Mesenchymal Stem Cell-Derived Extracellular Vesicles Protect Human Corneal Endothelial Cells from Endoplasmic Reticulum Stress-Mediated Apoptosis

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2021 Jun 2

PMID 34066474

Citations 22

Authors

Lola Buono

Simona Scalabrin

Marco De Iuliis

Adele Tanzi

Cristina Grange

Marta Tapparo

Raffaele Nuzzi

Benedetta Bussolati

Affiliations

Soon will be listed here.

Abstract

Corneal endothelial dystrophy is a relevant cause of vision loss and corneal transplantation worldwide. In the present study, we analyzed the effect of mesenchymal stem cell (MSC)-derived extracellular vesicles (MSC-EVs) in an in vitro model of corneal dystrophy, characterized by endoplasmic reticulum stress. The effects of MSC-EVs were compared with those of serum-derived EVs, reported to display a pro-angiogenic activity. MSC-EVs were able to induce a significant down-regulation of the large majority of endoplasmic reticulum stress-related genes in human corneal endothelial cells after exposure to serum deprivation and tunicamycin. In parallel, they upregulated the Akt pathway and limited caspase-3 activation and apoptosis. At variance, the effect of the serum EVs was mainly limited to Akt phosphorylation, with minimal or absent effects on endoplasmic reticulum stress modulation and apoptosis prevention. The effects of MSC-EVs were correlated to the transfer of numerous endoplasmic reticulum (ER)-stress targeting miRNAs to corneal endothelial cells. These data suggest a potential therapeutic effect of MSC-EVs for corneal endothelial endoplasmic reticulum stress, a major player in corneal endothelial dystrophy.

Citing Articles

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References

Camussi G, Deregibus M, Cantaluppi V . Role of stem-cell-derived microvesicles in the paracrine action of stem cells. Biochem Soc Trans. 2013; 41(1):283-7. DOI: 10.1042/BST20120192. View

Gain P, Jullienne R, He Z, Aldossary M, Acquart S, Cognasse F . Global Survey of Corneal Transplantation and Eye Banking. JAMA Ophthalmol. 2015; 134(2):167-73. DOI: 10.1001/jamaophthalmol.2015.4776. View

Duan Q, Chen C, Yang L, Li N, Gong W, Li S . MicroRNA regulation of unfolded protein response transcription factor XBP1 in the progression of cardiac hypertrophy and heart failure in vivo. J Transl Med. 2015; 13:363. PMC: 4647486. DOI: 10.1186/s12967-015-0725-4. View

Mead B, Tomarev S . Bone Marrow-Derived Mesenchymal Stem Cells-Derived Exosomes Promote Survival of Retinal Ganglion Cells Through miRNA-Dependent Mechanisms. Stem Cells Transl Med. 2017; 6(4):1273-1285. PMC: 5442835. DOI: 10.1002/sctm.16-0428. View

Camussi G, Deregibus M, Bruno S, Cantaluppi V, Biancone L . Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney Int. 2010; 78(9):838-48. DOI: 10.1038/ki.2010.278. View

Kovalenko O, Yang X, Kolesnikova T, Hemler M . Evidence for specific tetraspanin homodimers: inhibition of palmitoylation makes cysteine residues available for cross-linking. Biochem J. 2003; 377(Pt 2):407-17. PMC: 1223880. DOI: 10.1042/BJ20031037. View

Brossa A, Tapparo M, Fonsato V, Papadimitriou E, Delena M, Camussi G . Coincubation as miR-Loading Strategy to Improve the Anti-Tumor Effect of Stem Cell-Derived EVs. Pharmaceutics. 2021; 13(1). PMC: 7826638. DOI: 10.3390/pharmaceutics13010076. View

Fusakio M, Willy J, Wang Y, Mirek E, Al Baghdadi R, Adams C . Transcription factor ATF4 directs basal and stress-induced gene expression in the unfolded protein response and cholesterol metabolism in the liver. Mol Biol Cell. 2016; 27(9):1536-51. PMC: 4850040. DOI: 10.1091/mbc.E16-01-0039. View

Giebel B, Kordelas L, Borger V . Clinical potential of mesenchymal stem/stromal cell-derived extracellular vesicles. Stem Cell Investig. 2017; 4:84. PMC: 5676188. DOI: 10.21037/sci.2017.09.06. View

10.

Bruno S, Grange C, Deregibus M, Calogero R, Saviozzi S, Collino F . Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol. 2009; 20(5):1053-67. PMC: 2676194. DOI: 10.1681/ASN.2008070798. View

11.

Kim E, Toyono T, Berlinicke C, Zack D, Jurkunas U, Usui T . Screening and Characterization of Drugs That Protect Corneal Endothelial Cells Against Unfolded Protein Response and Oxidative Stress. Invest Ophthalmol Vis Sci. 2017; 58(2):892-900. PMC: 5295784. DOI: 10.1167/iovs.16-20147. View

12.

Taylor A . Ocular Immune Privilege and Transplantation. Front Immunol. 2016; 7:37. PMC: 4744940. DOI: 10.3389/fimmu.2016.00037. View

13.

Tao S, Yuan T, Rui B, Zhu Z, Guo S, Zhang C . Exosomes derived from human platelet-rich plasma prevent apoptosis induced by glucocorticoid-associated endoplasmic reticulum stress in rat osteonecrosis of the femoral head via the Akt/Bad/Bcl-2 signal pathway. Theranostics. 2017; 7(3):733-750. PMC: 5327646. DOI: 10.7150/thno.17450. View

14.

Yamashita K, Inagaki E, Hatou S, Higa K, Ogawa A, Miyashita H . Corneal Endothelial Regeneration Using Mesenchymal Stem Cells Derived from Human Umbilical Cord. Stem Cells Dev. 2018; 27(16):1097-1108. DOI: 10.1089/scd.2017.0297. View

15.

Matthaei M, Hribek A, Clahsen T, Bachmann B, Cursiefen C, Jun A . Fuchs Endothelial Corneal Dystrophy: Clinical, Genetic, Pathophysiologic, and Therapeutic Aspects. Annu Rev Vis Sci. 2019; 5:151-175. DOI: 10.1146/annurev-vision-091718-014852. View

16.

Vereb Z, Poliska S, Albert R, Olstad O, Boratko A, Csortos C . Role of Human Corneal Stroma-Derived Mesenchymal-Like Stem Cells in Corneal Immunity and Wound Healing. Sci Rep. 2016; 6:26227. PMC: 4872602. DOI: 10.1038/srep26227. View

17.

Feizi S . Corneal endothelial cell dysfunction: etiologies and management. Ther Adv Ophthalmol. 2018; 10:2515841418815802. PMC: 6293368. DOI: 10.1177/2515841418815802. View

18.

Grange C, Tritta S, Tapparo M, Cedrino M, Tetta C, Camussi G . Stem cell-derived extracellular vesicles inhibit and revert fibrosis progression in a mouse model of diabetic nephropathy. Sci Rep. 2019; 9(1):4468. PMC: 6418239. DOI: 10.1038/s41598-019-41100-9. View

19.

Harrell C, Jovicic N, Djonov V, Arsenijevic N, Volarevic V . Mesenchymal Stem Cell-Derived Exosomes and Other Extracellular Vesicles as New Remedies in the Therapy of Inflammatory Diseases. Cells. 2019; 8(12). PMC: 6952783. DOI: 10.3390/cells8121605. View

20.

Cnop M, Toivonen S, Igoillo-Esteve M, Salpea P . Endoplasmic reticulum stress and eIF2α phosphorylation: The Achilles heel of pancreatic β cells. Mol Metab. 2017; 6(9):1024-1039. PMC: 5605732. DOI: 10.1016/j.molmet.2017.06.001. View