Mesenchymal Stem Cell–Derived Extracellular Vesicles Induce Regulatory T Cells to Ameliorate Chronic Kidney Injury

Abstract

Metabolic syndrome (MetS) profoundly changes the contents of mesenchymal stem cells and mesenchymal stem cells–derived extracellular vesicles (EVs). The anti-inflammatory TGF-β (transforming growth factor-β) is selectively enriched in EVs from Lean but not from MetS pigs, but the functional impact of this endowment remains unknown. We hypothesized that Lean-EVs more effectively induce regulatory T cells in injured kidneys. Five groups of pigs (n=7 each) were studied after 16 weeks of diet-induced MetS and unilateral renal artery stenosis (RAS; MetS+RAS). Two groups of MetS+RAS were treated 4 weeks earlier with an intrarenal injection of either Lean-EVs or MetS-EVs. MetS+RAS had lower renal volume, renal blood flow, and glomerular filtration rate than MetS pigs. Compared with Lean-EVs, MetS-EVs were less effective in improving renal function and decreasing tubular injury and fibrosis in MetS+RAS. Lean-EVs upregulated TGF-β expression in stenotic kidney and increased regulatory T cells numbers more prominently. Furthermore, markedly upregulated anti-inflammatory M2 macrophages reduced proinflammatory M1 macrophages, and CD8 + T cells were detected in stenotic kidneys treated with Lean-EVs compared with MetS-EVs, and renal vein levels of interleukin-1β were reduced. In vitro, coculture of Lean-EVs with activated T cells led to greater TGF-β-dependent regulatory T cells induction than did MetS-EVs. Therefore, the beneficial effects of mesenchymal stem cells–derived EVs on injured kidneys might be partly mediated by their content of TGF-β signaling components, which permitting increased Treg preponderance. Modulating EV cargo and transforming their functionality might be useful for renal repair.

Mesenchymal stem cell-derived extracellular vesicles alter disease outcomes via endorsement of macrophage polarization

“…In pigs with diet-induced metabolic syndrome and renal artery stenosis, the same group also showed that MSC-EVs from pigs with metabolic syndrome were less potent than MSC-EVs from lean pigs in reducing tubular injury and fibrosis. There were significant upregulation of M2 macrophages and downregulation of M1 macrophages in stenotic kidneys treated with MSC-EVs from lean pigs [100]. Shen et al documented that MSC-EVs had high expression of C-C motif chemokine receptor-2 (CCR2).…”

“… Eirin et al [ 99 ] Pig autologous adipose-derived MSC-EVs Pig with metabolic syndrome + renal artery stenosis IL-10 MSC-EVs attenuated renal stenosis and elevated the number of reparative M2 macrophages via IL-10. Song et al [ 100 ] Pig autologous adipose-derived MSC-EVs Pig with metabolic syndrome + renal artery stenosis MSC-EVs from lean pigs alleviated tubular injury and fibrosis, upregulated M2 macrophages, and downregulated M1 macrophages in stenotic kidneys. Shen et al [ 101 ] Mouse BM-derived MSC-EVs Mouse ischemia/reperfusion-induced renal injury CCR2 MSC-EVs ameliorated renal ischemia/reperfusion injury and blocked macrophage NF- κ B activation via CCR2.…”

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

“…The physiological relevance of delivering EVs is supported by previous studies in murine models of kidney injury suggesting that administration of MSCderived EVs recapitulate the beneficial effect in kidney repair of their parent MSCs [55,56] and were considered superior to MSCs in some respects [57], suggesting that EVs may confer additional renoprotective effects. We have previously shown that intrarenal delivery of EVs released from adipose tissue-derived MSCs of lean pigs attenuated renal injury in chronic experimental MetS+RAS [12][13][14], whereas MSCderived EVs isolated from pigs with MetS failed to decrease stenotic kidney fibrosis or improve GFR [15]. We have also shown that MetS modifies the miRNA cargo of porcine MSC-derived EVs, limiting their efficacy to repair renal tubular cells in vitro [22].…”

“…MetS can also exert deleterious effects on MSCs and their daughter EVs, altering their cargo and in vitro reparative potency [12][13][14]. Moreover, we have recently found that delivery of EVs released by MSCs isolated from MetS pigs failed to repair the injured kidney [15]. However, the mechanisms by which MetS impairs the ability of MSCs to repair the damaged kidney remain unknown.…”

Extracellular Vesicle-Dependent Communication Between Mesenchymal Stromal Cells and Immune Effector Cells

“…Other groups reported no significant changes in Treg number, regardless the higher IL-10 levels after MSC-EV treatment, thus questioning the involvement of Tregs in the upregulation of IL-10 expression by MSC-EVs ( Hai et al, 2018 ). However, the promoting effects of MSC-EVs on Tregs could be partially mediated by their content in TGF-β signaling components ( Song et al, 2020 ). Another possible molecular mechanism is the transfer of miR-1470 from MSC-EVs to CD4 + T cells, thus upregulating P27KIP1 expression through c-Jun targeting ( Zhuansun et al, 2019 ).…”