Like other muscles, craniofacial muscles are also derived from mesoderm, however, groups of craniofacial muscles arise from distinct regions of mesoderm (reviewed in Noden and Francis-West, 2006
; Figure ). Somitic mesoderm forms much of the muscle of the trunk and extremities, but in the face, only the muscles of the tongue and anterior neck are derived from the somites. In contrast, the muscles of mastication and facial expression arise from pharyngeal arch mesoderm, where they develop in close association with the neural crest-derived bones and tendons (Grenier et al., 2009
). Finally, extraocular muscles arise from anterior paraxial and prechordal mesoderm (Noden and Francis-West, 2006
; Sambasivan et al., 2009
). The differences in embryologic origin of face muscles and body muscles are accompanied by differences in the signaling molecules that trigger muscle differentiation in these locations (Sambasivan et al., 2009
; reviewed in Kelly, 2010
Similarly, satellite cells, the tissue-resident muscle stem cells, have different gene expression patterns and characteristics in the face compared with the body. For example, in the trunk, satellite cells express Pax7 and Pax3 (Relaix et al., 2005
). However, only Pax7 is expressed in the muscles of the face (Harel et al., 2009
; Otto et al., 2009
; Kelly, 2010
). Satellite cell frequency in muscle fibers also differs. Extraocular, laryngeal, and masseteric muscles have a greater frequency of satellite cells than other skeletal muscles (McLoon et al., 2007
). Furthermore, uninjured extraocular and laryngeal muscles contain significant populations of activated satellite cells under normal conditions. These muscles have a high level of basal regenerative activity, and are resistant to the myotoxicity of local anesthetics (Kalhovde et al., 2005
; McLoon et al., 2007
). Determining whether these differences in satellite cells are intrinsic and how they contribute to regenerative potential is unclear, however. In one comparison of satellite cells between the masseter and limb, there was no difference with regards to myogenic potential in vitro
(Grefte et al., 2012
). Another study showed that masseteric satellite cells differentiated more slowly, but contributed to limb muscle regeneration in vivo
(Ono et al., 2010
). Limb satellite cells have not been studied in models of facial muscle injury and so the prospects for using limb muscle stem cells to regenerate facial muscles are not yet defined.
Assessment of regenerative potential from satellite cells must include analysis of both the satellite cell proliferative response and the regenerated muscle fiber type and function. Skeletal muscles and craniofacial muscles differ in the myosin isoforms that they express. The muscle fibers of the face express embryonic and neonatal myosin in addition to adult myosin isoforms. Occasionally, facial muscles express multiple myosin isoforms within a single muscle fiber, which has not been observed in other muscles (Stal, 1994
; Porter, 2002
). Distinct myosin isoforms and a greater number of mitochondria in craniofacial muscle cells may contribute to the resistance to fatigue that craniofacial muscles exhibit. Assuming these unique characteristics of craniofacial muscles are important to their structure or function, recreating these nuances using body muscle stem cells may not be straightforward.
Finally, craniofacial muscles exhibit different susceptibility to pathological conditions. In diseases such as amyotrophic lateral sclerosis (OMIM 105400), the extraocular muscles are not affected. Other craniofacial muscles such as the masseter are affected less severely than body skeletal muscles (Valdez et al., 2012
). In contrast, diseases such as myasthenia gravis (OMIM 254200), oculopharyngeal muscular dystrophy (OMIM 164300), and chronic progressive external ophthalmoplegia (OMIM 157640) preferentially affect the extraocular and facial muscles (Benveniste et al., 2005
; Greaves et al., 2010
With regards to regenerative strategies for muscles, the importance of the differences between craniofacial and body muscles in developmental origins, satellite cells, and contractile elements is unclear. The phenotypic differences between extraocular, masseteric, and limb skeletal muscle may be important for regenerating muscle for craniofacial diseases. It is unknown whether satellite cells from the same muscle subset are required to achieve the same phenotype, or whether transplanted satellite cells will adopt the phenotype of their new environment. The answers to these questions could have critical implications for the treatment of muscle-group specific dystrophies. For example, if satellite cells retain adequate intrinsic plasticity, one potential regenerative strategy would be to use autologous transplantation of cells from unaffected or less affected muscle groups to more severely affected muscles. Similarly, satellite cells could be harvested from expendable muscles of the body to regenerate craniofacial muscle defects, with the goal of achieving function in addition to form.
Innervation to the different groups of facial muscles is by the cranial nerves, which have a highly conserved organization among vertebrates. Unlike spinal motor neurons, stemming from columns along the spine, cranial motor neurons extend from discrete nuclei in the midbrain and hindbrain (reviewed in Gilland and Baker, 2005
; Guthrie, 2007
). Each cranial motor nerve innervates a large number of distinct muscles, many of which can be controlled individually. Some cranial nerves are strictly efferent motor neurons, including cranial nerves III, IV, and VI to the extraocular muscles and cranial nerve XII controlling tongue movement. Other cranial nerves are mixed with motor and sensory components. These “branchiomeric” nerves have sensory ganglia that are formed by contributions from neural crest cells (Figure ), and motor components that extend to striated muscles as well as to parasympathetic ganglia (cranial nerves III, VII, IX, and X), and the mechanosensory hair cells of the inner ear (cranial nerve VIII; reviewed in Guthrie, 2007
). Also unique in craniofacial nervous system development is the development of the sensory organs from the cranial placodes (reviewed in Streit, 2004
; Schlosser, 2006
). Despite the unique organization and development of the cranial nerves, however, they appear to be functionally similar to other peripheral nerves of the body and there is no known difference in their regenerative capacity.
In the following sections, we present clinical vignettes to illustrate typical craniofacial disorders and how regenerative approaches may be applied in order to treat the conditions.