A component of the niche surrounding muscle stem cells regulates their differentiation by controlling the activation of Notch signaling, Pisconti et al. report.
Satellite cells—adult muscle progenitors—express Syndecan-3, a transmembrane proteoglycan that interacts with the extracellular environment to regulate the stem cells' fate. Syndecan-3 is already known to modulate HGF and FGF signaling, but Pisconti et al. found that satellite cells lacking the proteoglycan failed to activate target genes of the Notch pathway.
Mutant progenitors stalled in S phase and were therefore slower to differentiate upon stem cell activation. Nevertheless, Syndecan-3–deficient cells were more likely to terminally differentiate than return to the quiescent pool of progenitors. Mice lacking Syndecan-3 thus developed abnormally large myofibers and retained fewer satellite cells following muscle injury.
Syndecan-3–null cells contained less Notch intracellular domain (NICD), a cleavage fragment of the Notch receptor that translocates to the nucleus to induce target gene expression. Expressing the NICD fragment rescued the proliferation and self-renewal of Syndecan-3–deficient progenitors, as did Notch receptor mutants that bypassed the requirement for cleavage by the ADAM17 metalloproteinase. Syndecan-3 promotes this essential step in the generation of NICD by forming a complex that contains the Notch receptor at the satellite cell plasma membrane.
Senior author Bradley Olwin says that Syndecan-3 may recruit ADAM17 into this complex or increase the enzyme's activity in some way to permit Notch signaling and regulate the size of the muscle satellite cell pool.