MFGE-8 identified in fetal mesenchymal-stromal-cell-derived exosomes ameliorates acute hepatic failure pathology

Adriana Psaraki; Dimitra Zagoura; Lydia Ntari; Manousos Makridakis; Christina Nikokiraki; Ourania Trohatou; Konstantina Georgila; Christos Karakostas; Ioanna Angelioudaki; Anastasios G Kriebardis; Roberto Gramignioli; Stratigoula Sakellariou; Maria Xilouri; Aristides G Eliopoulos; Antonia Vlahou; Maria G Roubelakis

doi:10.1016/j.isci.2023.108100

MFGE-8 identified in fetal mesenchymal-stromal-cell-derived exosomes ameliorates acute hepatic failure pathology

iScience. 2023 Sep 30;26(11):108100. doi: 10.1016/j.isci.2023.108100. eCollection 2023 Nov 17.

Authors

Adriana Psaraki^{1

2}, Dimitra Zagoura¹, Lydia Ntari¹, Manousos Makridakis³, Christina Nikokiraki^{1

2}, Ourania Trohatou¹, Konstantina Georgila¹, Christos Karakostas¹, Ioanna Angelioudaki¹, Anastasios G Kriebardis⁴, Roberto Gramignioli^{5

6}, Stratigoula Sakellariou⁷, Maria Xilouri⁸, Aristides G Eliopoulos¹, Antonia Vlahou³, Maria G Roubelakis^{1

2}

Affiliations

¹ Laboratory of Biology, School of Medicine, National and Kapodistrian University of Athens (NKUA), Athens, Greece.
² Cell and Gene Therapy Laboratory, Centre of Basic Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece.
³ Biotechnology Laboratory, Centre of Basic Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece.
⁴ Laboratory of Reliability and Quality Control in Laboratory Hematology (HemQcR), Department of Biomedical Sciences, Section of Medical Laboratories, School of Health & Caring Sciences, University of West Attica (UniWA), Ag. Spyridonos Str, 12243 Egaleo, Greece.
⁵ Clinical Pathology and Cancer Diagnosis Unit, Karolinska Institute, 141 57 Huddinge, Sweden.
⁶ Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, 171 77 Stockholm, Sweden.
⁷ First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens (NKUA), Athens, Greece.
⁸ Center of Clinical Research, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens, Greece.

Abstract

Liver transplantation is the gold-standard therapy for acute hepatic failure (AHF) with limitations related to organ shortage and life-long immunosuppressive therapy. Cell therapy emerges as a promising alternative to transplantation. We have previously shown that IL-10 and Annexin-A1 released by amniotic fluid human mesenchymal stromal cells (AF-MSCs) and their hepatocyte progenitor-like (HPL) or hepatocyte-like (HPL) cells induce liver repair and downregulate systemic inflammation in a CCl₄-AHF mouse model. Herein, we demonstrate that exosomes (EXO) derived from these cells improve liver phenotype in CCl₄-induced mice and promote oval cell proliferation. LC-MS/MS proteomic analysis identified MEFG-8 in EXO cargo that facilitates rescue of AHF by suppressing PI3K signaling. Administration of recombinant MFGE-8 protein also reduced liver damage in CCl₄-induced mice. Clinically, MEFG-8 expression was decreased in liver biopsies from AHF patients. Collectively, our study provides proof-of-concept for an innovative, cell-free, less immunogenic, and non-toxic alternative strategy for AHF.

Keywords: Biological sciences; Cell biology; Molecular biology; Stem cells research.