Stem Cell-Derived Extracellular Vesicles as Potential Therapeutic Approach for Acute Kidney Injury

Abstract

Acute kidney injury is a frequent complication of hospitalized patients and significantly increases morbidity and mortality, worsening costs and length of hospital stay. Despite this impact on healthcare system, treatment still remains only supportive (dialysis). Stem cell-derived extracellular vesicles are a promising option as they recapitulate stem cells properties, overcoming safety issues related to risks or rejection or aberrant differentiation. A growing body of evidence based on pre-clinical studies suggests that extracellular vesicles may be effective to treat acute kidney injury and to limit fibrosis through direct interference with pathogenic mechanisms of vascular and tubular epithelial cell damage. We herein analyze the state-of-the-art knowledge of therapeutic approaches with stem cell-derived extracellular vesicles for different forms of acute kidney injury (toxic, ischemic or septic) dissecting their cytoprotective, regenerative and immunomodulatory properties. We also analyze the potential impact of extracellular vesicles on the mechanisms of transition from acute kidney injury to chronic kidney disease, with a focus on the pivotal role of the inhibition of complement cascade in this setting. Despite some technical limits, nowadays the development of therapies based on stem cell-derived extracellular vesicles holds promise as a new frontier to limit acute kidney injury onset and progression.

Dual Role of Extracellular Vesicles in Sepsis-Associated Kidney and Lung Injury

“…An important point is that the dysfunction of other organs is one of the main causes of poor outcomes from AKI: The inflammatory response following AKI, due to the loss of tubular function, has been shown to induce early and late cardiovascular, brain, lung, liver, and immune dysfunction even in the absence of progression toward CKD [ 30 , 31 , 32 ].…”

“…Future clinical studies should cope with crucial aspects which could help expand the implementation of this therapy: the possibility of EVs manipulation to enrich them with drugs or protective miRNAs to target specific cell types (for example, ECs) of lung or kidney [ 153 ]; standardized methods for EV isolation and storage; preconditioning procedures to enhance their therapeutic properties; definition of dose-response relationship; availability of new biomarkers to assess effectiveness of MSC-derived EVs after administration [ 32 , 154 ].…”

Biodistribution of Intratracheal, Intranasal, and Intravenous Injections of Human Mesenchymal Stromal Cell-Derived Extracellular Vesicles in a Mouse Model for Drug Delivery Studies

“…It has been shown that the MSC-derived EVs (MSC-EVs) partly mediate the MSC therapeutic functions through a paracrine way. Their mechanism of action can be summarized in their capability to directly regenerate different tissues, by protecting from damage-related inflammation events and inducing pro-proliferative and angiogenic programs in different organs [ 9 , 10 , 11 , 12 , 13 , 14 ]. On the clinical side, MSC-EVs provide important advantages, in respect to their cells of origin, such as their reduced immunogenicity and their efficient homing and uptake by different organs [ 15 , 16 ].…”

Exosomes Derived From Mesenchymal Stem Cells: Novel Effects in the Treatment of Ischemic Stroke

“…They contain several biologically active genomic and non-genomic molecules, including DNA, miRNAs, mRNA, lncRNA, various proteins, lipids, and enzymes, which can change the biological behavior of cells through paracrine or autocrine mechanisms ( Baruah and Wary, 2019 ). The special phospholipid bilayer of the exosomal membrane can prevent the decomposition of biologically active substances under harsh conditions and facilitate the storage of these exosomes in vitro ( Quaglia et al, 2022 ). These biological properties provide the basis for potentially new treatment modalities.…”