Abstract
Acute kidney injury (AKI) and chronic kidney disease (CKD) are rising in global prevalence and cause significant morbidity for patients. Current treatments are limited to slowing instead of stabilising or reversing disease progression. In this review, we describe mesenchymal stem cells (MSCs) and their constituents, extracellular vesicles (EVs) as being a novel therapeutic for CKD. MSC-derived EVs (MSC-EVs) are membrane-enclosed particles, including exosomes, which carry genetic information that mimics the phenotype of their cell of origin. MSC-EVs deliver their cargo of mRNA, miRNA, cytokines, and growth factors to target cells as a form of paracrine communication. This genetically reprograms pathophysiological pathways, which are upregulated in renal failure. Since the method of exosome preparation significantly affects the quality and function of MSC-exosomes, this review compares the methodologies for isolating exosomes from MSCs and their role in tissue regeneration. More specifically, it summarises the therapeutic efficacy of MSC-EVs in 60 preclinical animal models of AKI and CKD and the cargo of biomolecules they deliver. MSC-EVs promote tubular proliferation and angiogenesis, and inhibit apoptosis, oxidative stress, inflammation, the epithelial-to-mesenchymal transition, and fibrosis, to alleviate AKI and CKD. By reprogramming these pathophysiological pathways, MSC-EVs can slow or even reverse the progression of AKI to CKD, and therefore offer potential to transform clinical practice.
Highlights
Faculty of Medicine and Health, Sydney Medical School, University of Sydney, Kolling Institute, Sydney Medical School, University of Sydney, Royal North Shore Hospital, Abstract: Acute kidney injury (AKI) and chronic kidney disease (CKD) are rising in global prevalence and cause significant morbidity for patients
Multiple animal models have demonstrated that mesenchymal stem cell (MSC)-extracellular vesicles (EVs) can ameliorate AKI induced by cisplatin, glycerol, gentamicin, or ischaemic-reperfusion injury (IRI) [43,98,99]
MSCs have shown increasing potential in immunomodulation and regenerative medicine and their paracrine effects are mediated by the secretion of EVs [42,181,182,183,184,185]
Summary
Acute kidney injury (AKI) and chronic kidney disease (CKD) are established as global health burdens, with a prevalence of one in ten adults for CKD [1]. The most common causes are pre-renal with hypovolaemia, ischaemia, toxic injury, and sepsis, leading to oxidative stress, inflammation, apoptosis, and necrosis of tubular epithelial cells (TECs) [5]. 25% risk of progression to CKD [8], and a 50% increase in 10-year mortality, from coronary events [9,10]. The most common cause of CKD is diabetes, followed by glomerulonephritis, hypertension, and polycystic kidney disease, with smoking, a family history of kidney failure, obesity, ≥60 years old, and being of Aboriginal or Torres Strait. In Type 2 diabetes mellitus (T2DM), hyperglycaemia induces oxidative stress and inflammation, which leads to maladaptive repair by fibroblasts and podocytes, and reduction of peritubular endothelial capillary (PTC) networks [5,12,13]. The fibrotic process strongly correlates with a loss of renal function and CKD is defined by elevated urinary albumin excretion ≥30 mg/g and/or a decrease in estimated glomerular filtration rate (eGFR) to
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