Self-renewal and expansion of single transplanted muscle stem cells

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Abstract
Muscle satellite cells are quiescent cells found in the spaces between a muscle fibre and its membranous sheath, where they respond to damage by forming progenitors that fuse with muscle fibres. There are reports that they can act as stem cells, but the mixed nature of satellite cell populations means that their 'stem-cell-ness' is difficult to prove. Sacco et al. have clarified matters by using clonal analysis to confirm that satellite cells are indeed stem cells, capable of self renewal. They transplant a single luciferase-expressing satellite cell into the muscle of mice, and show that it is capable of extensive proliferation, contributes to muscle fibres, and can be re-transplanted. Clonal analysis is used to show that muscle satellite cells are in fact stem cells and are capable of self renewal. A single luciferase-expressing muscle stem cell is transplanted into the muscle of mice, and it is shown that it is capable of extensive proliferation, contributes to muscle fibres and can be transplanted. Imaging is also used to show that the muscle stem cells are highly proliferative following muscle damage in the course of repair. Adult muscle satellite cells have a principal role in postnatal skeletal muscle growth and regeneration1. Satellite cells reside as quiescent cells underneath the basal lamina that surrounds muscle fibres2 and respond to damage by giving rise to transient amplifying cells (progenitors) and myoblasts that fuse with myofibres. Recent experiments showed that, in contrast to cultured myoblasts, satellite cells freshly isolated3,4,5 or satellite cells derived from the transplantation of one intact myofibre6 contribute robustly to muscle repair. However, because satellite cells are known to be heterogeneous4,6,7, clonal analysis is required to demonstrate stem cell function. Here we show that when a single luciferase-expressing muscle stem cell is transplanted into the muscle of mice it is capable of extensive proliferation, contributes to muscle fibres, and Pax7+luciferase+ mononucleated cells can be readily re-isolated, providing evidence of muscle stem cell self-renewal. In addition, we show using in vivo bioluminescence imaging that the dynamics of muscle stem cell behaviour during muscle repair can be followed in a manner not possible using traditional retrospective histological analyses. By imaging luciferase activity, real-time quantitative and kinetic analyses show that donor-derived muscle stem cells proliferate and engraft rapidly after injection until homeostasis is reached. On injury, donor-derived mononucleated cells generate massive waves of cell proliferation. Together, these results show that the progeny of a single luciferase-expressing muscle stem cell can both self-renew and differentiate after transplantation in mice, providing new evidence at the clonal level that self-renewal is an autonomous property of a single adult muscle stem cell.