Watch your notch: a link between aging and stem cell fate?

Abstract

9 PROGENITOR STEM CELLS can be found in nearly every tissue. These quiescent precursor cells are involved in the continual maintenance and repair of the tissues throughout the life span of the individual. In skeletal muscle, these cells are positioned between the basal lamina and the plasma membrane of muscle fibers. Growth and repair of muscles is mediated by this resident population of mononuclear myogenic progenitor cells, often called satellite cells. These satellite cells form myoblasts, which in turn give rise to muscle cells. The fate of a stem cell is controlled by different genes.1 Of special interest is the Notch gene. Notch genes encode single path transmembrane glycoprotein receptors that are found on embryonic stem (ES) cells, adult bone marrow stem cells, and tissue specific progenitor cells. Notch activation leads to suppression of lineage-specific genes.2,3 There are at least four different Notch genes in mammals, and five Notch ligands have been identified so far in humans: Jagged-1, Jagged-2, Delta-like-1, Delta-like-3, and Delta-like-4.4 Modulators of Notch signaling include Fringe, Disheveled, Numb, and Neuralized.5 Cells vary in their expression of receptors, ligands, and inhibitors. In tissue, the interplay of these parameters constitutes a localized differentiation profile.5 The relevant pairing combinations for our present purposes are receptor Notch-1, its ligand Delta-1, and its inhibitor Numb. With age, it is thought that more and more progenitor cells become quiescent and stop dividing. Notch has been connected with the aging of stem cells.6 The specific role of Notch in the regeneration of aging muscle tissue has been investigated in the paper by Conboy et al.7 discussed here. Conboy et al.7 observed that the injured muscle of old mice had a diminished ability to generate myoblasts. However, the authors’ findings would suggest that this was not due to a reduction in the number of satellite cells. Thus it was suggested that injury-dependent activation of satellite cells was impaired during aging. Indeed, Conboy et al. demonstrated that old satellite cells had lower levels of activated Notch and, moreover, that cells did not upregulate the activating ligand Delta-1 after injury. But the group did not stop there. They proceeded to induce activation of Notch in old muscle. This showed improved muscle regeneration, suggesting that Notch was “sufficient to promote effective regeneration of aged muscle.” In a further step, inhibition of Notch-1 in cells from young animals produced a marked decrease in regenerative ability. In summary, the authors concluded that “inadequate activation of Notch-1 by Delta contributes to the loss of regenerative potential in old skeletal muscle.”