Human umbilical cord perivascular cells-derived extracellular vesicles mediate the transfer of IGF-I to the liver and ameliorate hepatic fibrogenesis in mice.
Adenoviridae
/ metabolism
Animals
Extracellular Vesicles
/ metabolism
Gene Expression
/ genetics
Hepatocytes
/ metabolism
Human Umbilical Vein Endothelial Cells
/ cytology
Humans
Insulin-Like Growth Factor I
/ metabolism
Liver
/ pathology
Liver Cirrhosis
/ therapy
Male
Mesenchymal Stem Cell Transplantation
/ methods
Mesenchymal Stem Cells
/ metabolism
Mice
Mice, Inbred BALB C
Transforming Growth Factor beta1
/ metabolism
Umbilical Cord
/ cytology
Journal
Gene therapy
ISSN: 1476-5462
Titre abrégé: Gene Ther
Pays: England
ID NLM: 9421525
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
15
01
2019
accepted:
26
08
2019
revised:
08
08
2019
pubmed:
26
9
2019
medline:
7
1
2021
entrez:
26
9
2019
Statut:
ppublish
Résumé
Extracellular vesicles (EVs) can mediate mesenchymal stromal cells (MSCs) paracrine effects. We aimed to evaluate the therapeutic potential of human umbilical cord perivascular cells (HUCPVCs) engineered to produce Insulin Growth Factor like-I (IGF-I) in experimental liver fibrosis and the role of EVs in this effect. HUCPVCs were engineered to produce human IGF-I (AdhIGF-I) or green fluorescence protein (AdGFP) using adenoviruses, and EVs were isolated from their conditioned medium (CM). In vitro effects of CM and EVs on hepatic stellate cells and hepatic macrophages were studied. Cells or EVs-based treatments were evaluated in thioacetamide-induced liver fibrosis in mice. The application of AdhIGF-I-HUCPVCs resulted in a further amelioration of liver fibrosis when compared to AdGFP-HUCPVCs and saline. Similarly, treatment with AdhIGF-I-HUCPVCs-derived EVs resulted in a reduction of collagen deposition and gene expression of the fibrogenic related molecules TGF-β1, α-SMA, and COL1A2. In vitro incubation of hepatic stellate cells with EVs-AdhIGF-I-HUCPVCs significantly reduced activation of fibrogenic cells. In addition, EVs-AdhIGF-I-HUCPVCs trigger hepatic macrophages to switch their phenotype towards anti-inflammatory phagocytes, which might be involved in the antifibrotic effect. Consistently, high levels of IGF-I were observed within EVs-AdhIGF-I-HUCPVCs but not in controls EVs. Our results showed that hIGF-I carrying EVs could mediate the paracrine mechanism by which AdhIGF-I-HUCPVCs reduce liver fibrosis.
Identifiants
pubmed: 31551525
doi: 10.1038/s41434-019-0102-7
pii: 10.1038/s41434-019-0102-7
doi:
Substances chimiques
IGF1 protein, human
0
Transforming Growth Factor beta1
0
Insulin-Like Growth Factor I
67763-96-6
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
62-73Références
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