Self-renewal and expansion of single transplanted muscle stem cells

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 isolated3–5 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.

Attributes of adult stem cells

“…Markers include Mcadherin [92], the transcription factor Pax7, but once activated by injury the myogenic genes Myf-5 and MyoD are switched on [93]. Transplantation of single satellite cells expressing CD34, Sca-1, Pax7 and the α7 integrin in mouse muscle results in their considerable expansion and, moreover, these cells could be reisolated, providing evidence of self-renewal [94].…”

Epigenetic regulation of aging stem cells

“…For example, muscle stem cells (satellite cells) are required for the regeneration of myofibers following injury or transplantation in humans and mice (Schultz et al, 1978;Zammit et al, 2002;Morgan and Partridge, 2003;Sacco et al, 2008;Corbu et al, 2010). Even for tissues with low turnover and regenerative capacity in response to injury, such as the brain, stem cells may play important roles in the adaptive nature of the tissue.…”

p38α MAPK Regulates Adult Muscle Stem Cell Fate by Restricting Progenitor Proliferation During Postnatal Growth and Repair

“…Satellite cells are the principal muscle stem cell [1][2][3][4], responsible for the majority of postnatal growth and repair [5], and are capable of remarkable regenerative capability [6]. In response to extracellular stimuli, they activate and undergo a crucial proliferative expansion, before either returning to quiescence or differentiating and fusing to existing myofibers.…”