Metabolic Syndrome Alters the Cargo of Mitochondria-Related microRNAs in Swine Mesenchymal Stem Cell-Derived Extracellular Vesicles, Impairing Their Capacity to Repair the Stenotic Kidney

Abstract

Background. Coexisting metabolic syndrome (MetS) and renal artery stenosis (RAS) are linked to poor renal outcomes. Mesenchymal stem/stromal cell- (MSC-) derived extracellular vesicles (EVs) from lean animals show superior ability to repair the experimental MetS+RAS kidney compared to EVs from MetS pig MSCs. We hypothesized that MetS leads to selective packaging in porcine EVs of microRNAs capable of targeting mitochondrial genes, interfering with their capacity to repair the MetS+RAS kidney. Methods. Five groups of pigs ( n = 7 each) were studied after 16 weeks of diet-induced MetS and RAS (MetS+RAS) and MetS+RAS 4 weeks after a single intrarenal delivery of EVs harvested from allogeneic adipose tissue-derived MSCs isolated from Lean or MetS pigs, and Lean or MetS sham controls. Single-kidney blood flow (RBF) and glomerular filtration rate (GFR) were assessed in vivo with multidetector CT, whereas EV microRNA cargo, renal tubular mitochondrial structure and bioenergetics, and renal injury pathways were assessed ex vivo. Results. microRNA sequencing revealed 19 dysregulated microRNAs capable of targeting several mitochondrial genes in MetS-EVs versus Lean-EVs. Lean- and MetS-EVs were detected in the stenotic kidney 4 weeks after administration. However, only MetS-EVs failed to improve renal mitochondrial density, structure, and function or attenuate oxidative stress, tubular injury, and fibrosis. Furthermore, Lean-EVs but not MetS-EVs restored RBF and GFR in MetS+RAS. Conclusion. MetS alters the cargo of mitochondria-related microRNAs in swine MSC-derived EVs, which might impair their capacity to repair the poststenotic kidney in MetS+RAS. These observations may contribute to develop approaches to improve the efficacy of MSC-EVs for patients with MetS.

Extracellular Vesicles in Organ Fibrosis: Mechanisms, Therapies, and Diagnostics

“…AD-MSC exosomes were therapeutic in a pig model of metabolic syndrome and renal artery stenosis in which improved kidney effects included reduced inflammation and fibrosis and appeared to be dependent on exosomal interleukin (IL)-10 [ 132 ]. Moreover, as compared to AD-MSC EVs from pigs with metabolic syndrome, those from lean pigs were more effective in improving renal function and decreasing inflammation and fibrosis in the stenotic kidney [ 133 , 134 ]. The therapeutic effects were associated with an enhanced M2:M1 ratio and frequency of CD8+ T cells possibly driven by anti-inflammatory actions of EV TGF-β as well as decreased oxidative stress due to EV mitochondria-regulating miRs [ 133 , 134 ].…”

“…Moreover, as compared to AD-MSC EVs from pigs with metabolic syndrome, those from lean pigs were more effective in improving renal function and decreasing inflammation and fibrosis in the stenotic kidney [ 133 , 134 ]. The therapeutic effects were associated with an enhanced M2:M1 ratio and frequency of CD8+ T cells possibly driven by anti-inflammatory actions of EV TGF-β as well as decreased oxidative stress due to EV mitochondria-regulating miRs [ 133 , 134 ]. In a deoxycorticosterone acetate (DOCA)-salt hypertensive model, AD-MSC EVs were therapeutic both in the kidney, in which filtration rate, fibrosis inflammatory reactions were attenuated, and in the cardiovascular system, as shown by attenuation of cardiac fibrosis and normalization of blood pressure [ 135 ].…”

Novel Drug Delivery Technologies and Targets for Renal Disease

“…Micro-RNAs ✓? 37 ✓ 36,38,39 Extra-cellular vesicles ✓? 40,41 ✓ 39,42-44 Based on their characteristics and renal cell affinity, it is possible that some carriers may be utilized for drug delivery in both disease settings (question mark) but additional studies are needed.…”

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

“…By contrast, MSC-EVs, derived from pigs with Metabolic Syndrome, failed to alleviate CKD. This indicates the importance of the source and phenotype of MSC-EVs, where Metabolic Syndrome altered the cargo of 19 mitochondria-related miRNAs and therefore impaired the therapeutic efficacy of EVs [ 164 ].…”