THESIS
2017
xii, 139 pages : illustrations (some color) ; 30 cm
Abstract
The adult muscle stem cells, also called the muscle satellite cells (MuSC), are
absolutely required in the injury induced muscle regeneration. The function and
homeostasis of the MuSC are under complex yet stringent control by various
mechanisms, among which is the JAK/STAT signaling pathway. STAT3 was
previously found to regulate myoblast proliferation and differentiation in cell culture
studies. Two recent papers showed that in vivo inhibition of STAT3 signaling by
small molecule inhibitors or small interfering RNAs (siRNAs) enhanced MuSC
proliferation as well as muscle regeneration. However, global inhibition of STAT3
function by intramuscular injection of inhibitors or siRNAs would target multiple cell
types within the muscle tissues, since Stat3 is ubiquitously expressed....[
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The adult muscle stem cells, also called the muscle satellite cells (MuSC), are
absolutely required in the injury induced muscle regeneration. The function and
homeostasis of the MuSC are under complex yet stringent control by various
mechanisms, among which is the JAK/STAT signaling pathway. STAT3 was
previously found to regulate myoblast proliferation and differentiation in cell culture
studies. Two recent papers showed that in vivo inhibition of STAT3 signaling by
small molecule inhibitors or small interfering RNAs (siRNAs) enhanced MuSC
proliferation as well as muscle regeneration. However, global inhibition of STAT3
function by intramuscular injection of inhibitors or siRNAs would target multiple cell
types within the muscle tissues, since Stat3 is ubiquitously expressed. Such
approaches would make the data interpretation complicated. We decided to adopt
knockout mouse models to study STAT3’s function specifically in MuSC. Our
conditional Stat3 deletion in MuSC did not affect normal muscle development and
the establishment of the adult MuSC pool, but resulted in impairments in stem cell
self-renewal after injury, partly due to defective MuSC proliferation. Transcriptome
analysis and chromatin immunoprecipitation assays revealed that Pax7 is a direct
transcription target of STAT3 in MuSC. More severe phenotypes were found in a
dystrophic STAT3 and Dystrophin (Dmd) double knockout (dKO) mouse line that
displayed reduced MuSC number, severe fibrosis and enhanced inflammation. Our
data demonstrated that STAT3 critically regulates the self-renewal of MuSC upon
muscle injuries.
In addition to STAT3, I also studied the role of Pax7 in MuSC. Pax7 is known to be
indispensable for stem cell pool maintenance and expansion in adult MuSC.
However, it remains unclear how Pax7 exerts its functions. Our preliminary work
showed that ablation of Pax7 interfered with the cell cycle re-entry of the quiescent
MuSC. By whole transcriptome analysis, we identified genes regulated by Pax7 in
MuSC, which will shed light on the mechanisms by which Pax7 regulates the cell
cycle re-entry of the quiescent MuSC.
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