Mesenchymal Stem/Stromal Cells and their Extracellular Vesicle Progeny Decrease Injury in Poststenotic Swine Kidney Through Different Mechanisms

Abstract

Novel therapies are needed to address the increasing prevalence of chronic kidney disease. Mesenchymal stem/ stromal cells (MSCs) and MSC-derived extracellular vesicles (EVs) augment tissue repair. We tested the hypothesis that EVs are as effective as MSCs in protecting the stenotic kidney, but target different injury pathways. Pigs were studied after 16 weeks of renal injury achieved by diet-induced metabolic syndrome (MetS) and renal artery stenosis (RAS). Pigs were untreated or treated 4 weeks earlier with intrarenal delivery of autologous adipose tissue-derived MSCs (10 7 ) or their EVs (10 11 ). Lean pigs and sham RAS served as controls (n = 6 each). Stenotic-kidney function was studied in vivo using computed tomography and magnetic resonance imaging. Histopathology and expression of necroptosis markers [receptor-interacting protein kinase (RIPK)-1 and RIPK-3], inflammatory, and growth factors (angiopoietin-1 and vascular endothelial growth factor) were studied ex vivo. Stenotic-kidney glomerular filtration rate and blood flow in MetS + RAS were both lower than Lean and increased in both MetS + RAS + MSC and MetS + RAS + EV. Both MSCs and EV improved renal function and decreased renal hypoxia, fibrosis, and apoptosis. MSCs were slightly more effective in preserving microvascular (0.02-0.2 mm diameters) density and prominently attenuated renal inflammation. However, EV more significantly upregulated growth factor expression and decreased necroptosis. In conclusion, adipose tissue-derived MSCs and their EV both improve stenotic kidney function and decrease tissue injury in MetS + RAS by slightly different mechanisms. MSCs more effectively preserved the microcirculation, while EV bestowed better preservation of renal cellular integrity. These findings encourage further exploration of this novel approach to attenuate renal injury.

Mesenchymal stem cells and extracellular vesicles in therapy against kidney diseases

“…MetS is able to change the amount of loading of miRNA on EVs, upregulate ageing-related miRNA in EVs, and even limit the use of EVs in exogenous regenerative therapy through abnormal transcription [99][100][101]. Zhao et al found that autologous ADMSCs can better preserve microcirculation through comparative studies, while ADMSC-EVs perform better in retaining intactness of nephrocytes and reducing necrosis [102]. In summary, the application value of MSC-EVs in the treatment of ARVD remains in dispute, and further research is warranted to reveal their efficacy.…”

Exogenous bone marrow derived-putative endothelial progenitor cells attenuate ischemia reperfusion-induced vascular injury and renal fibrosis in mice dependent on pericytes

“…Besides, stem cells were shown to use paracrine pathways, for example, through microvesicles for transferring proteins and RNAs to endothelial cells 9 , 32 - 34 . In Lerman's study autologous endothelial and/or mesenchymal progenitor cells improved renal microvasculature via regulating growth factors Ang-1, VEGF and attenuated renal inflammation etc., which have direct meaning to stem cells' effect on nephrology 35 , 36 . Our study demonstrated that b-pEPCs promoted vascular tube formation and improved IR-induced vascular injury.…”

Extracellular Vesicles and Renal Fibrosis: An Odyssey toward a New Therapeutic Approach

“…Interestingly, labeled EVs were detected in the stenotic kidney (9% of the injected amount) on day 2 after injection and decreased thereafter, remaining at 2% by four weeks after injection [103]. The same group reported a role for AD-MSC-derived EVs in preserving kidney cellular integrity after renal injury through their effect on necroptosis [114]. Consistently, exosomes derived from human AD-MSCs mitigated renal fibrosis in mice after unilateral renal I/R injury via activation of tubular Sox9 [105].…”