1. Baxter Laboratory in Genetic Pharmacology, Department of Microbiology and Immunology, Stem Cell Institute, Stanford University School of Medicine, Stanford, California 94305-5175, USA
2. These authors contributed equally to this work.
3. Present address: Pfizer Global Research & Development, Genetically Modified Models Center of Emphasis, Groton, Connecticut 06340, USA.

Correspondence to: Helen M. Blau¹ Correspondence and requests for materials should be addressed to H.M.B. (Email: hblau@stanford.edu).

Abstract

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 isolated^{3, 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 heterogeneous^{4, 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.

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