Human umbilical cord perivascular cells-derived extracellular vesicles mediate the transfer of IGF-I to the liver and ameliorate hepatic fibrogenesis in mice

被引：32

作者：

Fiore, Esteban ^{[1
,2
]}

Dominguez, Luciana M. ^{[1
]}

Bayo, Juan ^{[1
,2
]}

Malvicini, Mariana ^{[1
,2
]}

Atorrasagasti, Catalina ^{[1
,2
]}

Rodriguez, Marcelo ^{[1
]}

Jose Cantero, Maria ^{[1
]}

Garcia, Mariana ^{[1
,2
]}

Yannarelli, Gustavo ^{[2
,3
]}

Mazzolini, Guillermo ^{[1
,2
]}

机构：

[1] Univ Austral, Gene Therapy Lab, Inst Invest Med Traslac, CONICET, Av Pte Peron 1500 B1629AHJ Derqui Pilar, Buenos Aires, DF, Argentina

[2] Consejo Nacl Invest Cient & Tecn, CONICET, Buenos Aires, DF, Argentina

[3] Univ Favaloro, Lab Regulac Gen & Celulas Madre, Inst Med Traslac Trasplante & Bioingn IMeTTyB, CONICET, Buenos Aires, DF, Argentina

来源：

GENE THERAPY | 2020年 / 27卷 / 1-2期

关键词：

MESENCHYMAL STROMAL CELLS; GROWTH-FACTOR-I; STEM-CELLS; EXOSOMES; FIBROSIS; REGENERATION; CIRRHOSIS; INJURY;

D O I：

10.1038/s41434-019-0102-7

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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-beta 1, alpha-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.

引用

页码：62 / 73

页数：12

共 36 条

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