Human Liver Stem Cell Derived Extracellular Vesicles Alleviate Kidney Fibrosis by Interfering with the β-Catenin Pathway through miR29b

Abstract

Human liver stem-cell-derived extracellular vesicles (HLSC-EVs) exhibit therapeutic properties in various pre-clinical models of kidney injury. We previously reported an overall improvement in kidney function following treatment with HLSC-EVs in a model of aristolochic acid nephropathy (AAN). Here, we provide evidence that HLSC-EVs exert anti-fibrotic effects by interfering with β-catenin signalling. A mouse model of AAN and an in vitro pro-fibrotic model were used. The β-catenin mRNA and protein expression, together with the pro-fibrotic markers α-SMA and collagen 1, were evaluated in vivo and in vitro following treatment with HLSC-EVs. Expression and functional analysis of miR29b was performed in vitro following HLSC-EV treatments through loss-of-function experiments. Results showed that expression of β-catenin was amplified both in vivo and in vitro, and β-catenin gene silencing in fibroblasts prevented AA-induced up-regulation of pro-fibrotic genes, revealing that β-catenin is an important factor in fibroblast activation. Treatment with HLSC-EVs caused increased expression of miR29b, which was significantly inhibited in the presence of α-amanitin. The suppression of the miR29b function with a selective inhibitor abolished the anti-fibrotic effects of HLSC-EVs, resulting in the up-regulation of β-catenin and pro-fibrotic α-Sma and collagen type 1 genes. Together, these data suggest a novel HLSC-EV-dependent regulatory mechanism in which β-catenin is down regulated by HLSC-EVs-induced miR29b expression.

Extracellular Vesicles Derived from Human Liver Stem Cells Attenuate Chronic Kidney Disease Development in an In Vivo Experimental Model of Renal Ischemia and Reperfusion Injury

“…Furthermore, HLSC-EVs expressed mesenchymal markers CD29, CD44, and CD105, but did not express endothelial (CD31), hematopoietic (CD45, CD3, CD8, etc. ), or epithelial (CD24 and CD326) markers [data not shown], as previously reported [36][37][38]. Nanoparticle tracking analysis on EVs revealed the typical size distribution of exosomes and shedding vesicles and transmission electron microscopy analysis confirmed that the EVs had a homogeneous pattern of nanosized membrane vesicles (Figure 1B).…”

Possible testosterone redundancy for 5α-dihydrotestosterone in the masculinization of mouse external genitalia

“…A previous paper suggests that endothelial β-catenin signaling is a promoting factor in angiogenesis [31]. In addition to being an angiogenic factor, it has been also reported that β-catenin is involved for collagen synthesis [32,33]. Further analyses on Wnt/β-catenin signaling will reveal molecular mechanisms of CC formation under androgen signaling.…”

Bibliometric analysis of scientific papers on extracellular vesicles in kidney disease published between 1999 and 2022

“…Camussi Giovanni (corresponding author) from the Department of Medical Sciences, University of Turin, was the top 5 prolific author for EVs in kidney disease. He mainly focused on the association of EVs with kidney-related diseases (AKI, CKD, systemic lupus erythematosus, ANCA-vasculitis, kidney fibrosis, and diabetic nephropathy) (Biancone and Camussi, 2014;Collino et al, 2015;Lener et al, 2015;Bussolati and Camussi, 2017;Dimuccio et al, 2020;Grange et al, 2020;Kholia et al, 2020;Ramírez-Bajo et al, 2020;Tetta et al, 2020;Kholia et al, 2021;Mazzariol et al, 2021;Bruno et al, 2022;Franzin et al, 2022). Additionally, Cortes Perez-Hernandez et al, 2016;Perez-Hernandez et al, 2017;Perez-Hernandez et al, 2018a;Perez-Hernandez et al, 2018b;Olivares et al, 2018;Olivares et al, 2020;Ortega et al, 2020;Perez-Hernandez et al, 2021a;Perez-Hernandez et al, 2021b;Redon et al, 2021;Martinez-Arroyo et al, 2022).…”

“…Camussi Giovanni (corresponding author) from the Department of Medical Sciences, University of Turin, was the top 5 prolific author for EVs in kidney disease. He mainly focused on the association of EVs with kidney-related diseases (AKI, CKD, systemic lupus erythematosus, ANCA-vasculitis, kidney fibrosis, and diabetic nephropathy) ( Biancone and Camussi, 2014 ; Collino et al, 2015 ; Lener et al, 2015 ; Bussolati and Camussi, 2017 ; Dimuccio et al, 2020 ; Grange et al, 2020 ; Kholia et al, 2020 ; Ramírez-Bajo et al, 2020 ; Tetta et al, 2020 ; Kholia et al, 2021 ; Mazzariol et al, 2021 ; Bruno et al, 2022 ; Franzin et al, 2022 ). Additionally, Cortes Raquel (corresponding author) from the Cardiometabolic and Renal Risk Research Group, INCLIVA Biomedical Research Institute, was the top 4 prolific author for EVs in kidney-related diseases.…”