TY - JOUR
TI - Functional secretome analysis reveals Annexin-A1 as important paracrine factor derived from fetal mesenchymal stem cells in hepatic regeneration
AU - Zagoura, D.
AU - Trohatou, O.
AU - Makridakis, M.
AU - Kollia, A.
AU - Kokla, N.
AU - Mokou, M.
AU - Psaraki, A.
AU - Eliopoulos, A.G.
AU - Vlahou, A.
AU - Roubelakis, M.G.
JO - EBioMedicine
PY - 2019
VL - 45
TODO - null
SP - 542-552
PB - Elsevier B.V.
SN - 2352-3964
TODO - 10.1016/j.ebiom.2019.07.009
TODO - alanine aminotransferase;  aspartate aminotransferase;  cathepsin D;  CD24 antigen;  connective tissue growth factor;  decorin;  lentivirus vector;  lipocortin 1;  metalloproteinase inhibitor;  osteonectin;  somatomedin binding protein 3;  vimentin;  lipocortin 1;  signal peptide, acute liver failure;  amnion fluid;  animal experiment;  animal model;  animal tissue;  apoptosis;  apoptosis assay;  Article;  bioassay;  bioinformatics;  cell infiltration;  cell isolation;  cell migration assay;  cell proliferation;  colony forming unit;  computer model;  controlled study;  down regulation;  echography;  enzyme linked immunosorbent assay;  ex vivo study;  genetic transduction;  hepatic progenitor cell;  in vivo study;  ingenuity pathway analysis;  liquid chromatography-mass spectrometry;  liver function;  liver injury;  liver regeneration;  mesenchymal stem cell;  mouse;  MTS assay;  MTS proliferation assay;  nonhuman;  periodic acid Schiff stain;  priority journal;  protein analysis;  protein expression;  proteomics;  real time polymerase chain reaction;  RNA interference;  ultra performance liquid chromatography;  upregulation;  Western blotting;  animal;  bone marrow cell;  conditioned medium;  fetus;  genetics;  human;  liver;  liver regeneration;  mesenchymal stem cell;  mesenchymal stem cell transplantation;  metabolism;  pathology;  pharmacology;  proteomics, Animals;  Annexin A1;  Bone Marrow Cells;  Cell Proliferation;  Culture Media, Conditioned;  Fetus;  Humans;  Intercellular Signaling Peptides and Proteins;  Liver;  Liver Regeneration;  Mesenchymal Stem Cell Transplantation;  Mesenchymal Stem Cells;  Mice;  Proteomics
TODO - Background: Human mesenchymal stem/stromal cells (MSCs) and their secreted molecules exert beneficial effects in injured tissues by promoting tissue regeneration and angiogenesis and by inhibiting inflammation and fibrosis. We have previously demonstrated that the therapeutic activity of fetal MSCs derived from amniotic fluid (AF-MSCs) and their hepatic progenitor-like cells (HPL) is mediated by paracrine effects in a mouse model of acute hepatic failure (AHF). Methods: Herein, we have combined proteomic profiling of the AF-MSCs and HPL cell secretome with ex vivo and in vivo functional studies to identify specific soluble factors, which underpin tissue regeneration in AHF. Findings: The anti-inflammatory molecule Annexin-A1 (ANXA1) was detected at high levels in both AF-MSC and HPL cell secretome. Further functional analyses revealed that the shRNA-mediated knock-down of ANXA1 in MSCs (shANXA1-MSCs) decreased their proliferative, clonogenic and migratory potential, as well as their ability to differentiate into HPL cells. Liver progenitors (oval cells) from AHF mice displayed reduced proliferation when cultured ex vivo in the presence of conditioned media from shANXA1-MSCs compared to control MSCs secretome. Intra-hepatic delivery of conditioned media from control MSCs but not shANXA1-MSCs reduced liver damage and circulating levels of pro-inflammatory cytokines in AHF. Interpretation: Collectively, our study uncovers secreted Annexin-A1 as a novel effector of MSCs in liver regeneration and further underscores the potential of cell-free therapeutic strategies for liver diseases. Fund: Fondation Santé, GILEAD Asklipeios Grant, Fellowships of Excellence – Siemens, IKY, Reinforcement of Postdoctoral Researchers, IKY. © 2019 The Authors
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