Extracellular Vesicles Derived from Human Liver Stem Cells Counteract Chronic Kidney Disease Development and Cardiac Dysfunction in Remnant Kidney Murine Model: The Possible Involvement of Proteases
Elena Ceccotti,
Giulia Chiabotto,
Massimo Cedrino,
Alessandro Gambella,
Luisa Delsedime,
Alessandra Ghigo,
Chiara Salio,
Cristina Grange,
Maria Beatriz Herrera Sanchez,
Saveria Femminò,
Marco Sassoè-Pognetto,
Maria Felice Brizzi,
Giovanni Camussi,
Stefania Bruno
Affiliations
Elena Ceccotti
Department of Medical Sciences, University of Torino, 10126 Torino, Italy
Giulia Chiabotto
Department of Medical Sciences, University of Torino, 10126 Torino, Italy
Massimo Cedrino
Unicyte S.r.l., 10126 Torino, Italy
Alessandro Gambella
Department of Medical Sciences, University of Torino, 10126 Torino, Italy
Luisa Delsedime
Pathology Unit, Città delle Salute e della Scienza Hospital, 10126 Torino, Italy
Alessandra Ghigo
Department of Molecular Biotechnology and Health Sciences, University of Torino, 10126 Torino, Italy
Chiara Salio
Department of Veterinary Sciences, University of Torino, Grugliasco, 10095 Torino, Italy
Cristina Grange
Department of Medical Sciences, University of Torino, 10126 Torino, Italy
Maria Beatriz Herrera Sanchez
2i3T, Società per la Gestione dell’Incubatore di Imprese e per il Trasferimento Tecnologico, University of Torino, 10126 Torino, Italy
Saveria Femminò
Department of Medical Sciences, University of Torino, 10126 Torino, Italy
Marco Sassoè-Pognetto
Department of Neurosciences “Rita Levi Montalcini”, University of Torino, 10126 Torino, Italy
Maria Felice Brizzi
Department of Medical Sciences, University of Torino, 10126 Torino, Italy
Giovanni Camussi
Department of Medical Sciences, University of Torino, 10126 Torino, Italy
Stefania Bruno
Department of Medical Sciences, University of Torino, 10126 Torino, Italy
Fibrosis is a marker of chronic kidney disease (CKD) and consists of the accumulation of the extracellular matrix (ECM) components, causing the progressive deterioration of kidney function. Human liver stem cells (HLSCs) have anti-fibrotic activity, and HLSC-derived extracellular vesicles (EVs) mediate this effect. Herein, we evaluated the ability of HLSC-EVs to reverse renal and cardiac alterations in a murine model of partial nephrectomy (PNx) that mimics human CKD development. Furthermore, we investigated the contribution of extracellular matrix remodeling-related proteases to the anti-fibrotic effect of HLSC-EVs. PNx was performed by ligation of both poles of the left kidney, followed one week later by the removal of the right kidney. EV treatment started 4 weeks after the nephrectomy, when renal and cardiac alternations were already established, and mice were sacrificed at week eight. HLSC-EV treatment improved renal function and morphology, significantly decreasing interstitial fibrosis, glomerular sclerosis, and capillary rarefaction. This improvement was confirmed by the decreased expression of pro-fibrotic genes. Moreover, EV treatment improved cardiac function and reduced cardiac fibrosis. HLSC-EVs shuttled different proteases with ECM remodeling activity, and matrix metalloproteinase 1 (MMP-1) was involved in their anti-fibrotic effect on renal tissue. HLSC-EV treatment interferes with CKD development and ameliorates cardiomyopathy in PNx mice.
