Administration of Human MSC-Derived Extracellular Vesicles for the Treatment of Primary Sclerosing Cholangitis: Preclinical Data in MDR2 Knockout Mice.
Roberta AngioniBianca CalìVasanthy VigneswaraMarika CrescenziAna MerinoRicardo Sánchez-RodríguezCristina LiboniMartin J HoogduijnPhilip Noel NewsomeMaurizio MuracaFrancesco Paolo RussoAntonella ViolaPublished in: International journal of molecular sciences (2020)
Primary Sclerosing Cholangitis (PSC) is a progressive liver disease for which there is no effective medical therapy. PSC belongs to the family of immune-mediated biliary disorders and it is characterized by persistent biliary inflammation and fibrosis. Here, we explored the possibility of using extracellular vesicles (EVs) derived from human, bone marrow mesenchymal stromal cells (MSCs) to target liver inflammation and reduce fibrosis in a mouse model of PSC. Five-week-old male FVB.129P2-Abcb4tm1Bor mice were intraperitoneally injected with either 100 µL of EVs (± 9.1 × 109 particles/mL) or PBS, once a week, for three consecutive weeks. One week after the last injection, mice were sacrificed and liver and blood collected for flow cytometry analysis and transaminase quantification. In FVB.129P2-Abcb4tm1Bor mice, EV administration resulted in reduced serum levels of alkaline phosphatase (ALP), bile acid (BA), and alanine aminotransferase (ALT), as well as in decreased liver fibrosis. Mechanistically, we observed that EVs reduce liver accumulation of both granulocytes and T cells and dampen VCAM-1 expression. Further analysis revealed that the therapeutic effect of EVs is accompanied by the inhibition of NFkB activation in proximity of the portal triad. Our pre-clinical experiments suggest that EVs isolated from MSCs may represent an effective therapeutic strategy to treat patients suffering from PSC.
Keyphrases
- liver fibrosis
- bone marrow
- mesenchymal stem cells
- flow cytometry
- endothelial cells
- high fat diet induced
- mouse model
- oxidative stress
- end stage renal disease
- healthcare
- induced pluripotent stem cells
- ejection fraction
- newly diagnosed
- poor prognosis
- multiple sclerosis
- chronic kidney disease
- randomized controlled trial
- electronic health record
- prognostic factors
- stem cells
- type diabetes
- cell therapy
- big data
- multidrug resistant
- artificial intelligence
- wild type
- ulcerative colitis
- gestational age
- deep learning
- study protocol
- combination therapy