https://doi.org/10.4081/ejh.2024.4040
Adipose mesenchymal stem cells-derived extracellular vesicles exert their preferential action in damaged central sites of SOD1 mice rather than peripherally
Submitted: 19 April 2024
Accepted: 10 June 2024
Published: 4 July 2024
Accepted: 10 June 2024
Abstract Views: 523
PDF: 251
HTML: 3
HTML: 3
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder involving motor neuron (MN) loss in the motor cortex, brainstem and spinal cord leading to progressive paralysis and death. Due to the pathogenetic complexity, there are no effective therapies available. In this context the use of mesenchymal stem cells and their vesicular counterpart is an emerging therapeutic strategy to counteract neurodegeneration. The extracellular vesicles derived from adipose stem cells (ASC-EVs) recapitulate and ameliorate the neuroprotective effect of stem cells and, thanks to their small dimensions, makes their use suitable to develop novel therapeutic approaches for neurodegenerative diseases as ALS. Here we investigate a therapeutic regimen of ASC-EVs injection in SOD1(G93A) mice, the most widely used murine model of ALS. Repeated intranasal administrations of high doses of ASC-EVs were able to ameliorate motor performance of injected SOD1(G93A) mice at the early stage of the disease and produce a significant improvement at the end-stage in the lumbar MNs rescue. Moreover, ASC-EVs preserve the structure of neuromuscular junction without counteracting the muscle atrophy. The results indicate that the intranasal ASC-EVs administration acts in central nervous system sites rather than at peripheral level in SOD1(G93A) mice. These considerations allow us to identify future applications of ASC-EVs that involve different targets simultaneously to maximize the clinical and neuropathological outcomes in ALS in vivo models.
Hardiman O, Al-Chalabi A, Chio A, Corr EM, Logroscino G, Robberecht W, et al. Amyotrophic lateral sclerosis. Nat Rev Dis Primers 2017;3:17085.
DOI: https://doi.org/10.1038/nrdp.2017.71
Tzeplaeff L, Wilfling S, Requardt MV, Herdick M. Current state and future directions in the therapy of ALS. Cells 2023;12:1523.
DOI: https://doi.org/10.3390/cells12111523
Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, Hentati A, et al. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993;362:59-62.
DOI: https://doi.org/10.1038/362059a0
Zou ZY, Zhou ZR, Che CH, Liu CY, He RL, Huang HP. Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2017;88:540-9.
DOI: https://doi.org/10.1136/jnnp-2016-315018
Ciuro M, Sangiorgio M, Leanza G, Gulino R. A Meta-analysis study of SOD1-mutant mouse models of ALS to analyse the determinants of disease onset and progression. Int J Mol Sc. 2022;24:216.
DOI: https://doi.org/10.3390/ijms24010216
Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 1994;264:1772-5.
DOI: https://doi.org/10.1126/science.8209258
Aishwarya R, Abdullah CS, Remex NS, Nitu S, Hartman B, King J, et al. Pathological sequelae associated with skeletal muscle atrophy and histopathology in G93A*SOD1 mice. Muscles 2023;2:51-74.
DOI: https://doi.org/10.3390/muscles2010006
Maragakis NJ, Rothstein JD. Mechanisms of disease: astrocytes in neurodegenerative disease. Nat Clin Pract Neurol 2006;2:679-89.
DOI: https://doi.org/10.1038/ncpneuro0355
Perrin S. Preclinical research: make mouse studies work. Nature 2014;507:423-5.
DOI: https://doi.org/10.1038/507423a
Philips T, Rothstein JD. Rodent models of amyotrophic lateral sclerosis. Curr Protoc Pharmacol 2015;69:5.67.1-5.67.21.
DOI: https://doi.org/10.1002/0471141755.ph0567s69
Gugliandolo A, Bramanti P, Mazzon E. Mesenchymal stem cells: a potential therapeutic approach for amyotrophic lateral sclerosis? Stem Cells Int 2019;2019:3675627.
DOI: https://doi.org/10.1155/2019/3675627
Marconi S, Bonaconsa M, Scambi I, Squintani GM, Rui W, Turano E, et al. Systemic treatment with adipose-derived mesenchymal stem cells ameliorates clinical and pathological features in the amyotrophic lateral sclerosis murine model. Neuroscience 2013;248:333-43.
DOI: https://doi.org/10.1016/j.neuroscience.2013.05.034
Shalaby SM, Sabbah NA, Saber T, Abdel Hamid RA. Adipose-derived mesenchymal stem cells modulate the immune response in chronic experimental autoimmune encephalomyelitis model. IUBMB Life 2016;68:106-15.
DOI: https://doi.org/10.1002/iub.1469
Gu Z, Akiyama K, Ma X, Zhang H, Feng X, Yao G, et al. Transplantation of umbilical cord mesenchymal stem cells alleviates lupus nephritis in MRL/lpr mice. Lupus 2010;19:1502-14.
DOI: https://doi.org/10.1177/0961203310373782
Bonafede R, Brandi J, Manfredi M, Scambi I, Schiaffino L, Merigo F, et al. The anti-apoptotic effect of ASC-exosomes in an in vitro ALS model and their proteomic analysis. Cells 2019;8:1087.
DOI: https://doi.org/10.3390/cells8091087
Bonafede R, Scambi I, Peroni D, Potrich V, Boschi F, Benati D, et al. Exosome derived from murine adipose-derived stromal cells: neuroprotective effect on in vitro model of amyotrophic lateral sclerosis. Exp Cell Res 2016;340:150-8.
DOI: https://doi.org/10.1016/j.yexcr.2015.12.009
Bonafede R, Turano E, Scambi I, Busato A, Bontempi P, Virla F, et al. ASC-exosomes ameliorate the disease progression in SOD1(G93A) murine model underlining their potential therapeutic use in human ALS. Int J Mol Sci 2020;21:3651.
DOI: https://doi.org/10.3390/ijms21103651
Giunti D, Marini C, Parodi B, Usai C, Milanese M, Bonanno G, et al. Role of miRNAs shuttled by mesenchymal stem cell-derived small extracellular vesicles in modulating neuroinflammation. Sci Rep 2021;11:1740.
DOI: https://doi.org/10.1038/s41598-021-81039-4
Provenzano F, Nyberg S, Giunti D, Torazza C, Parodi B, Bonifacino T, et al. Micro-RNAs shuttled by extracellular vesicles secreted from mesenchymal stem cells dampen astrocyte pathological activation and support neuroprotection in in-vitro models of ALS. Cells 2022;11:3923.
DOI: https://doi.org/10.3390/cells11233923
Gnecchi M, Danieli P, Malpasso G, Ciuffreda MC. Paracrine mechanisms of mesenchymal stem cells in tissue repair. Methods Mol Biol 2016;1416:123-46.
DOI: https://doi.org/10.1007/978-1-4939-3584-0_7
Melling GE, Carollo E, Conlon R, Simpson JC, Carter DRF. The Challenges and possibilities of extracellular vesicles as therapeutic vehicles. Eur J Pharm Biopharm 2019;144:50-6.
DOI: https://doi.org/10.1016/j.ejpb.2019.08.009
Witwer KW, Théry C. Extracellular vesicles or exosomes? On primacy, precision, and popularity influencing a choice of nomenclature. J Extracell Vesicles 2019;8:1648167.
DOI: https://doi.org/10.1080/20013078.2019.1648167
Peroni D, Scambi I, Pasini A, Lisi V, Bifari F, Krampera M, et al. Stem molecular signature of adipose-derived stromal cells. Exp Cell Res 2008;314:603-15.
DOI: https://doi.org/10.1016/j.yexcr.2007.10.007
Constantin G, Marconi S, Rossi B, Angiari S, Calderan L, Anghileri E, et al. Adipose-derived mesenchymal stem cells ameliorate chronic experimental autoimmune encephalomyelitis. Stem Cells 2009;27:2624-35.
DOI: https://doi.org/10.1002/stem.194
Pascua-Maestro R, Gonzalez E, Lillo C, Ganfornina MD, Falcon-Perez JM, Sanchez D. Extracellular vesicles secreted by astroglial cells transport apolipoprotein D to neurons and mediate neuronal survival upon oxidative stress. Front Cell Neurosci 2018;12:526.
DOI: https://doi.org/10.3389/fncel.2018.00526
Royo F, Moreno L, Mleczko J, Palomo L, Gonzalez E, Cabrera D, et al. Hepatocyte-secreted extracellular vesicles modify blood metabolome and endothelial function by an arginase-dependent mechanism. Sci Rep 2017;7:42798.
DOI: https://doi.org/10.1038/srep42798
Bankole O, Scambi I, Parrella E, Muccilli M, Bonafede R, Turano E, et al. Beneficial and sexually dimorphic response to combined HDAC inhibitor valproate and AMPK/SIRT1 Pathway activator resveratrol in the treatment of ALS mice. Int J Mol Sci 2022;23:1047.
DOI: https://doi.org/10.3390/ijms23031047
Zabeo D, Cvjetkovic A, Lasser C, Schorb M, Lotvall J, Hoog JL. Exosomes purified from a single cell type have diverse morphology. J Extracell Vesicles 2017;6:1329476.
DOI: https://doi.org/10.1080/20013078.2017.1329476
Emelyanov A, Shtam T, Kamyshinsky R, Garaeva L, Verlov N, Miliukhina I, et al. Cryo-electron microscopy of extracellular vesicles from cerebrospinal fluid. PLoS One 2020;15:e0227949.
DOI: https://doi.org/10.1371/journal.pone.0227949
Las Heras K, Royo F, Garcia-Vallicrosa C, Igartua M, Santos-Vizcaino E, Falcon-Perez JM, et al. Extracellular vesicles from hair follicle-derived mesenchymal stromal cells: isolation, characterization and therapeutic potential for chronic wound healing. Stem Cell Res Ther 2022;13:147.
DOI: https://doi.org/10.1186/s13287-022-02824-0
Doyle LM, Wang MZ. Overview of extracellular vesicles, their origin, composition, purpose, and methods for exosome isolation and analysis. Cells 2019;8:727.
DOI: https://doi.org/10.3390/cells8070727
Kowal J, Arras G, Colombo M, Jouve M, Morath JP, Primdal-Bengtson B, et al. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc Natl Acad Sci USA 2016;113:E968-77.
DOI: https://doi.org/10.1073/pnas.1521230113
Fang T, Al Khleifat A, Meurgey JH, Jones A, Leigh PN, Bensimon G, et al. Stage at which riluzole treatment prolongs survival in patients with amyotrophic lateral sclerosis: a retrospective analysis of data from a dose-ranging study. Lancet Neurol 2018;17:416-22.
DOI: https://doi.org/10.1016/S1474-4422(18)30054-1
Staff NP, Jones DT, Singer W. Mesenchymal stromal cell therapies for neurodegenerative diseases. Mayo Clin Proc 2019;94:892-905.
DOI: https://doi.org/10.1016/j.mayocp.2019.01.001
Swindell WR, Kruse CPS, List EO, Berryman DE, Kopchick JJ. ALS blood expression profiling identifies new biomarkers, patient subgroups, and evidence for neutrophilia and hypoxia. J Transl Med 2019;17:170.
DOI: https://doi.org/10.1186/s12967-019-1909-0
Garbuzova-Davis S, Borlongan CV. Stem cell-derived extracellular vesicles as potential mechanism for repair of microvascular damage within and outside of the central nervous system in amyotrophic lateral sclerosis: perspective schema. Neural Regen Res 2021;16:680-1.
DOI: https://doi.org/10.4103/1673-5374.294337
Lee M, Ban JJ, Kim KY, Jeon GS, Im W, Sung JJ, et al. Adipose-derived stem cell exosomes alleviate pathology of amyotrophic lateral sclerosis in vitro. Biochem Biophys Res Commun 2016;479:434-9.
DOI: https://doi.org/10.1016/j.bbrc.2016.09.069
Zeng ZL, Xie H. Mesenchymal stem cell-derived extracellular vesicles: a possible therapeutic strategy for orthopaedic diseases: a narrative review. Biomater Transl 2022;3:175-87.
Ciervo Y, Ning K, Jun X, Shaw PJ, Mead RJ. Advances, challenges and future directions for stem cell therapy in amyotrophic lateral sclerosis. Mol Neurodegener 2017;12:85.
DOI: https://doi.org/10.1186/s13024-017-0227-3
Jin J, Sklar GE, Min Sen Oh V, Chuen Li S. Factors affecting therapeutic compliance: A review from the patient's perspective. Ther Clin Risk Manag 2008;4:269-86.
DOI: https://doi.org/10.2147/TCRM.S1458
Gupta D, Zickler AM, El Andaloussi S. Dosing extracellular vesicles. Adv Drug Deliv Rev 2021;178:113961.
DOI: https://doi.org/10.1016/j.addr.2021.113961
Cheng X, Zhang G, Zhang L, Hu Y, Zhang K, Sun X, et al. Mesenchymal stem cells deliver exogenous miR-21 via exosomes to inhibit nucleus pulposus cell apoptosis and reduce intervertebral disc degeneration. J Cell Mol Med 2018;22:261-76.
DOI: https://doi.org/10.1111/jcmm.13316
Gschwendtberger T, Thau-Habermann N, von der Ohe J, Luo T, Hass R, Petri S. Protective effects of EVs/exosomes derived from permanently growing human MSC on primary murine ALS motor neurons. Neurosci Lett 2023;816:137493.
DOI: https://doi.org/10.1016/j.neulet.2023.137493
Alhindi A, Boehm I, Chaytow H. Small junction, big problems: Neuromuscular junction pathology in mouse models of amyotrophic lateral sclerosis (ALS). J Anat 2022;241:1089-107.
DOI: https://doi.org/10.1111/joa.13463
Schaefer AM, Sanes JR, Lichtman JW. A compensatory subpopulation of motor neurons in a mouse model of amyotrophic lateral sclerosis. J Comp Neurol 2005;490:209-19.
DOI: https://doi.org/10.1002/cne.20620
Dupuis L, Loeffler JP. Neuromuscular junction destruction during amyotrophic lateral sclerosis: insights from transgenic models. Curr Opin Pharmacol 2009;9:341-6.
DOI: https://doi.org/10.1016/j.coph.2009.03.007
Shefner JM, Musaro A, Ngo ST, Lunetta C, Steyn FJ, Robitaille R, et al. Skeletal muscle in amyotrophic lateral sclerosis. Brain 2023;146:4425-36.
DOI: https://doi.org/10.1093/brain/awad202
Dadon-Nachum M, Melamed E, Offen D. The "dying-back" phenomenon of motor neurons in ALS. J Mol Neurosci 2011;43:470-7.
DOI: https://doi.org/10.1007/s12031-010-9467-1
Eisen A, Vucic S, Mitsumoto H. History of ALS and the competing theories on pathogenesis: IFCN handbook chapter. Clin Neurophysiol Pract 2024;9:1-12.
DOI: https://doi.org/10.1016/j.cnp.2023.11.004
Bottero V, Santiago JA, Quinn JP, Potashkin JA. Key disease mechanisms linked to amyotrophic lateral sclerosis in spinal cord motor neurons. Front Mol Neurosci 2022;15:825031.
DOI: https://doi.org/10.3389/fnmol.2022.825031
Maranzano A, Verde F, Colombo E, Poletti B, Doretti A, Bonetti R, et al. Regional spreading pattern is associated with clinical phenotype in amyotrophic lateral sclerosis. Brain 2023;146:4105-16.
DOI: https://doi.org/10.1093/brain/awad129
Martínez-Muriana A, Pastor D, Mancuso R, Rando A, Osta R, Martínez S, et al. Combined intramuscular and intraspinal transplant of bone marrow cells improves neuromuscular function in the SOD1(G93A) mice. Stem Cell Res Ther 2020;11:53.
DOI: https://doi.org/10.1186/s13287-020-1573-6
Řehořová M, Vargová I, Forostyak S, Vacková I, Turnovcová K, Kupcová Skalníková H, et al. A combination of intrathecal and intramuscular application of human mesenchymal stem cells partly reduces the activation of necroptosis in the spinal cord of SOD1(G93A) rats. Stem Cells Transl Med 2019;8:535-47.
DOI: https://doi.org/10.1002/sctm.18-0223
Ethics Approval
the study was approved by the University of Verona Committee on Animal Research and by the Italian Ministry of Health (ministerial authorization number 56DC9.72)Supporting Agencies
Polish National Agency for Academic ExchangeHow to Cite
Turano, E., Virla, F., Scambi, I., Dabrowska, S., Bankole, O., & Mariotti, R. (2024). Adipose mesenchymal stem cells-derived extracellular vesicles exert their preferential action in damaged central sites of SOD1 mice rather than peripherally. European Journal of Histochemistry, 68(3). https://doi.org/10.4081/ejh.2024.4040
Copyright (c) 2024 The Author(s)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.
Similar Articles
- Kazuhiko Hashimoto, Yutaka Oda, Koichi Nakagawa, Terumasa Ikeda, Kazuhiro Ohtani, Masao Akagi, LOX-1 deficient mice show resistance to zymosan-induced arthritis , European Journal of Histochemistry: Vol. 62 No. 1 (2018)
- Claudia Frick, Hanna Luisa Martin, Johanna Bruder, Kerstin Lang, Heinz Breer, Topographic distribution pattern of morphologically different G cells in the murine antral mucosa , European Journal of Histochemistry: Vol. 61 No. 3 (2017)
- Nan Li, Xue Fan, Lihong Liu, Yanbing Liu, Therapeutic effects of human umbilical cord mesenchymal stem cell-derived extracellular vesicles on ovarian functions through the PI3K/Akt cascade in mice with premature ovarian failure , European Journal of Histochemistry: Vol. 67 No. 3 (2023)
- Tadashi Yasui, Kenya Miyata, Chie Nakatsuka, Azuma Tsukise, Hiroshi Gomi, Morphological and histochemical characterization of the secretory epithelium in the canine lacrimal gland , European Journal of Histochemistry: Vol. 65 No. 4 (2021)
- Y. Dong, C. Yang, Z. Wang, Z. Qin, J. Cao, Y. Chen, The injury of serotonin on intestinal epithelium cell renewal of weaned diarrhoea mice , European Journal of Histochemistry: Vol. 60 No. 4 (2016)
- H. Zhang, X. Guo, S. Zhong, T. Ge, S. Peng, P. Yu, Z. Zhou, Heterogeneous vesicles in mucous epithelial cells of posterior esophagus of Chinese giant salamander (Andrias davidianus) , European Journal of Histochemistry: Vol. 59 No. 3 (2015)
- Alimu Keremu, Pazila Aila, Aikebaier Tusun , Maimaitiaili Abulikemu, Xiaoguang Zou, Extracellular vesicles from bone mesenchymal stem cells transport microRNA-206 into osteosarcoma cells and target NRSN2 to block the ERK1/2-Bcl-xL signaling pathway , European Journal of Histochemistry: Vol. 66 No. 3 (2022)
- S. Huang, S. Guo, F. Guo, Q. Yang, X. Xiao, M. Murata, S. Ohnishi, S. Kawanishi, N. Ma, CD44v6 expression in human skin keratinocytes as a possible mechanism for carcinogenesis associated with chronic arsenic exposure , European Journal of Histochemistry: Vol. 57 No. 1 (2013)
- F. Merigo, F. Boschi, C. Lasconi, D. Benati, A. Sbarbati, Molecules implicated in glucose homeostasis are differentially expressed in the trachea of lean and obese Zucker rats , European Journal of Histochemistry: Vol. 60 No. 1 (2016)
- Wenjing Liu, Shanshan Ming, Xiaobing Zhao, Xin Zhu, Yuxiang Gong, Developmental expression of high-mobility group box 1 (HMGB1) in the mouse cochlea , European Journal of Histochemistry: Vol. 67 No. 3 (2023)
You may also start an advanced similarity search for this article.
