The Anti-Apoptotic Effect of ASC-Exosomes in an In Vitro ALS Model and Their Proteomic Analysis

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2019 Sep 22

PMID 31540100

Citations 42

Authors

Roberta Bonafede

Jessica Brandi

Marcello Manfredi

Ilaria Scambi

Lorenzo Schiaffino

Flavia Merigo

Ermanna Turano

Bruno Bonetti

Emilio Marengo

Daniela Cecconi

Raffaella Mariotti

Affiliations

Soon will be listed here.

Abstract

Stem cell therapy represents a promising approach in the treatment of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). The beneficial effect of stem cells is exerted by paracrine mediators, as exosomes, suggesting a possible potential use of these extracellular vesicles as non-cell based therapy. We demonstrated that exosomes isolated from adipose stem cells (ASC) display a neuroprotective role in an in vitro model of ALS. Moreover, the internalization of ASC-exosomes by the cells was shown and the molecules and the mechanisms by which exosomes could exert their beneficial effect were addressed. We performed for the first time a comprehensive proteomic analysis of exosomes derived from murine ASC. We identified a total of 189 proteins and the shotgun proteomics analysis revealed that the exosomal proteins are mainly involved in cell adhesion and negative regulation of the apoptotic process. We correlated the protein content to the anti-apoptotic effect of exosomes observing a downregulation of pro-apoptotic proteins Bax and cleaved caspase-3 and upregulation of anti-apoptotic protein Bcl-2 α, in an in vitro model of ALS after cell treatment with exosomes. Overall, this study shows the neuroprotective effect of ASC-exosomes after their internalization and their global protein profile, that could be useful to understand how exosomes act, demonstrating that they can be employed as therapy in neurodegenerative diseases.

Citing Articles

Stem cell therapy: A promising therapeutic approach for skeletal muscle atrophy.

Wang Y, Chen Z, Shen Y, Wang K, Han Y, Zhang C World J Stem Cells. 2025; 17(2):98693.

PMID: 40061264 PMC: 11885941. DOI: 10.4252/wjsc.v17.i2.98693.

Neuroprotective effect of NSCs-derived extracellular vesicles in Parkinson's disease models.

Diaz Reyes M, Gatti S, Delgado Ocana S, Ortega H, Banchio C Sci Rep. 2025; 15(1):6092.

PMID: 39971975 PMC: 11839983. DOI: 10.1038/s41598-025-87238-7.

Exosomes derived from bone marrow mesenchymal stem cells ameliorate chemotherapeutically induced damage in rats' parotid salivary gland.

Zakaria A, Sultan N, Nabil N, Elgamily M Oral Maxillofac Surg. 2025; 29(1):39.

PMID: 39821446 PMC: 11742274. DOI: 10.1007/s10006-025-01331-9.

Secretome - the role of extracellular vesicles in the pathogenesis and therapy of neurodegenerative diseases.

Sulek A Postep Psychiatr Neurol. 2024; 33(3):147-162.

PMID: 39678458 PMC: 11635433. DOI: 10.5114/ppn.2024.144686.

Extracellular vesicles: biological mechanisms and emerging therapeutic opportunities in neurodegenerative diseases.

Wang L, Zhang X, Yang Z, Wang B, Gong H, Zhang K Transl Neurodegener. 2024; 13(1):60.

PMID: 39643909 PMC: 11622582. DOI: 10.1186/s40035-024-00453-6.

References

Farinazzo A, Turano E, Marconi S, Bistaffa E, Bazzoli E, Bonetti B . Murine adipose-derived mesenchymal stromal cell vesicles: in vitro clues for neuroprotective and neuroregenerative approaches. Cytotherapy. 2015; 17(5):571-8. DOI: 10.1016/j.jcyt.2015.01.005. View

Pasinelli P, Belford M, Lennon N, Bacskai B, Hyman B, Trotti D . Amyotrophic lateral sclerosis-associated SOD1 mutant proteins bind and aggregate with Bcl-2 in spinal cord mitochondria. Neuron. 2004; 43(1):19-30. DOI: 10.1016/j.neuron.2004.06.021. View

Weydert C, Cullen J . Measurement of superoxide dismutase, catalase and glutathione peroxidase in cultured cells and tissue. Nat Protoc. 2010; 5(1):51-66. PMC: 2830880. DOI: 10.1038/nprot.2009.197. View

Padhi A, Narain P, Dave U, Satija R, Patir A, Gomes J . Insights into the role of ribonuclease 4 polymorphisms in amyotrophic lateral sclerosis. J Biomol Struct Dyn. 2017; 37(1):116-130. DOI: 10.1080/07391102.2017.1419147. View

Cvijetic S, Bortolotto V, Manfredi M, Ranzato E, Marengo E, Salem R . Cell autonomous and noncell-autonomous role of NF-κB p50 in astrocyte-mediated fate specification of adult neural progenitor cells. Glia. 2016; 65(1):169-181. DOI: 10.1002/glia.23085. View

Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A . ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics. 2009; 25(8):1091-3. PMC: 2666812. DOI: 10.1093/bioinformatics/btp101. View

Xin H, Li Y, Cui Y, Yang J, Zhang Z, Chopp M . Systemic administration of exosomes released from mesenchymal stromal cells promote functional recovery and neurovascular plasticity after stroke in rats. J Cereb Blood Flow Metab. 2013; 33(11):1711-5. PMC: 3824189. DOI: 10.1038/jcbfm.2013.152. View

Kourembanas S . Exosomes: vehicles of intercellular signaling, biomarkers, and vectors of cell therapy. Annu Rev Physiol. 2014; 77:13-27. DOI: 10.1146/annurev-physiol-021014-071641. View

Amutha P, Rajkumar T . Role of Insulin-like Growth Factor, Insulin-like Growth Factor Receptors, and Insulin-like Growth Factor-binding Proteins in Ovarian Cancer. Indian J Med Paediatr Oncol. 2017; 38(2):198-206. PMC: 5582559. DOI: 10.4103/ijmpo.ijmpo_3_17. View

10.

Vincent A, Feldman E . Control of cell survival by IGF signaling pathways. Growth Horm IGF Res. 2002; 12(4):193-7. DOI: 10.1016/s1096-6374(02)00017-5. View

11.

Baglio S, Pegtel D, Baldini N . Mesenchymal stem cell secreted vesicles provide novel opportunities in (stem) cell-free therapy. Front Physiol. 2012; 3:359. PMC: 3434369. DOI: 10.3389/fphys.2012.00359. View

12.

Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J . STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2014; 43(Database issue):D447-52. PMC: 4383874. DOI: 10.1093/nar/gku1003. View

13.

Sau D, De Biasi S, Vitellaro-Zuccarello L, Riso P, Guarnieri S, Porrini M . Mutation of SOD1 in ALS: a gain of a loss of function. Hum Mol Genet. 2007; 16(13):1604-18. DOI: 10.1093/hmg/ddm110. View

14.

Tagoug I, Sauty de Chalon A, Dumontet C . Inhibition of IGF-1 signalling enhances the apoptotic effect of AS602868, an IKK2 inhibitor, in multiple myeloma cell lines. PLoS One. 2011; 6(7):e22641. PMC: 3143180. DOI: 10.1371/journal.pone.0022641. View

15.

Lewis C, Suzuki M . Therapeutic applications of mesenchymal stem cells for amyotrophic lateral sclerosis. Stem Cell Res Ther. 2014; 5(2):32. PMC: 4035799. DOI: 10.1186/scrt421. View

16.

Jarmalaviciute A, Tunaitis V, Pivoraite U, Venalis A, Pivoriunas A . Exosomes from dental pulp stem cells rescue human dopaminergic neurons from 6-hydroxy-dopamine-induced apoptosis. Cytotherapy. 2015; 17(7):932-9. DOI: 10.1016/j.jcyt.2014.07.013. View

17.

Li M, Ona V, Chen M, Kaul M, Tenneti L, Zhang X . Functional role and therapeutic implications of neuronal caspase-1 and -3 in a mouse model of traumatic spinal cord injury. Neuroscience. 2000; 99(2):333-42. DOI: 10.1016/s0306-4522(00)00173-1. View

18.

Martin L, Price A, Kaiser A, Shaikh A, Liu Z . Mechanisms for neuronal degeneration in amyotrophic lateral sclerosis and in models of motor neuron death (Review). Int J Mol Med. 1999; 5(1):3-13. DOI: 10.3892/ijmm.5.1.3. View

19.

Yoshihara T, Ishigaki S, Yamamoto M, Liang Y, Niwa J, Takeuchi H . Differential expression of inflammation- and apoptosis-related genes in spinal cords of a mutant SOD1 transgenic mouse model of familial amyotrophic lateral sclerosis. J Neurochem. 2002; 80(1):158-67. DOI: 10.1046/j.0022-3042.2001.00683.x. View

20.

Dennis Jr G, Sherman B, Hosack D, Yang J, Gao W, Lane H . DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol. 2003; 4(5):P3. View