, Hammad R, Barczyk-Woznicka O, Cathomen T, Zuba-Surma E, Madeja Z, Ferdek PE, Bobis-Wozowicz S. Hypoxia enhances anti-fibrotic properties of extracellular vesicles derived from hiPSCs via the miR302b-3p/TGFβ/SMAD2 axis. BMC Med. 2023;21:412. https://doi.org/10.1186/s12916-023-03117-w .
doi: 10.1186/s12916-023-03117-w
pubmed: 37904135
pmcid: 10617123
Sharma P, Wang X, Ming CLC, Vettori L, Figtree G, Boyle A, Gentile C. Considerations for the bioengineering of advanced cardiac in vitro models of myocardial infarction. Small. 2021;17:e2003765. https://doi.org/10.1002/smll.202003765 .
doi: 10.1002/smll.202003765
pubmed: 33464713
Onódi Z, Visnovitz T, Kiss B, Hambalkó S, Koncz A, Ágg B, Váradi B, Tóth VÉ, Nagy RN, Gergely TG, Gergő D, Makkos A, Pelyhe C, Varga N, Reé D, Apáti Á, Leszek P, Kovács T, Nagy N, Ferdinandy P, Buzás EI, Görbe A, Giricz Z, Varga ZV. Systematic transcriptomic and phenotypic characterization of human and murine cardiac myocyte cell lines and primary cardiomyocytes reveals serious limitations and low resemblances to adult cardiac phenotype. J Mol Cell Cardiol. 2022;165:19–30. https://doi.org/10.1016/j.yjmcc.2021.12.007 .
doi: 10.1016/j.yjmcc.2021.12.007
pubmed: 34959166
Chen QM, Maltagliati AJ. Nrf2 at the heart of oxidative stress and cardiac protection. Physiol Genomics. 2018;50:77–97. https://doi.org/10.1152/physiolgenomics.00041.2017 .
doi: 10.1152/physiolgenomics.00041.2017
pubmed: 29187515
Zhang Q, Wang L, Wang S, Cheng H, Xu L, Pei G, Wang Y, Fu C, Jiang Y, He C, Wei Q. Signaling pathways and targeted therapy for myocardial infarction. Signal Transduct Target Ther. 2022;7:78. https://doi.org/10.1038/s41392-022-00925-z .
doi: 10.1038/s41392-022-00925-z
pubmed: 35273164
pmcid: 8913803
Ning H, Chen H, Deng J, Xiao C, Xu M, Shan L, Yang C, Zhang Z. Exosomes secreted by FNDC5-BMMSCs protect myocardial infarction by anti-inflammation and macrophage polarization via NF-κB signaling pathway and Nrf2/HO-1 axis. Stem Cell Res Ther. 2021;12:519. https://doi.org/10.1186/s13287-021-02591-4 .
doi: 10.1186/s13287-021-02591-4
pubmed: 34583757
pmcid: 8480009
Xiao H, Wu D, Yang T, Fu W, Yang L, Hu C, Wan H, Hu X, Zhang C, Wu T. Extracellular vesicles derived from HBMSCs improved myocardial infarction through inhibiting zinc finger antisense 1 and activating Akt/Nrf2/HO-1 pathway. Bioengineered. 2022;13:905–16. https://doi.org/10.1080/21655979.2021.2014389 .
doi: 10.1080/21655979.2021.2014389
pubmed: 34974805
pmcid: 8805844
Xu L, Fan Y, Wu L, Zhang C, Chu M, Wang Y, Zhuang W. Exosomes from bone marrow mesenchymal stem cells with overexpressed Nrf2 inhibit Cardiac Fibrosis in rats with Atrial Fibrillation. Cardiovasc Ther. 2022;2022:2687807. https://doi.org/10.1155/2022/2687807 .
doi: 10.1155/2022/2687807
pubmed: 35360547
pmcid: 8941574
Hou Z, Yang F, Chen K, Wang Y, Qin J, Liang F. hUC-MSC-EV-miR-24 enhances the protective effect of dexmedetomidine preconditioning against myocardial ischemia-reperfusion injury through the KEAP1/Nrf2/HO-1 signaling. Drug Deliv Transl Res. 2024;14:143–57. https://doi.org/10.1007/s13346-023-01388-7 .
doi: 10.1007/s13346-023-01388-7
pubmed: 37540334
Lian X, Zhang J, Azarin SM, Zhu K, Hazeltine LB, Bao X, Hsiao C, Kamp TJ, Palecek SP. Directed cardiomyocyte differentiation from human pluripotent stem cells by modulating Wnt/β-catenin signaling under fully defined conditions. Nat Protoc. 2013;8:162–75. https://doi.org/10.1038/nprot.2012.150 .
doi: 10.1038/nprot.2012.150
pubmed: 23257984
Tohyama S, Hattori F, Sano M, Hishiki T, Nagahata Y, Matsuura T, Hashimoto H, Suzuki T, Yamashita H, Satoh Y, Egashira T, Seki T, Muraoka N, Yamakawa H, Ohgino Y, Tanaka T, Yoichi M, Yuasa S, Murata M, Suematsu M, Fukuda K. Distinct metabolic flow enables large-scale purification of mouse and human pluripotent stem cell-derived cardiomyocytes. Cell Stem Cell. 2013;12:127–37. https://doi.org/10.1016/j.stem.2012.09.013 .
doi: 10.1016/j.stem.2012.09.013
pubmed: 23168164
Zadlo A, Szewczyk G, Sarna M, Kozinska A, Pilat A, Kaczara P, Sarna T. Photoaging of retinal pigment epithelial melanosomes: the effect of photobleaching on morphology and reactivity of the pigment granules. Free Radic Biol Med. 2016;97:320–9. https://doi.org/10.1016/j.freeradbiomed.2016.06.012 .
doi: 10.1016/j.freeradbiomed.2016.06.012
pubmed: 27338854
Wiśniewski JR. Filter-aided sample preparation for proteome analysis. Methods Mol Biol. 2018;1841:3–10. https://doi.org/10.1007/978-1-4939-8695-8_1 .
doi: 10.1007/978-1-4939-8695-8_1
pubmed: 30259475
Goedhart J, Luijsterburg MS. VolcaNoseR is a web app for creating, exploring, labeling and sharing volcano plots. Sci Rep. 2020;10:20560. https://doi.org/10.1038/s41598-020-76603-3 .
doi: 10.1038/s41598-020-76603-3
pubmed: 33239692
pmcid: 7689420
Yu G, He QY. ReactomePA: an R/Bioconductor package for reactome pathway analysis and visualization. Mol Biosyst. 2016;12:477–9. https://doi.org/10.1039/c5mb00663e .
doi: 10.1039/c5mb00663e
pubmed: 26661513
Walter W, Sánchez-Cabo F, Ricote M. GOplot: an R package for visually combining expression data with functional analysis. Bioinformatics. 2015;31:2912–4. https://doi.org/10.1093/bioinformatics/btv300 .
doi: 10.1093/bioinformatics/btv300
pubmed: 25964631
Szklarczyk D, Kirsch R, Koutrouli M, Nastou K, Mehryary F, Hachilif R, Gable AL, Fang T, Doncheva NT, Pyysalo S, Bork P, Jensen LJ, von Mering C. The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res. 2023;51:D638-46. https://doi.org/10.1093/nar/gkac1000 .
doi: 10.1093/nar/gkac1000
pubmed: 36370105
Martens M, Ammar A, Riutta A, Waagmeester A, Slenter DN, Hanspers K, Miller A, Digles R, Lopes D, Ehrhart EN, Dupuis F, Winckers LJ, Coort LA, Willighagen SL, Evelo EL, Pico CT, Kutmon AR. WikiPathways: connecting communities. Nucleic Acids Res. 2021;49:D613-21. https://doi.org/10.1093/nar/gkaa1024 .
doi: 10.1093/nar/gkaa1024
pubmed: 33211851
Sun L, Fan H, Yang L, Shi L, Liu Y. Tyrosol prevents ischemia/reperfusion-induced cardiac injury in H9c2 cells: involvement of ROS, Hsp70, JNK and ERK, and apoptosis. Molecules. 2015;20:3758–375. https://doi.org/10.3390/molecules20033758 .
doi: 10.3390/molecules20033758
pubmed: 25723850
pmcid: 6272375
Paw M, Borek I, Wnuk D, Ryszawy D, Piwowarczyk K, Kmiotek K, Wojcik-Pszczoła KA, Pierzchalska M, Madeja Z, Sanak M, Błyszczuk P, Michalik M, Czyz J. Connexin43 controls the myofibroblastic differentiation of bronchial fibroblasts from patients with asthma. Am J Respir Cell Mol Biol. 2017;57:100–10. https://doi.org/10.1165/rcmb.2015-0255OC .
doi: 10.1165/rcmb.2015-0255OC
pubmed: 28245135
Wang Z, Yao M, Jiang L, Wang L, Yang Y, Wang Q, Qian X, Zhao Y, Qian J. Dexmedetomidine attenuates myocardial ischemia/reperfusion-induced ferroptosis via AMPK/GSK-3beta/Nrf2 axis. Biomed Pharmacother. 2022;154:113572. https://doi.org/10.1016/j.biopha.2022.113572 .
doi: 10.1016/j.biopha.2022.113572
pubmed: 35988428
Koczurkiewicz P, Podolak I, Skrzeczyńska-Moncznik J, Sarna M, Wójcik KA, Ryszawy D, Galanty A, Lasota S, Madeja Z, Czyż J, Michalik M. Triterpene saponosides from Lysimachia ciliata differentially attenuate invasive potential of prostate cancer cells. Chem Biol Interact. 2013;206:6–17. https://doi.org/10.1016/j.cbi.2013.08.003 .
doi: 10.1016/j.cbi.2013.08.003
pubmed: 23954719
Wiktor A, Sarna M, Wnuk D, Sarna T. Lipofuscin-mediated photodynamic stress induces adverse changes in nanomechanical properties of retinal pigment epithelium cells. Sci Rep. 2018;8:17929. https://doi.org/10.1038/s41598-018-36322-2 .
doi: 10.1038/s41598-018-36322-2
pubmed: 30560899
pmcid: 6298986
Heusch G, Andreadou I, Bell R, Bertero E, Botker HE, Davidson SM, Downey J, Eaton P, Ferdinandy P, Gersh BJ, Giacca M, Hausenloy DJ, Ibanez B, Krieg T, Maack C, Schulz R, Sellke F, Shah AM, Thiele H, Yellon DM, Di Lisa F. Health position paper and redox perspectives on reactive oxygen species as signals and targets of cardioprotection. Redox Biol. 2023;67:102894. https://doi.org/10.1016/j.redox.2023.102894 .
doi: 10.1016/j.redox.2023.102894
pubmed: 37839355
pmcid: 10590874
Dewenter M, von der Lieth A, Katus HA, Backs J. Calcium signaling and transcriptional regulation in cardiomyocytes. Circ Res. 2017;121:1000–20. https://doi.org/10.1161/CIRCRESAHA.117.310355 .
doi: 10.1161/CIRCRESAHA.117.310355
pubmed: 28963192
Hashimoto H, Olson EN, Bassel-Duby R. Therapeutic approaches for cardiac regeneration and repair. Nat Rev Cardiol. 2018;15:585–600. https://doi.org/10.1038/s41569-018-0036-6 .
doi: 10.1038/s41569-018-0036-6
pubmed: 29872165
pmcid: 6241533
Claridge B, Lozano J, Poh QH, Greening DW. Development of Extracellular Vesicle therapeutics: challenges, considerations, and opportunities. Front Cell Dev Biol. 2021;9:734720. https://doi.org/10.3389/fcell.2021.734720 .
doi: 10.3389/fcell.2021.734720
pubmed: 34616741
pmcid: 8488228
Roefs MT, Sluijter JPG, Vader P. Extracellular vesicle-associated proteins in tissue repair. Trends Cell Biol. 2020;30:990–1013. https://doi.org/10.1016/j.tcb.2020.09.009 .
doi: 10.1016/j.tcb.2020.09.009
pubmed: 33069512
Gorgun C, Ceresa D, Lesage R, Villa F, Reverberi D, Balbi C, Santamaria S, Cortese K, Malatesta P, Geris L, Quarto R, Tasso R. Dissecting the effects of preconditioning with inflammatory cytokines and hypoxia on the angiogenic potential of mesenchymal stromal cell (MSC)-derived soluble proteins and extracellular vesicles (EVs). Biomaterials. 2021;269:120633. https://doi.org/10.1016/j.biomaterials.2020.120633 .
doi: 10.1016/j.biomaterials.2020.120633
pubmed: 33453634
Zhang L, Wei W, Ai X, Kilic E, Hermann DM, Venkataramani V, Bähr M, Doeppner TR. Extracellular vesicles from hypoxia-preconditioned microglia promote angiogenesis and repress apoptosis in stroke mice via the TGF-β/Smad2/3 pathway. Cell Death Dis. 2021;12:1068. https://doi.org/10.1038/s41419-021-04363-7 .
doi: 10.1038/s41419-021-04363-7
pubmed: 34753919
pmcid: 8578653
Dong L, Wang Y, Zheng T, Pu Y, Ma Y, Qi X, Zhang W, Xue F, Shan Z, Liu J, Wang X, Mao C. Hypoxic hUCMSC-derived extracellular vesicles attenuate allergic airway inflammation and airway remodeling in chronic asthma mice. Stem Cell Res Ther. 2021;12:4. https://doi.org/10.1186/s13287-020-02072-0 .
doi: 10.1186/s13287-020-02072-0
pubmed: 33407872
pmcid: 7789736
Gregorius J, Wang C, Stambouli O, Hussner T, Qi Y, Tertel T, Börger V, Mohamud Yusuf A, Hagemann N, Yin D, Dittrich R, Mouloud Y, Mairinger FD, Magraoui FE, Popa-Wagner A, Kleinschnitz C, Doeppner TR, Gunzer M, Meyer HE, Giebel B, Hermann DM. Small extracellular vesicles obtained from hypoxic mesenchymal stromal cells have unique characteristics that promote cerebral angiogenesis, brain remodeling and neurological recovery after focal cerebral ischemia in mice. Basic Res Cardiol. 2021;116:40. https://doi.org/10.1007/s00395-021-00881-9 .
doi: 10.1007/s00395-021-00881-9
pubmed: 34105014
pmcid: 8187185
Lu Y, Zhang J, Han B, Yu Y, Zhao W, Wu T, Mao Y, Zhang F. Extracellular vesicles DJ-1 derived from hypoxia-conditioned hMSCs alleviate cardiac hypertrophy by suppressing mitochondria dysfunction and preventing ATRAP degradation. Pharmacol Res. 2023;187:106607. https://doi.org/10.1016/j.phrs.2022.106607 .
doi: 10.1016/j.phrs.2022.106607
pubmed: 36509316
Liu W, Li L, Rong Y, Qian D, Chen J, Zhou Z, Luo Y, Jiang D, Cheng L, Zhao S, Kong F, Wang J, Zhou Z, Xu T, Gong F, Huang Y, Gu C, Zhao X, Bai J, Wang F, Zhao W, Zhang L, Li X, Yin G, Fan J, Cai W. Hypoxic mesenchymal stem cell-derived exosomes promote bone fracture healing by the transfer of miR-126. Acta Biomater. 2020;103:196–212. https://doi.org/10.1016/j.actbio.2019.12.020 .
doi: 10.1016/j.actbio.2019.12.020
pubmed: 31857259
Yang Y, Li XB, Li Y, Li TX, Li P, Deng GM, Guo Q, Zhou X, Chen XH. Extracellular vesicles derived from hypoxia-conditioned adipose-derived mesenchymal stem cells enhance Lymphangiogenesis. Cell Transpl. 2022;31:9636897221107536. https://doi.org/10.1177/09636897221107536 .
doi: 10.1177/09636897221107536
Mao CY, Zhang TT, Li DJ, Zhou E, Fan YQ, He Q, Wang CQ, Zhang JF. Extracellular vesicles from hypoxia-preconditioned mesenchymal stem cells alleviates myocardial injury by targeting thioredoxin-interacting protein-mediated hypoxia-inducible factor-1α pathway. World J Stem Cells. 2022;14:183–99. https://doi.org/10.4252/wjsc.v14.i2.183 .
doi: 10.4252/wjsc.v14.i2.183
pubmed: 35432732
pmcid: 8963381
Deng RM, Zhou J. The role of PI3K/AKT signaling pathway in myocardial ischemia-reperfusion injury. Int Immunopharmacol. 2023;123:110714. https://doi.org/10.1016/j.intimp.2023.110714 .
doi: 10.1016/j.intimp.2023.110714
pubmed: 37523969
Barile L, Cervio E, Lionetti V, Milano G, Ciullo A, Biemmi V, Bolis S, Altomare C, Matteucci M, Di Silvestre D, Brambilla F, Fertig TE, Torre T, Demertzis S, Mauri P, Moccetti T, Vassalli G. Cardioprotection by cardiac progenitor cell-secreted exosomes: role of pregnancy-associated plasma protein-A. Cardiovasc Res. 2018;114:992–1005. https://doi.org/10.1093/cvr/cvy055 .
doi: 10.1093/cvr/cvy055
pubmed: 29518183
Gilbert CJ, Longenecker JZ, Accornero F. ERK1/2: an integrator of signals that alters cardiac homeostasis and growth. Biology (Basel). 2021;10:346. https://doi.org/10.3390/biology10040346 .
doi: 10.3390/biology10040346
pubmed: 33923899
Qi D, Young LH. AMPK: energy sensor and survival mechanism in the ischemic heart. Trends Endocrinol Metab. 2015;26:422–9. https://doi.org/10.1016/j.tem.2015.05.010 .
doi: 10.1016/j.tem.2015.05.010
pubmed: 26160707
pmcid: 4697457
Liu L, Jin X, Hu CF, Li R, Zhou Z, Shen CX. Exosomes derived from Mesenchymal stem cells rescue myocardial ischaemia/reperfusion injury by inducing cardiomyocyte autophagy via AMPK and Akt pathways. Cell Physiol Biochem. 2017;43:52–68. https://doi.org/10.1159/000480317 .
doi: 10.1159/000480317
pubmed: 28848091
Gatica D, Chiong M, Lavandero S, Klionsky DJ. The role of autophagy in cardiovascular pathology. Cardiovasc Res. 2022;118:934–50. https://doi.org/10.1093/cvr/cvab158 .
doi: 10.1093/cvr/cvab158
pubmed: 33956077
Kabanov D, Klimovic S, Rotrekl V, Pesl M, Pribyl J. Atomic force spectroscopy is a promising tool to study contractile properties of cardiac cells. Micron. 2022;155:103199. https://doi.org/10.1016/j.micron.2021.103199 .
doi: 10.1016/j.micron.2021.103199
pubmed: 35140035
Tian C, Gao L, Zucker IH. Regulation of Nrf2 signaling pathway in heart failure: role of extracellular vesicles and non-coding RNAs. Free Radic Biol Med. 2021;167:218–31. https://doi.org/10.1016/j.freeradbiomed.2021.03.013 .
doi: 10.1016/j.freeradbiomed.2021.03.013
pubmed: 33741451
pmcid: 8096694
Tian C, Gao L, Zimmerman MC, Zucker IH. Myocardial infarction-induced microRNA-enriched exosomes contribute to cardiac Nrf2 dysregulation in chronic heart failure. Am J Physiol Heart Circ Physiol. 2018;314:H928-39. https://doi.org/10.1152/ajpheart.00602.2017 .
doi: 10.1152/ajpheart.00602.2017
pubmed: 29373037
pmcid: 6008149
Lisi V, Senesi G, Bertola N, Pecoraro M, Bolis S, Gualerzi A, Picciolini S, Raimondi A, Fantini C, Moretti E, Parisi A, Sgrò P, Di Luigi L, Geiger R, Ravera S, Vassalli G, Caporossi D, Balbi C. Plasma-derived extracellular vesicles released after endurance exercise exert cardioprotective activity through the activation of antioxidant pathways. Redox Biol. 2023;63:102737. https://doi.org/10.1016/j.redox.2023.102737 .
doi: 10.1016/j.redox.2023.102737
pubmed: 37236143
pmcid: 10220283
Shah AM, Giacca M. Small non-coding RNA therapeutics for cardiovascular disease. Eur Heart J. 2022;43:4548–61. https://doi.org/10.1093/eurheartj/ehac463 .
doi: 10.1093/eurheartj/ehac463
pubmed: 36106499
pmcid: 9659475
Sun G, Lu Y, Li Y, Mao J, Zhang J, Jin Y, Li Y, Sun Y, Liu L, Li L. miR-19a protects cardiomyocytes from hypoxia/reoxygenation-induced apoptosis via PTEN/PI3K/p-Akt pathway. Biosci Rep. 2017;37(BSR20170899). https://doi.org/10.1042/BSR20170899 .
Tian Y, Liu Y, Wang T, Zhou N, Kong J, Chen L, Snitow M, Morley M, Li D, Petrenko N, Zhou S, Lu M, Gao E, Koch WJ, Stewart KM, Morrisey EE. A microRNA-Hippo pathway that promotes cardiomyocyte proliferation and cardiac regeneration in mice. Sci Transl Med. 2015;7:279ra38. https://doi.org/10.1126/scitranslmed.3010841 .
doi: 10.1126/scitranslmed.3010841
pubmed: 25787764
pmcid: 6295313