Comparison of the Effects of Mesenchymal Stem Cells with Their Extracellular Vesicles on the Treatment of Kidney Damage Induced by Chronic Renal Artery Stenosis

Abstract

Background. Chronic renal artery stenosis is considered one of the most common causes of renovascular hypertension (RH). Chronic hypoxia can lead to irreversible damage to renal tissue and to a progressive deterioration of renal function. We have previously shown that bone marrow-derived mesenchymal stem cells (BMSCs) improved renal parenchyma and function in a model of RH (2 kidneys, 1 clip model (2K-1C) in rats. Microvesicles (MVs) and exosomes (EXs) released by MSCs have been shown to induce effects similar to those induced by whole cells but with fewer side effects. In this study, we compared the effects of adipose-derived MSCs (ASCs) with those of the MVs and EXs released by ASCs on tissue inflammation and renal function in 2 K-1C rats. Results. Flow cytometry analysis showed that even after 15 days, ASCs were still detected in both kidneys. The expression of a stem cell homing marker (SDF1-α) was increased in ASC-treated animals in both the stenotic and contralateral kidneys. Interestingly, SDF1-α expression was also increased in MV- and EX-treated animals. A hypoxia marker (HIF1-α) was upregulated in the stenotic kidney, and treatments with ASCs, MVs, and EXs were effective in reducing the expression of this marker. Stenotic animals showed a progressive increase in systolic blood pressure (SBP), while animals treated with ASCs, MVs, and EXs showed a stabilization of SBP, and this stabilization was similar among the different treatments. Stenotic animals developed significant proteinuria, which was reduced by ASCs and MVs but not by EXs. The increased expression of Col I and TGFβ in both kidneys was reduced by all the treatments, and these treatments also effectively increased the expression of the anti-inflammatory cytokine IL-10 in both kidneys; however, only ASCs were able to reduce the overexpression of the proinflammatory cytokine IL-1β in both kidneys of 2K-1C animals. Conclusion. The results of this study demonstrated that the EVs released by ASCs produced beneficial results but with lower efficacy than whole cells. ASCs produced stronger effects in this model of renal chronic hypoxia, and the use of EVs instead of whole cells should be evaluated depending on the parameter to be corrected.

Mesenchymal Stem Cell-Derived Exosomes: Toward Cell-Free Therapeutic Strategies in Chronic Kidney Disease

“…The addition of MSC-EVs during HMP attenuated the ischemic kidney injury through maintaining the enzymatic machinery critical for cell survival and reduced the reperfusion damage to kidney ( 117 ). Beneficial properties of AD-MSC-Exos were also reported in the 2K-1C ( 118 ), a renal artery stenosis model. Administration of AD-MSC-Exos were demonstrated to stabilize the systolic blood pressure (SBP), downregulate hypoxia marker HIF-1a and reduce profibrotic gene collogen and TGF-β expression, thus mitigating kidney fibrosis ( 118 ).…”

“…Beneficial properties of AD-MSC-Exos were also reported in the 2K-1C ( 118 ), a renal artery stenosis model. Administration of AD-MSC-Exos were demonstrated to stabilize the systolic blood pressure (SBP), downregulate hypoxia marker HIF-1a and reduce profibrotic gene collogen and TGF-β expression, thus mitigating kidney fibrosis ( 118 ). Interestingly, the treatments with AD-MSC-Exos, AD-MSC or AD-MSC-EVs were equally effective in reducing the expression of the fibrotic markers collagen-1 (COL-1) and TGF-β.…”

Mesenchymal Stem Cell-Derived Extracellular Vesicles to the Rescue of Renal Injury

“…Additionally, there are functional differences in efficacy between EV subtypes. A recent study found adipose-MSC-MVs reduced proteinuria while only exosomes promoted natriuresis following chronic renal artery stenosis [ 147 ]. To minimise these effects, studies were compared based on the ISEV recommendations, according to the source of MSCs, EV subtype, protein content of administered EVs, and route of injection [ 49 ].…”

“…In β-integrin signalling, TGF-β forms a complex with Smad and binds transcription factors, such as Snail, to downregulate expression of epithelial cell markers (E-cadherin), and activate expression of fibrosis-associated stromal cell markers (α-SMA, fibronectin, collagen I) [ 143 ]. Erythropoietin (EPO)-transfected microparticles in mice with UUO [ 144 , 145 ], Wharton jelly’s MSC-EVs in cyclosporin A injury [ 146 ], and adipose-MSC-EVs in renal artery stenosis [ 147 ] all inhibited the EMT and tubulointerstitial fibrosis by downregulating phosphorylated Smad2, Smad3, and p38 MAPK signalling, and increasing E-cadherin.…”

Techniques for increasing the yield of stem cell-derived exosomes: what factors may be involved?

“…Stem cell-derived exosomes possess favorable pharmacokinetic property, biocompatibility, and tissue-targeting ability owing to their bilayer structures and constituents of mRNAs, microRNAs, cytokines, chemokines, and immunomodulatory compounds (Mendt et al, 2019;Harrell et al, 2019;Haraszti et al, 2019;Fernández-Francos et al, 2021). Moreover, the ability of the exosomes to suppress inflammation, regulate cell proliferation, and promote damaged tissue repair has been corroborated (Harrell et al, 2019;Massa et al, 2020), for example, in the skin , muscle and bone (Nakamura et al, 2015;Hao et al, 2017;Mianehsaz et al, 2019), nerve (Tsintou et al, 2021), heart (Bahardoust and Baghoi-Hosseinabadi, 2021), liver , kidney (Ishiy et al, 2020), lung (Xu et al, 2020), immune system (Burrello et al, 2016), cancer (Sharma, 2018), and virus infection (Jamshidi et al, 2021) (Figure 2). Introduction of the exosomes into biomaterials, such as exosome-laden hydrogel (Wang et al, 2019a;Wang et al, 2019b), exosome-coated scaffold (Zhai et al, 2020;Kyung Kim et al, 2021), and exosome-based drug delivering vectors (Barile and Vassalli, 2017;Mehryab et al, 2020), has Figure 1 Biogenesis and identification of exosomes.…”