Biodistribution of mesenchymal stem cell-derived extracellular vesicles in a model of acute kidney injury monitored by optical imaging

Grange,Cristina; Tapparo,Marta; Bruno,Stefania; Chatterjee,Devasis; Quesenberry,Peter J.; Tetta,Ciro; Camussi,Giovanni

doi:10.3892/ijmm.2014.1663

Biodistribution of mesenchymal stem cell-derived extracellular vesicles in a model of acute kidney injury monitored by optical imaging

Authors:
- Cristina Grange
- Marta Tapparo
- Stefania Bruno
- Devasis Chatterjee
- Peter J. Quesenberry
- Ciro Tetta
- Giovanni Camussi
View Affiliations

Affiliations: Department of Medical Sciences, University of Torino, Torino, Italy, Translational Center for Regenerative Medicine, University of Torino, Torino, Italy, Department of Molecular Biotechnology and Health Science, University of Torino, Torino, Italy, Department of Medicine, The Warren Alpert Medical School of Brown University, Providence, RI, USA, EMEA LA Medical Board, Fresenius Medical Care, Bad Homburg, Germany
Published online on: February 20, 2014 https://doi.org/10.3892/ijmm.2014.1663
Pages: 1055-1063
Copyright: © Grange et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Mesenchymal stem cells (MSCs) contribute to the recovery of tissue injury, providing a paracrine support. Cell-derived extracellular vesicles (EVs), carrying membrane and cytoplasmatic constituents of the cell of origin, have been described as a fundamental mechanism of intercellular communication. We previously demonstrated that EVs derived from human MSCs accelerated recovery following acute kidney injury (AKI) in vivo. The aim of the present study was to investigate the biodistribution and the renal localization of EVs in AKI. For this purpose, two methods for EV labeling suitable for in vivo tracking with optical imaging (OI), were employed using near infrared (NIR) dye (DiD): i) labeled EVs were generated by MSCs pre-incubated with NIR dye and collected from cell supernatants; ii) purified EVs were directly labeled with NIR dye. EVs obtained with these two procedures were injected intravenously (i.v.) into mice with glycerol-induced AKI and into healthy mice to compare the efficacy of the two labeling methods for in vivo detection of EVs at the site of damage. We found that the labeled EVs accumulated specifically in the kidneys of the mice with AKI compared with the healthy controls. After 5 h, the EVs were detectable in whole body images and in dissected kidneys by OI with both types of labeling procedures. The directly labeled EVs showed a higher and brighter fluorescence compared with the labeled EVs produced by cells. The signal generated by the directly labeled EVs was maintained in time, but provided a higher background than that of the labeled EVs produced by cells. The comparison of the two methods indicated that the latter displayed a greater specificity for the injured kidney.

View Figures

View References

1	Aliotta JM, Pereira M, Johnson KW, et al: Microvesicle entry into marrow cells mediates tissue-specific changes in mRNA by direct delivery of mRNA and induction of transcription. Exp Hematol. 38:233–245. 2010. View Article : Google Scholar : PubMed/NCBI
2	Ludwig AK and Giebel B: Exosomes: small vesicles participating in intercellular communication. Int J Biochem Cell Biol. 44:11–15. 2012. View Article : Google Scholar : PubMed/NCBI
3	van Dommelen SM, Vader P, Lakhal S, Kooijmans SA, van Solinge WW, Wood MJ and Schiffelers RM: Microvesicles and exosomes: opportunities for cell-derived membrane vesicles in drug delivery. J Control Release. 161:635–644. 2012.PubMed/NCBI
4	Deregibus MC, Cantaluppi V, Calogero R, Lo Iacono M, Tetta C, Biancone L, Bruno S, et al: Endothelial progenitor cell-derived microvescicles activate an angiogenic program in endothelial cells by a horizontal transfer of mRNA. Blood. 110:2440–2448. 2007. View Article : Google Scholar : PubMed/NCBI
5	Valadi H, Ekström K, Bossios A, Sjöstrand M, Lee JJ and Lötvall JO: Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 9:654–659. 2007. View Article : Google Scholar : PubMed/NCBI
6	Aliotta JM, Sanchez-Guijo FM, Dooner GJ, et al: Alteration of marrow cell gene expression, protein production, and engraftment into lung by lung-derived microvesicles: a novel mechanism for phenotype modulation. Stem Cells. 25:2245–2256. 2007. View Article : Google Scholar : PubMed/NCBI
7	Collino F, Deregibus MC, Bruno S, et al: Microvesicles derived from adult human bone marrow and tissue specific mesenchymal stem cells shuttle selected pattern of miRNAs. PLoS One. 5:e118032010. View Article : Google Scholar : PubMed/NCBI
8	Ratajczak J, Miekus K, Kucia M, Zhang J, Reca R, Dvorak P and Ratajczak MZ: Embryonic stem cell-derived microvesicles reprogram hematopoietic progenitors: evidence for horizontal transfer of mRNA and protein delivery. Leukemia. 20:847–856. 2006. View Article : Google Scholar : PubMed/NCBI
9	Jin HJ, Bae YK, Kim M, et al: Comparative analysis of human mesenchymal stem cells from bone marrow, adipose tissue, and umbilical cord blood as sources of cell therapy. Int J Mol Sci. 14:17986–8001. 2013.PubMed/NCBI
10	Humphreys BD and Bonventre JV: Mesenchymal stem cells in acute kidney injury. Annu Rev Med. 59:311–325. 2008. View Article : Google Scholar : PubMed/NCBI
11	Bi B, Schmitt R, Israilova M, Nishio H and Cantley LG: Stromal cells protect against acute tubular injury via an endocrine effect. J Am Soc Nephrol. 18:2486–2496. 2007. View Article : Google Scholar : PubMed/NCBI
12	Quesenberry PJ and Aliotta JM: Cellular phenotype switching and microvesicles. Adv Drug Deliv Rev. 62:1141–1148. 2010. View Article : Google Scholar : PubMed/NCBI
13	Bruno S, Grange C, Deregibus MC, et al: Mesenchymal stem cell-derived microvesicles protect against acute tubular injury. J Am Soc Nephrol. 20:1053–1067. 2009. View Article : Google Scholar : PubMed/NCBI
14	Camussi G, Deregibus MC and Cantaluppi V: Role of stem-cell-derived microvesicles in the paracrine action of stem cells. Biochem Soc Trans. 41:283–287. 2013. View Article : Google Scholar : PubMed/NCBI
15	Goldstein SL, Jaber BL, Faubel S and Chawla LS; Acute Kidney Injury Advisory Group of American Society of Nephrology. AKI transition of care: a potential opportunity to detect and prevent CKD. Clin J Am Soc Nephrol. 8:476–483. 2013. View Article : Google Scholar : PubMed/NCBI
16	Herrera MB, Bussolati B, Bruno S, et al: Exogenous mesenchymal stem cells localize to the kidney by means of CD44 following acute tubular injury. Kidney Int. 72:430–441. 2007. View Article : Google Scholar
17	Morigi M, Introna M, Imberti B, et al: Human bone marrow mesenchymal stem cells accelerate recovery of acute renal injury and prolong survival in mice. Stem Cells. 26:2075–2082. 2008. View Article : Google Scholar : PubMed/NCBI
18	Qi S and Wu D: Bone marrow-derived mesenchymal stem cells protect against cisplatin-induced acute kidney injury in rats by inhibiting cell apoptosis. Int J Mol Med. 32:1262–1272. 2013.PubMed/NCBI
19	Bruno S, Grange C, Collino F, Deregibus MC and Cantaluppi V: Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury. PLoS One. 7:e331152012. View Article : Google Scholar : PubMed/NCBI
20	Gatti S, Bruno S, Deregibus MC, Sordi A, Cantaluppi V, Tetta C and Camussi G: Microvesicles derived from human adult mesenchymal stem cells protect against ischaemia-reperfusion-induced acute and chronic kidney injury. Nephrol Dial Transplant. 26:1474–1483. 2011. View Article : Google Scholar : PubMed/NCBI
21	Boddington S, Henning TD, Sutton EJ and Daldrup-Link HE: Labeling stem cells with fluorescent dyes for non-invasive detection with optical imaging. J Vis Exp. 14:pii6862008.PubMed/NCBI
22	Tögel F, Yang Y, Zhang P, Hu Z and Westenfelder C: Bioluminescence imaging to monitor the in vivo distribution of administered mesenchymal stem cells in acute kidney injury. Am J Physiol Renal Physiol. 295:F315–F321. 2008.PubMed/NCBI
23	Sutton EJ, Henning TD, Boddington S, Demos S, Krug C, Meier R, Kornak J, et al: In vivo magnetic resonance imaging and optical imaging comparison of viable and nonviable mesenchymal stem cells with a bifunctional label. Mol Imaging. 9:278–290. 2010.PubMed/NCBI
24	Garrovo C, Bergamin N, Bates D, et al: In vivo tracking of murine adipose tissue-derived multipotent adult stem cells and ex vivo cross-validation. Int J Mol Imaging. 2013:4269612013. View Article : Google Scholar : PubMed/NCBI
25	Chatterjee DK, Gnanasammandhan MK and Zhang Y: Small upconverting fluorescent nanoparticles for biomedical applications. Small. 6:2781–2795. 2010. View Article : Google Scholar : PubMed/NCBI
26	Rao J, Dragulescu-Andrasi A and Yao H: Fluorescence imaging in vivo: recent advances. Curr Opin Biotechnol. 18:17–25. 2007. View Article : Google Scholar
27	Boddington SE, Sutton EJ, Henning TD, Nedopil AJ, Sennino B, Kim A and Daldrup-Link HE: Labeling human mesenchymal stem cells with fluorescent contrast agents: the biological impact. Mol Imaging Biol. 13:3–9. 2011. View Article : Google Scholar : PubMed/NCBI
28	Hood JL, San RS and Wickline SA: Exosomes released by melanoma cells prepare sentinel lymph nodes for tumor metastasis. Cancer Res. 71:3792–3801. 2011. View Article : Google Scholar : PubMed/NCBI
29	Ansa-Addo EA, Lange S, Stratton D, et al: Human plasma membrane-derived vesicles halt proliferation and induce differentiation of THP-1 acute monocytic leukemia cells. J Immunol. 185:5236–5246. 2010. View Article : Google Scholar : PubMed/NCBI
30	Grant R, Ansa-Addo E, Stratton D, et al: A filtration-based protocol to isolate human plasma membrane-derived vesicles and exosomes from blood plasma. J Immunol Methods. 371:143–151. 2011. View Article : Google Scholar : PubMed/NCBI
31	Sutton EJ, Boddington SE, Nedopil AJ, Henning TD, Demos SG, Baehner R, Sennino B, et al: An optical imaging method to monitor stem cell migration in a model of immune-mediate arthritis. Opt Express. 17:24403–24413. 2009. View Article : Google Scholar : PubMed/NCBI
32	Herrera MB, Fonsato V, Bruno S, et al: Human liver stem cells improve liver injury in a model of fulminant liver failure. Hepatology. 57:311–319. 2013. View Article : Google Scholar : PubMed/NCBI
33	Zou P, Xu S, Povoski SP, et al: Near-infrared fluorescence labeled anti-TAG-72 monoclonal antibodies for tumor imaging in colorectal cancer xenograft mice. Mol Pharm. 6:428–440. 2009. View Article : Google Scholar : PubMed/NCBI
34	Lai CP, Tannous BA and Breakefield XO: Noninvasive in vivo monitoring of extracellular vesicles. Methods Mol Biol. 1098:249–258. 2014. View Article : Google Scholar : PubMed/NCBI
35	Suetsugu A, Honma K, Saji S, Moriwaki H, Ochiya T and Hoffman RM: Imaging exosome transfer from breast cancer cells to stroma at metastatic sites in orthotopic nude-mouse models. Adv Drug Deliv Rev. 65:383–390. 2013. View Article : Google Scholar : PubMed/NCBI
36	Takahashi Y, Nishikawa M, Shinotsuka H, Matsui Y, Ohara S, Imai T and Takakura Y: Visualization and in vivo tracking of the exosomes of murine melanoma B16-BL6 cells in mice after intravenous injection. J Biotechnol. 165:77–84. 2013. View Article : Google Scholar : PubMed/NCBI
37	Raposo G and Stoorvogel W: Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol. 200:373–383. 2013. View Article : Google Scholar : PubMed/NCBI
38	Camussi G, Deregibus MC, Bruno S, Cantaluppi V and Biancone L: Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney Int. 78:838–848. 2010. View Article : Google Scholar : PubMed/NCBI
39	Kalchenko V, Shivtiel S, Malina V, Lapid K, Haramati S, Lapidot T, Brill A and Harmelin A: Use of lipophilic near-infrared dye in whole-body optical imaging of hematopoietic cell homing. J Biomed Opt. 11:0505072006. View Article : Google Scholar : PubMed/NCBI