Apaper in this issue from the laboratory of Guilio Cossu ( De Angelis et al. 1999) is of particular interest because it goes against the grain of what we think we know about two fundamental aspects of muscle biology: first, the embryonic origin of muscle cells; and, second, how damaged muscle repairs itself. Current models indicate that the nuclei in skeletal muscle myofibers originate from the embryonic somites, specifically from the cells located in the dorsal somite epithelium ( Fig. 1 and Fig. 2). Adult skeletal muscle tissue is complex, consisting of multinucleated, contractile myofibers wrapped in connective tissue through which the blood vessels and nerves course ( Fig. 3). Satellite cells are mononucleated cells that reside inside the basal lamina secreted by adult myofibers. When activated through injury, satellite cells initiate stem cell activity and gene expression that leads to the regeneration, replacement and/or hypertophy of vertebrate skeletal muscle fibers ( Bischoff 1994; Yablonka-Reuveni 1995; Cornelison and Wold 1997). Evidence supporting the somitic origin of the nuclei that compose skeletal myofibers is substantial (recently reviewed in Ordahl et al. 1999). The source(s) of satellite cells, on the other hand, has never been unequivocally established ( Armand et al. 1983). A recent paper that resulted from a collaboration that included the Cossu group, showed that blood-borne cells constituted a small but detectable source of myocytes during muscle regeneration in vivo ( Ferrari et al. 1998). A finding that is consistent with previous predictions and reports of a class of multipotential stem cells within bone marrow and circulating blood ( Owen 1988; Caplan 1991, Caplan 1994; Dennis and Caplan 1996; Prockop 1997; Dennis et al. 1999; Pittenger et al. 1999), and possibly, consistent with recent inclinations that the thymus may also be a source of myogenic stem cells ( Wong et al. 1999).
Given that regenerative potential, De Angelis et al., 1999, sought to determine if such myogenic cells could be isolated from embryonic aorta endothelium, one of the first blood vessels to form in the early embryo ( Fig. 1 and Fig. 2). Using an impressive combination of embryological, cell biological and transgenic technology, they show that isolated aorta does indeed give rise to small populations of myogenic cells. Moreover, when such endothelium is grafted directly into a muscle in which regeneration has been induced by injury, graft-derived myogenic cells can be found both in the injured muscle as well as in the muscle on the contralateral side, consistent with a blood-borne migratory capacity of such cells. The authors appropriately and carefully qualify their conclusions that blood-borne, endothelial-derived cells can have myogenic capacity with two considerations: first, that such cells may contribute to, but not necessarily constitute all of, the regenerative capacity in adult muscle; and, second, that endothelial-derived cells have not been demonstrated to exist within the anatomically defined satellite cell compartment ( Fig. 3). So, it remains to be determined if satellite cells are derived from the blood-borne cells analyzed by the Cossu group or if the latter represent an alternative source of myogenic repair cells.
With that in mind it is interesting to note that the origins of aortic endothelium and somites are not so far removed from one another during early development. Aortic precursor cells undergo vasculogenesis (a process distinct from angiogenesis) ( Dieterlen-Lievre and Le Douarin 1993, and references therein) immediately subjacent to the pre-somitic mesoderm, the unsegmented portion of the paraxial mesoderm ( Fig. 1). Approximately concomitant with somite epithelialization, vasculogenic clusters fuse to form bilateral, patent dorsal aortae that are adherent to the somite ventral surface ( Fig. 2). The close proximity in origins of these two lineages is also reflected in the fact that both are responsible for generation of endothelial cells ( Pardanaud and Dieterlen-Lievre 1995; Wilting et al. 1995). One hopes that this paper ( De Angelis et al. 1999), along with previous studies from this group ( Ferrari et al. 1998), will spur embryologists around the world to design experiments to fill in this specific gap in our understanding of the embryonic origin(s) of satellite cells and other adult cells with potential for muscle regenerative capacity.
While the De Angelis paper provides grist for competing views of how stable tissues are built and maintained during vertebrate development, the outcome of that competition bodes well for an interested segment of the muscle field; patients for whom muscle repair or replacement is a medical necessity. Even assuming blood carries only a relatively small capacity for muscle regeneration, those cells possess a cardinal property that is essential if muscle replacement therapy is to become a reality: the ability to travel within the blood stream and then exit the bloodstream to colonize skeletal muscles. The ability to travel is present in migratory muscle precursor cells that populate the embryonic limb bud (see Fig. 2) but such capacity is no longer evident after grafting of replicating myoblasts (presumptive true satellite cells) isolated from muscle tissue and expanded in vitro ( Gussoni et al. 1992, Gussoni et al. 1997). So, the biology and molecular genetics that we will learn about such blood-borne myogenic cells over the next few years may suggest strategies for either expanding their numbers or engineering their essential qualities into other myogenic cells. Either approach would constitute a potential win–win situation for research into myoblast transfer therapy for the treatment of muscle loss, through genetic diseases such as Duchenne's muscular dystrophy, or even non–life-threatening muscle loss that follows injury or exercise abuse.