IL-10 partly mediates the ability of MSC-derived extracellular vesicles to attenuate myocardial damage in experimental metabolic renovascular hypertension

Abstract

Extracellular vesicles (EVs) obtain properties of immunomodulation and tissue repair from their parental mesenchymal stem cells (MSCs), and upon delivery may be associated with fewer adverse events. EVs derived from adipose-tissue MSCs restored kidney function by attenuating kidney inflammation in a swine model of metabolic syndrome (MetS) and renal artery stenosis via anti-inflammatory pathways. EVs also ameliorated myocardial injury in renovascular hypertension (RVH) secondary to inflammation in cardiorenal disease, but the mechanisms regulating this effect are unknown. We hypothesize that the anti-inflammatory cytokine interleukin (IL)-10 mediates the reparative effects of EVs on cardiovascular complications in a preclinical swine model with coexisting MetS and RVH. Twenty-three pigs established as Lean controls or RVH models were observed for 16 weeks. At 12 weeks RVH subgroups received an intrarenal delivery of 1011 either wildtype (WT) EVs or EVs after IL-10 knockdown (KD) (RVH+WT-EVs or RVH+IL-10-KD-EVs, respectively). Cardiac and renal function were studied in-vivo and myocardial tissue injury in-vitro 4 weeks later. RVH pigs showed myocardial inflammation, fibrosis, and left ventricular diastolic dysfunction. WT-EVs attenuated these impairments, increased capillary density, and decreased myocardial inflammation in-vivo. In-vitro, co-incubation with IL-10-containing WT-EVs decreased activated T-cells proliferation and endothelial cells inflammation and promoted their migration. Contrarily, these cardioprotective effects were largely blunted using IL-10-KD-EVs. Thus, the anti-inflammatory and pro-angiogenic effects of EVs in RVH may be partly attributed to their cargo of anti-inflammatory IL-10. Early intervention of IL-10-containing EVs may be helpful to prevent cardiovascular complications of MetS concurrent with RVH.

Human Bone Marrow Mesenchymal Stem Cells Promote the M2 Phenotype in Macrophages Derived from STEMI Patients

“…Interestingly, we identified the presence of IL-1Ra under M1 and BM-MSC conditions. Previous data indicate that this cytokine is secreted by inflammatory macrophages [46] and MSCs, supporting an increase in the expression of IL-10 and CD206, similar to our results [47,48]. These results show that there is communication in which BM-MSCs modulate the polarization of macrophages from patients with STEMI toward an M2 phenotype through IL-10 and IL-1Ra.…”

“…Additionally, we found that BM-MSCs express IL-10 and M-CSF under M2 macrophage conditions. It has been reported that the IL-10 and M-CSF present in MSCs promote M2 polarization [48,50] and reduce the presence of IL-6 in damaged tissue, reducing myocardial injury in renovascular hypertension in a murine model [49]. Additionally, it has been reported that the presence of M-CSF favors the restoration of cardiac function in a murine model after ischemic injury because it favors VEGF-mediated angiogenesis [51].…”

Mesenchymal stromal cell derived extracellular vesicles as a therapeutic tool: immune regulation, MSC priming, and applications to SLE

“…showed cardioprotective effects of MSC-EVs using in vivo models of pigs, which were “largely blunted” after IL-10 knockdown (IL10KD). Using in vitro models, IL10KD MSC-EVs achieved less inhibition of T-cell proliferation than control MSC-EVs ( 42 ). These results are in accordance with Eirin et al.…”

Application of mesenchymal stem cells for anti-senescence and clinical challenges

“…IL-10 is an anti-inflammatory cytokine, mainly secreted by immune cells, which can limit the proliferation of T cells and inhibit the production and expression of pro-inflammatory factors such as IL-2, IFN-γ, IL-6, TNF-α [ 262 ]. Overexpressing IL-10 MSCs were found to increase autophagy and protect rats from neuronal damage induced by traumatic brain injury [ 263 ]. There were many similar studies regarding IL-10-modified MSCs showing better therapeutic effects than naive MSCs.…”