Extracellular Vesicles Released from Stem Cells as a New Therapeutic Strategy for Primary and Secondary Glomerulonephritis

Abstract

Current treatment of primary and secondary glomerulopathies is hampered by many limits and a significant proportion of these disorders still evolves towards end-stage renal disease. A possible answer to this unmet challenge could be represented by therapies with stem cells, which include a variety of progenitor cell types derived from embryonic or adult tissues. Stem cell self-renewal and multi-lineage differentiation ability explain their potential to protect and regenerate injured cells, including kidney tubular cells, podocytes and endothelial cells. In addition, a broad spectrum of anti-inflammatory and immunomodulatory actions appears to interfere with the pathogenic mechanisms of glomerulonephritis. Of note, mesenchymal stromal cells have been particularly investigated as therapy for Lupus Nephritis and Diabetic Nephropathy, whereas initial evidence suggest their beneficial effects in primary glomerulopathies such as IgA nephritis. Extracellular vesicles mediate a complex intercellular communication network, shuttling proteins, nucleic acids and other bioactive molecules from origin to target cells to modulate their functions. Stem cell-derived extracellular vesicles recapitulate beneficial cytoprotective, reparative and immunomodulatory properties of parental cells and are increasingly recognized as a cell-free alternative to stem cell-based therapies for different diseases including glomerulonephritis, also considering the low risk for potential adverse effects such as maldifferentiation and tumorigenesis. We herein summarize the renoprotective potential of therapies with stem cells and extracellular vesicles derived from progenitor cells in glomerulonephritis, with a focus on their different mechanisms of actions. Technological progress and growing knowledge are paving the way for wider clinical application of regenerative medicine to primary and secondary glomerulonephritis: this multi-level, pleiotropic therapy may open new scenarios overcoming the limits and side effects of traditional treatments, although the promising results of experimental models need to be confirmed in the clinical setting.

Bone Marrow Mesenchymal Stromal/Stem Cell-Derived Extracellular Vesicles Promote Corneal Wound Repair by Regulating Inflammation and Angiogenesis

“…This is in line with previous findings, whereby EVs derived from BMSCs protected renal tubular epithelial cells from apoptosis in different mouse models of acute kidney injury through an RNA-based mechanism [ 55 , 56 ]. EVs derived from MSCs from different sources carry several important anti-apoptotic microRNAs (miRNAs) such as miR-21/-30/-125b/-130a/ 199a/-210/-223/-242 , or proteins, such as PCNA, BCL-XL and BCL-2 [ 57 , 58 ]. Moreover, several studies have investigated and reported on the functional proteins inside EVs by MS/MS proteomic analysis, highlighting the presence of proteins involved in proliferation, cell adhesion and other key signaling pathways [ 59 , 60 ].…”

Genotype-phenotype correlation of WT1 mutation-related nephropathy in Chinese children

“…Mesenchymal stem cell supplementation in azithromycin-induced rat nephropathy models maintains podocyte viability, reduces glomerular inflammation, and delay the progression of glomerular sclerosis (30). Stem cell therapy for podocytedamaged nephropathy still requires further research to progress from experimental models to clinical application (31). In addition, recent studies have shown that knock out the of the sphingoline kinase 2 (Sphk2) gene or using the highly selective Sphk2 inhibitor, SLM6031434, can upregulate WT1 expression in podocytes, protect against podocyte disease, and prevent proteinuria (32).…”

Extracellular Vesicles as Source of Biomarkers in Glomerulonephritis

“…In fact, although stem cells play an immunomodulatory role and can regenerate injured tissues, they also carry a potential risk for dedifferentiation and tumorigenesis. Stem-cell-derived extracellular vesicles were shown to possess the same anti-inflammatory/immunomodulatory properties of MSC and to be able to modulate fibrosis, and delay tubular and glomerular damage, without the inherent risks [ 128 ]. There is still a paucity of clinical studies about the role of EVs in KD.…”