Mesenchymal Stem Cells-Derived Exosomes Ameliorate Ischemia/Reperfusion Induced Acute Kidney Injury in a Porcine Model

Abstract

Exosomes are membrane-enclosed vesicles secreted by cells, containing a variety of biologically active ingredients including proteins, nucleic acids and lipids. In this study, we investigated the therapeutic effects of the exosomes and underlying mechanisms in a miniature pig model of ischemia/reperfusion-induced acute kidney injury (I/R-AKI). The exosomes were extracted from cultured human umbilical cord derived mesenchymal stem cells (hUC-MSCs) and infused into a miniature pig model of I/R AKI. Our results showed that 120 min of unilateral ischemia followed by reperfusion and contralateral nephrectomy resulted in renal dysfunction, severe kidney damage, apoptosis and necroptosis. Intravenous infusion of one dose of exosomes collected from about 4 × 108 hUC-MSCs significantly improved renal function and reduced apoptosis and necroptosis. Administration of hUC-MSC exosomes also reduced the expression of some pro-inflammatory cytokines/chemokines, decreased infiltration of macrophages to the injured kidneys and suppressed the phosphorylation of nuclear factor-κB and signal transducer and activator of transcription 3, two transcriptional factors related to inflammatory regulation. Moreover, hUC-MSC exosomes could promote proliferation of renal tubular cells, angiogenesis and upregulation of Klotho and Bone Morphogenetic Protein 7, two renoprotective molecules and vascular endothelial growth factor A and its receptor. Collectively, our results suggest that injection of hUC-MSC exosomes could ameliorate I/R-AKI and accelerate renal tubular cell repair and regeneration, and that hUC-MSC exosomes may be used as a potential biological therapy for Acute kidney injury patients.

Neonatal‐Tissue‐Derived Extracellular Vesicle Therapy (NEXT): A Potent Strategy for Precision Regenerative Medicine

“…[38] More importantly, abundant evidence has demonstrated that EVs have rare toxic effects and low immunogenicity. In line with previous reports, [21][22] we also found that xenogeneic EVs are well tolerated in vivo in this study. However, the use of xenotissue-derived EVs may still face some possible issues, such as immunologic and infectious (e.g., animal-derived viruses) effects, [39] which may be resolved by rapid progress in the gene editing system (e.g., CRISPR-Cas9) of large animals.…”

“…[ 1b ] Importantly, many studies have reported that cross‐species EV therapies still have tissue repair roles with rare toxic or adverse effects in preclinical models. For example, human MSC‐EVs could promote renal repair and reduce inflammation in mouse [ 21 ] or porcine models [ 22 ] of ischemic AKI. For future clinical translation, xenotissues may be potential sources of tissue‐EVs since it is difficult to collect enough tissue samples from humans for therapeutic purposes.…”

Extracellular Vesicles and Hydrogels: An Innovative Approach to Tissue Regeneration

“…MSCs-sEVs may also induce angiogenesis in kidney injury models, as postulated. Recent research 298 indicates that kidney-derived MSCs-sEVs promote angiogenesis in renal tissue. The therapeutic effects of sEVs, which are vesicles secreted by cells and contain various biologically active components, in a pig model of I/R-AKI was investigated.…”

JMJD3 activation contributes to renal protection and regeneration following acute kidney injury in mice

“…Klotho and BMP-7 are two renoprotective proteins that are frequently downregulated in the kidney following acute and chronic injury induced by various insults. 33,34 We examined whether JMJD3 would contribute to their expression by examining the effect of GSKJ4 on their expression. As expected, I/R and FA injury caused downregulation of klotho and BMP-7; treatment with GSKJ4 further reduced their levels (Figure 7A-F).…”