Senescence-Associated Molecular and Epigenetic Alterations in Mesenchymal Stem Cell Cultures from Amniotic Fluid of Normal and Fetus-Affected Pregnancy.
Human amniotic-fluid-derived mesenchymal stem cells (AF-MSCs) are interesting for their multilineage differentiation potential and wide range of therapeutic applications due to the ease of culture expansion. However, MSCs undergo replicative senescence. So far, the molecular mechanisms that underlie fetal diseases and cell senescence are still poorly understood. Here, we analyzed senescence-associated morphologic, molecular, and epigenetic characteristics during propagation of MSCs derived from AF of normal and fetus-affected pregnancy. AF-MSCs cultures from both cell sources displayed quite similar morphology and expression of specific cell surface (CD44, CD90, and CD105) and stemness (Oct4, Nanog, Sox2, and Rex1) markers but had interindividual variability in proliferation capability and time to reach senescence. Within passages 4 and 8, senescent cultures exhibited typical morphological features, senescence-associatedβ-galactosidase activity, increased levels of p16, and decreased levels of miR-17 and miR-21 but showed differential expression of p21, p53, and ATM dependently on the onset of cell senescence. These differences correlated with changes in the level of chromatin modifiers (DNMT1 and HDAC1) and polycomb group proteins (EZH2, SUZ12, and BMI1) paralleling with changes in the expression of repressive histone marks (H3K9me3 and H3K27me3) and stemness markers (Oct4, Nanog, Sox2, and Rex1). Therefore epigenetic factors are important for AF-MSCs senescence process that may be related with individuality of donor or a fetus malignancy status.
Department of Molecular Cell Biology, Institute of Biochemistry, Vilnius University, LT-10257 Vilnius, Lithuania.
Jūratė
J
Savickienė
Department of Molecular Cell Biology, Institute of Biochemistry, Vilnius University, LT-10257 Vilnius, Lithuania.
Sandra
S
Baronaitė
Department of Molecular Cell Biology, Institute of Biochemistry, Vilnius University, LT-10257 Vilnius, Lithuania.
Aistė
A
Zentelytė
Department of Molecular Cell Biology, Institute of Biochemistry, Vilnius University, LT-10257 Vilnius, Lithuania.
Gražina
G
Treigytė
Department of Molecular Cell Biology, Institute of Biochemistry, Vilnius University, LT-10257 Vilnius, Lithuania.
Rūta
0000-0002-1077-9439
R
Navakauskienė