Mesenchymal Stem Cells-Derived Exosomes Ameliorate Ischemia/Reperfusion Induced Acute Kidney Injury in a Porcine Model

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Abstract

Exosomes are membrane-enclosed vesicles secreted by cells, containing a variety of biologically active ingredients including proteins, nucleic acids and lipids. In this study, we investigated the therapeutic effects of the exosomes and underlying mechanisms in a miniature pig model of ischemia/reperfusion-induced acute kidney injury (I/R-AKI). The exosomes were extracted from cultured human umbilical cord derived mesenchymal stem cells (hUC-MSCs) and infused into a miniature pig model of I/R AKI. Our results showed that 120 min of unilateral ischemia followed by reperfusion and contralateral nephrectomy resulted in renal dysfunction, severe kidney damage, apoptosis and necroptosis. Intravenous infusion of one dose of exosomes collected from about 4 × 10 ⁸ hUC-MSCs significantly improved renal function and reduced apoptosis and necroptosis. Administration of hUC-MSC exosomes also reduced the expression of some pro-inflammatory cytokines/chemokines, decreased infiltration of macrophages to the injured kidneys and suppressed the phosphorylation of nuclear factor-κB and signal transducer and activator of transcription 3, two transcriptional factors related to inflammatory regulation. Moreover, hUC-MSC exosomes could promote proliferation of renal tubular cells, angiogenesis and upregulation of Klotho and Bone Morphogenetic Protein 7, two renoprotective molecules and vascular endothelial growth factor A and its receptor. Collectively, our results suggest that injection of hUC-MSC exosomes could ameliorate I/R-AKI and accelerate renal tubular cell repair and regeneration, and that hUC-MSC exosomes may be used as a potential biological therapy for Acute kidney injury patients.

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Membrane vesicles as conveyors of immune responses.

Clotilde Théry, Matias Ostrowski, Elodie Segura (2009)

In multicellular organisms, communication between cells mainly involves the secretion of proteins that then bind to receptors on neighbouring cells. But another mode of intercellular communication - the release of membrane vesicles - has recently become the subject of increasing interest. Membrane vesicles are complex structures composed of a lipid bilayer that contains transmembrane proteins and encloses soluble hydrophilic components derived from the cytosol of the donor cell. These vesicles have been shown to affect the physiology of neighbouring recipient cells in various ways, from inducing intracellular signalling following binding to receptors to conferring new properties after the acquisition of new receptors, enzymes or even genetic material from the vesicles. This Review focuses on the role of membrane vesicles, in particular exosomes, in the communication between immune cells, and between tumour and immune cells.

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Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup

Lakhmir S Chawla, Rinaldo Bellomo, Azra Bihorac … (2017)

Acute kidney injury (AKI) and chronic kidney disease are increasingly recognized as interconnected entities and the term acute kidney disease (AKD) has been proposed to define ongoing pathophysiologic processes following an episode of AKI. In this Consensus statement, the Acute Disease Quality Initiative 16 Workgroup propose definitions and staging criteria for AKD, and strategies for the management of affected patients. They also make recommendations for areas of future research with the aims of improving understanding of the underlying processes and improving outcomes.

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Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms.

Florian Tögel, Zhuma Hu, Kathleen A. Weiss … (2005)

Severe acute renal failure (ARF) remains a common, largely treatment-resistant clinical problem with disturbingly high mortality rates. Therefore, we tested whether administration of multipotent mesenchymal stem cells (MSC) to anesthetized rats with ischemia-reperfusion-induced ARF (40-min bilateral renal pedicle clamping) could improve the outcome through amelioration of inflammatory, vascular, and apoptotic/necrotic manifestations of ischemic kidney injury. Accordingly, intracarotid administration of MSC (approximately 10(6)/animal) either immediately or 24 h after renal ischemia resulted in significantly improved renal function, higher proliferative and lower apoptotic indexes, as well as lower renal injury and unchanged leukocyte infiltration scores. Such renoprotection was not obtained with syngeneic fibroblasts. Using in vivo two-photon laser confocal microscopy, fluorescence-labeled MSC were detected early after injection in glomeruli, and low numbers attached at microvasculature sites. However, within 3 days of administration, none of the administered MSC had differentiated into a tubular or endothelial cell phenotype. At 24 h after injury, expression of proinflammatory cytokines IL-1beta, TNF-alpha, IFN-gamma, and inducible nitric oxide synthase was significantly reduced and that of anti-inflammatory IL-10 and bFGF, TGF-alpha, and Bcl-2 was highly upregulated in treated kidneys. We conclude that the early, highly significant renoprotection obtained with MSC is of considerable therapeutic promise for the cell-based management of clinical ARF. The beneficial effects of MSC are primarily mediated via complex paracrine actions and not by their differentiation into target cells, which, as such, appears to be a more protracted response that may become important in late-stage organ repair.

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Binbin Cui: URI : https://loop.frontiersin.org/people/1596433/overview

Xiaoyan Ma: URI : https://loop.frontiersin.org/people/1366198/overview

Ling Gao: URI : https://loop.frontiersin.org/people/1193620/overview

Chao Yu: URI : https://loop.frontiersin.org/people/847996/overview

Fengchen Shen: URI : https://loop.frontiersin.org/people/1704851/overview

Na Liu: URI : https://loop.frontiersin.org/people/964127/overview

Shougang Zhuang: URI : https://loop.frontiersin.org/people/200627/overview

Journal

Journal ID (nlm-ta): Front Cell Dev Biol

Journal ID (iso-abbrev): Front Cell Dev Biol

Journal ID (publisher-id): Front. Cell Dev. Biol.

Title: Frontiers in Cell and Developmental Biology

Publisher: Frontiers Media S.A.

ISSN (Electronic): 2296-634X

Publication date (Electronic): 24 May 2022

Publication date Collection: 2022

Volume: 10

Electronic Location Identifier: 899869

Affiliations

[1] ¹ Department of Nephrology , Shanghai East Hospital , Tongji University School of Medicine , Shanghai, China

[2] ² Department of Cardiac Surgery , Shanghai East Hospital , Tongji University School of Medicine , Shanghai, China

[3] ³ Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine , Shanghai East Hospital , Tongji University School of Medicine , Shanghai, China

[4] ⁴ School of Life Science and Technology , Advanced Institute of Translational Medicine , Tongji University , Shanghai, China

[5] ⁵ Department of Nephrology , Chinese PLA General Hospital , Beijing, China

Author notes

Edited by: Ming Li, Osaka University, Japan

Reviewed by: Alp Can, Ankara University, Turkey

Rikke Norregaard, Aarhus University, Denmark

Norashikin Zakaria, Universiti Sains Malaysia (USM), Malaysia

*Correspondence: Shougang Zhuang, gangzhuang@ 123456hotmail.com

This article was submitted to Stem Cell Research, a section of the journal Frontiers in Cell and Developmental Biology

Article

Publisher ID: 899869

DOI: 10.3389/fcell.2022.899869

PMC ID: 9171021

PubMed ID: 35686052

SO-VID: b1dcafb8-6f14-4ba2-a403-b2903f88a148

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This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Mesenchymal Stem Cells-Derived Exosomes Ameliorate Ischemia/Reperfusion Induced Acute Kidney Injury in a Porcine Model

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Stress signalling in stem cells

Most cited references 62

Membrane vesicles as conveyors of immune responses.

Acute kidney disease and renal recovery: consensus report of the Acute Disease Quality Initiative (ADQI) 16 Workgroup

Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms.

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