THESIS
2020
x leaves, 65 pages : illustrations (some color) ; 30 cm
Abstract
Muscle stem cells (MuSCs) are the resident stem cells in skeletal muscle responsible for adult
muscle regeneration. They remain quiescent in G
0 state and enter the cell cycle in response to
stimuli such as muscle injury. Aged MuSCs have a decreased regeneration capacity, which
can be attributed to two possible causes. The first one is related to the niche in which MuSCs
reside, containing mesenchymal stromal cells, immune cells, endothelial cells, and the
extracellular matrix. The deficiency in aged MuSCs regeneration capacity has been associated
with the extrinsic signals provided by the niche through Notch signaling, Wnt signaling, and
others. Another possible reason is that cells change intrinsically with age. The most plausible
hypothesis is that the intrinsic change is regu...[
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Muscle stem cells (MuSCs) are the resident stem cells in skeletal muscle responsible for adult
muscle regeneration. They remain quiescent in G
0 state and enter the cell cycle in response to
stimuli such as muscle injury. Aged MuSCs have a decreased regeneration capacity, which
can be attributed to two possible causes. The first one is related to the niche in which MuSCs
reside, containing mesenchymal stromal cells, immune cells, endothelial cells, and the
extracellular matrix. The deficiency in aged MuSCs regeneration capacity has been associated
with the extrinsic signals provided by the niche through Notch signaling, Wnt signaling, and
others. Another possible reason is that cells change intrinsically with age. The most plausible
hypothesis is that the intrinsic change is regulated by epigenetic change, which can be cell-autonomous
and/or downstream the signaling pathways. For example, aging is strongly
correlated with changes in DNA methylation. However, how histone modifications control
aged MuSC function remains unclear. It has been shown that H3K27me3 increases
significantly in MuSCs with age, which is related to gene silencing by polycomb repressive complex 2 (PRC2). Our study characterized the pattern of a histone mark on the same residue
that is associated with transcriptional activation, H3K27ac, in young and aged MuSC
quiescence and activation. We found a globally elevated H3K27ac level in aged quiescent
MuSCs despite the minor alteration in the distribution pattern. Since acetylation neutralizes
the charge of lysine and weakens the bond between histone and DNA, our result suggests that
aged MuSCs have a more open chromatin structure than young MuSCs. Furthermore, the
increase of the H3K27ac level observed in some of the genes may contribute to the impaired
function with age. Taken together, aged MuSCs may have a weaker control of the gene
expression that leads to the declined function.
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