Extracellular Vesicles Derived from Induced Pluripotent Stem Cells Promote Renoprotection in Acute Kidney Injury Model

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Abstract

Induced pluripotent stem cells (iPSC) have been the focus of several studies due to their wide range of application, including in cellular therapy. The use of iPSC in regenerative medicine is limited by their tumorigenic potential. Extracellular vesicles (EV) derived from stem cells have been shown to support renal recovery after injury. However, no investigation has explored the potential of iPSC-EV in the treatment of kidney diseases. To evaluate this potential, we submitted renal tubule cells to hypoxia-reoxygenation injury, and we analyzed cell death rate and changes in functional mitochondria mass. An in vivo model of ischemia-reperfusion injury was used to evaluate morphological and functional alterations. Gene array profile was applied to investigate the mechanism involved in iPSC-EV effects. In addition, EV derived from adipose mesenchymal cells (ASC-EV) were also used to compare the potential of iPSC-EV in support of tissue recovery. The results showed that iPSC-EV were capable of reducing cell death and inflammatory response with similar efficacy than ASC-EV. Moreover, iPSC-EV protected functional mitochondria and regulated several genes associated with oxidative stress. Taken together, these results show that iPSC can be an alternative source of EV in the treatment of different aspects of kidney disease.

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Most cited references 40

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

Cristina Grange, Marta Tapparo, Stefania Bruno … (2014)

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.

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Raymond F. Burk, Kristina Hill (2009)

Selenoprotein P (Sepp1) is a secreted protein that is made up of 2 domains. The larger N-terminal domain contains 1 selenocysteine residue in a redox motif and the smaller C-terminal domain contains the other 9 selenocysteines. Sepp1 isoforms of varying lengths occur but quantitation of them has not been achieved. Hepatic synthesis of Sepp1 affects whole-body selenium content and the liver is the source of most plasma Sepp1. ApoER2, a member of the lipoprotein receptor family, binds Sepp1 and facilitates its uptake into the testis and retention of its selenium by the brain. Megalin, another lipoprotein receptor, facilitates uptake of filtered Sepp1 into proximal tubule cells of the kidney. Thus, Sepp1 serves in homeostasis and distribution of selenium. Mice with deletion of Sepp1 suffer greater morbidity and mortality from infection with Trypanosoma congolense than do wild-type mice. Mice that express only the N-terminal domain of Sepp1 have the same severity of illness as wild-type mice, indicating that the protective function of Sepp1 against the infection resides in the N-terminal (redox) domain. Thus, Sepp1 has several functions. In addition, plasma Sepp1 concentration falls in selenium deficiency and, therefore, it can be used as an index of selenium nutritional status.

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Journal

Journal ID (nlm-ta): Cells

Journal ID (iso-abbrev): Cells

Journal ID (publisher-id): cells

Title: Cells

Publisher: MDPI

ISSN (Electronic): 2073-4409

Publication date (Electronic): 17 February 2020

Publication date Collection: February 2020

Volume: 9

Issue: 2

Electronic Location Identifier: 453

Affiliations

[1 ]Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil; federica.collino@ 123456unipd.it (F.C.); jarlenelopes@ 123456biof.ufrj.br (J.A.L.); giovanegt@ 123456gmail.com (G.G.T.); tais@ 123456cenabio.ufrj.br (T.H.K.-B.); gugaclopes@ 123456hotmail.com (G.M.C.L.); douglas-7451@ 123456hotmail.com (D.B.A.);

[2 ]National Institute of Science and Technology for Regenerative Medicine-REGENERA, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil

[3 ]Department of Biomedical Sciences, University of Padova, 35131 Padua, Italy

[4 ]National Center for Structural Biology and Bioimaging/CENABIO, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil

[5 ]Department of Medical Sciences, Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy; marta.tapparo@ 123456gmail.com

[6 ]Department of Pediatrics’ Section of Pediatric Nephrology, Tulane University School of Medicine, New Orleans, LA 70112, USA

[7 ]Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Turin, Italy benedetta.bussolati@ 123456unito.it (B.B.)

[8 ]National Institute of Science and Technology of Structural Biology and Bioimaging-INBEB, Federal University of Rio de Janeiro, 21941-902 Rio de Janeiro, Brazil

[9 ]Graduate Program of Translational Biomedicine/BIOTRANS, Grande Rio University, 25071-202 Duque de Caxias, Brazil

Author notes

[* ]Correspondence: avieyra@ 123456biof.ufrj.br (A.V.); lindoso@ 123456biof.ufrj.br (R.S.L.); Tel.: +55-21-3938-6521 (A.V.); +55-21-3938-6520 (R.S.L.)

Author information

Federica Collino https://orcid.org/0000-0002-3619-7701

Benedetta Bussolati https://orcid.org/0000-0002-3663-5134

Adalberto Vieyra https://orcid.org/0000-0002-8009-7273

Rafael Soares Lindoso https://orcid.org/0000-0002-7297-0781

Article

Publisher ID: cells-09-00453

DOI: 10.3390/cells9020453

PMC ID: 7072760

PubMed ID: 32079274

SO-VID: 0a67442b-f7b5-411a-893d-2c8b1b63513d

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

History

Date received : 24 November 2019

Date accepted : 12 February 2020

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Extracellular Vesicles Derived from Induced Pluripotent Stem Cells Promote Renoprotection in Acute Kidney Injury Model

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Most cited references 40

Superoxide radical and superoxide dismutases.

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

Selenoprotein P-expression, functions, and roles in mammals.

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Cited by 17

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