Epigenetic Modifications upon Senescence of Mesenchymal Stem Cells

Abstract

Cellular senescence is a continuous and highly organized process that alters the intricate genomic network in order to maintain cellular homeostasis. It occurs in all primary cell cultures-including mesenchymal stem cells (MSCs), which are concurrently tested for a wide variety of clinical applications. Differentiation potential as well as paracrine secretion of MSCs is severely affected by cellular senescence. There is a growing perception that nuclear reorganization and epigenetic modifications contribute to trigger and maintain functional differences in long-term culture. In this review, we discuss molecular and epigenetic aspects that evoke functional changes in cellular aging-indicating that the underlying process is not only an accumulation of cellular defects, but rather epigenetically orchestrated.

Engineering Lineage Potency and Plasticity of Stem Cells using Epigenetic Molecules

“…Frazen et al . recently showed that epigenetic modifications are associated with senescence in hMSCs 72 . Our study has further demonstrated that age related loss of differentiation potential can be rescued through modulating epigenetic modifications by innovatively employing small molecules.…”

Mesenchymal Stromal/Stem Cells in Regenerative Medicine and Tissue Engineering

“…With regard to aging, CFU-F frequency within the bone marrow generally declines with age, and the capacity of the remaining MSCs to withstand oxidative stress appears to also decline along with their function and therapeutic efficacy [ 129 – 131 ]. Such functional changes may be the result of progressively shortening telomeres, accumulated molecular damage, and stochastic genetic and epigenetic changes over time [ 132 – 136 ]. Such age-associated epigenetic dysregulation may also contribute to alterations in the differentiation potential and heterogeneity of MSCs [ 137 , 138 ].…”

RANK links senescence to stemness in the mammary epithelia, delaying tumor onset but increasing tumor aggressiveness

“…Here, we show that Rank-induced senescence is essential for Rank-driven stemness: upon elimination of senescent cells located in the luminal compartment, the enhanced stemness phenotype is lost. TLX and EZH2 targets are enriched in luminal Rank +/tg MECs, suggesting that the stemness/senescence phenotypes may be controlled by epigenetic mechanisms ( Franzen et al., 2016 ; Lee and Schmitt, 2019 ; Orioli and Dellambra, 2018 ; Yang and Sen, 2018 ). Of note, multiple genes were differentially expressed in Rank +/tg basal cells, including downregulation of the p53 target p21 , indicative of a luminal/basal crosstalk.…”