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  • br Results br Discussion An important barrier


    Discussion An important barrier for the use of satellite c14ɑ demethylase in regenerative medicine, for instance in the field of muscular dystrophies, is the lack of understanding of how to maintain isolated satellite cells in culture such that they are of therapeutic use (Aziz et al., 2012). The PC muscle seems to have high regenerative activity (Brazelton et al., 2003) and is not only accessible but also dispensable and, as such, can be repeatedly biopsied. For these reasons the PC may be considered as a good muscle for the study of satellite cell biology. In this article we unravel unique aspects of PC muscle biology and describe the origin and role of satellite cells upon skin and muscle wounding. In response to full-thickness skin wounding, we show an increase in muscle regeneration but no contribution of the Pax7-derived cell lineage to the myofibroblasts in the wound bed. This is relevant because a putative role of PC muscle in facilitating the rapid healing (by second intention) observed in rodents has been hypothesized (Greenwood, 2010; Volk and Bohling, 2013). At the wound edge, skNAC, a factor regulating postnatal muscle regeneration (Park et al., 2010), is upregulated in the adjacent PC fibers (Munz et al., 1999), and TAp63+ cells appear in both the PC and newly formed granulation tissue (Bamberger et al., 2005). TAp63 has been linked to dermal stem cell function (Su et al., 2009), and contraction of the granulation tissue supports rapid healing (Billingham and Medawar, 1955; Brunius et al., 1968; Watts et al., 1958). Our lineage-tracing data demonstrate no contribution of Pax7 lineage-derived cells, i.e., activated satellite cells or components of the regenerated myofibers into the granulation tissue, although we cannot discard the contribution from other cell lineages present in PC muscle. In the TA muscle irradiation/CTX model, which is a more standardized muscle injury model, we see that the dermis-derived cells are able to regenerate myofibers, as expected for transplanted satellite cells in such a model. Previous reports had shown an increased contribution of bone marrow-derived cells (possibly HSCs) to PC muscle (Brazelton et al., 2003; Corbel et al., 2003). This incorporation is unique in that it is highly divergent to other muscle groups (Camargo et al., 2003; Ferrari et al., 1998, 2001; Ferrari and Mavilio, 2002; Sherwood et al., 2004a; Sherwood et al., 2004b; Wagers et al., 2002). However, the donor bone marrow cells, even if able to engraft into the PC satellite cell niche, were unable to generate myotubes from dermis-derived sphere cultures. This may be due to several reasons, but it is tempting to speculate that the engrafted cells failed to reach full conversion to the satellite cell fate, as previously shown in other systems (Cossu, 2004; Lapidos et al., 2004). The relevance of circulating HSC fusion into heart and skeletal muscle are unclear, but the phenomenon keeps arising in the literature (Quijada and Sussman, 2015), and occurs also in human muscle (Stromberg et al., 2013). Based on these results we propose the PC as the most appropriate system to further understand the role of mobilized cells that engraft in skeletal muscle, a research area that has been neglected possibly because of the extreme rarity of the fusion events in the muscle groups that are most often analyzed. Determining the identity of the homing factor(s) that facilitate an increased engraftment of mobilized cells into the PC in comparison with other skeletal muscles might be exploited for therapeutic use (Asakura, 2012). Potential candidates include the SDF-1/CXCR4 axis (Cheng et al., 2015), although it is important to note that as the PC is signaling for mobilized cell engraftment in the absence of injury, the nature of the signal might be different. Regarding the developmental origin of PC satellite cells, we have shown that this muscle is no different to other trunk muscles in that it originates from Myf5, Pax3/Pax7 progenitors. This will help in respect of comparability with studies performed in satellite cells from other trunk muscles. Finally, for many years it has been known that a small population of dermal cells, of unknown origin, presents myogenic properties (reviewed by White and Grounds, 2003). Our results unequivocally demonstrate that PC satellite cells are the myogenic precursor cells of murine dermis. The present article and other recent data showing that dermis-derived neural stem cells arise from the Schwann cell lineage (Etxaniz et al., 2014; Gresset et al., 2015) urge us to interpret with caution some of the multipotency wrongly attributed to tissue-resident precursors.