Wound Healing Society

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Contribution Of Individual Satellite Cells To Muscle Regeneration Assessed Using A Confetti Mouse Model
Hans Heemskerk1, N Suhas Jagannathan1, Binh Phu Nguyen1, Keshmarathy D/O Sacadevan2, Paul Matsudaira2, Peter TC So3, Lisa Tucker-Kellogg1.
1Duke-NUS Medical School, Singapore, Singapore, 2National University of Singapore, Singapore, Singapore, 3Massachusetts Institute of Technology, Cambridge, MA, USA.

Background: Satellite cells are capable of completely replacing muscle fibers after injury, by producing a large number of myoblasts. However, the contribution of individual satellite cells is poorly understood in vivo.
Methods: To assess the relative contribution of individual satellite cells, we developed a mouse with inducible fluorescence in satellite cells [1]. After tamoxifen induction, the mice express one of four fluorescent colors in Pax7+ cells, while the remaining muscle tissue is non-fluorescent.
Results: Sixteen days after a cardiotoxin injury in healthy 6-month-old mice, up to ninety percent of muscle fibers in the injured area were fluorescent, indicating that fluorescent satellite cells contributed to regeneration of almost all fibers. Most strikingly, the four fluorescent colors of the confetti mouse appeared in regional patches, rather than uniformly distributed across the fibers. Using computational image analysis [2] and stochastic modeling, we analyzed the distribution of observed isochromatic patches, and concluded that the observed color patches were not statistically compatible with satellite cells contributing myonuclei to only a single fiber. Instead we infer that roughly a third of the fluorescent satellite cells must have contributed myonuclei toward multiple fibers.
Conclusions: These results have implications for our understanding of the muscle regeneration process, not only in normal circumstances, but also in pathologies such as muscular dystrophy, sarcopenia, and chronic ulcers. Furthermore, this confetti mouse will be useful for further studies of muscle regeneration, particularly for interrogating the ability of candidate interventions [3-4] to alter the regenerative function of endogenous satellite cells.
[1] Tucker-Kellogg et al., Wound Repair and Regeneration 24(2):A26, 2016.
[2] Nguyen et al., BMC Systems Biology 10(5):124, 2016.
[3] Heemskerk et al., Annals of the New York Academy of Sciences 1175(1):71, 2009.
[4] Jagannathan et al., Journal of Biomechanics 49(8):1311, 2016.


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