Orofacial Muscles: Embryonic Development and Regeneration after Injury

Abstract

Orofacial congenital defects such as cleft lip and/or palate are associated with impaired muscle regeneration and fibrosis after surgery. Also, other orofacial reconstructions or trauma may end up in defective muscle regeneration and fibrosis. The aim of this review is to discuss current knowledge on the development and regeneration of orofacial muscles in comparison to trunk and limb muscles. The orofacial muscles include the tongue muscles and the branchiomeric muscles in the lower face. Their main functions are chewing, swallowing, and speech. All orofacial muscles originate from the mesoderm of the pharyngeal arches under the control of cranial neural crest cells. Research in vertebrate models indicates that the molecular regulation of orofacial muscle development is different from that of trunk and limb muscles. In addition, the regenerative ability of orofacial muscles is lower, and they develop more fibrosis than other skeletal muscles. Therefore, specific approaches need to be developed to stimulate orofacial muscle regeneration. Regeneration may be stimulated by growth factors such fibroblast growth factors and hepatocyte growth factor, while fibrosis may be reduced by targeting the transforming growth factor β1 (TGFβ1)/myofibroblast axis. New approaches that combine these 2 aspects will improve the surgical treatment of orofacial muscle defects.

Keywords: cleft palate; fibrosis; growth factors; satellite cells; skeletal muscle; tissue regeneration.

Figure 1.

The orofacial muscles. (A) Schematic of the skull. 1. Temporalis. 2. Masseter. 3. Buccinator. 4. Orbicularis oris. (B) Sagittal view of the head. N, nose; M, mandible; U, upper jaw. 5. Lateral pterygoid. 6. Medial pterygoid. (C) Upper jaw and soft palate. SP, soft palate. 7. Tensor veli palatini. 8. Levator veli palatini. 9. Musculus uvulae. 10. Palatoglossus. 11. Palatopharyngeous. (D) Muscles of the tongue. Hy, hyoid bone. 12. Styloglossus. (D) 13. Superior longitudinalis. 14. Transverse muscle. 15. Vertical muscle. 16. Inferior longitudinalis. 17. Genioglossus. 18. Hyoglossus. (E) Suprahyoid muscles. Hy, hyoid bone. 19. Mylohyoid. 20. Geniohyoid. 21. Stylohyoid. 22. Digastricus (anterior and posterior belly).

Figure 2.

Branchiomeric muscle development. Cranial neural crest cells (CNCCs, pink) migrate toward the first, second, and fourth (1, 2, 4) pharyngeal arches (purple). Pitx2 stimulates Tbx1 expression in CNCCs and mesodermal cells (brown color). The mesodermal cells concentrate in the core of the pharyngeal arches and become surrounded by CNCCs (step 1). Noggin (Nog), Gr (gremlin), and Frzb secreted by CNCCs prevent the downregulation of Pax7 and MyoD by Bmp and Wnt. Fgf10 produced by CNCCs expressing Dlx5 stimulates the expression of Mrfs. The CNCCs finally express Scx and differentiate into the intramuscular connective tissue and the tendons, while the mesodermal cells differentiate into myofibers (steps 2 and 3). Notch expressed by proliferating myoblasts limits their differentiation into myofibers.

Figure 3.

Tongue muscle development. Cranial neural crest cells (CNCCs; pink) and mesodermal cells (brown) regulate tongue myogenesis in the first pharyngeal arch (PA). CNCCs migrate directly from the neural crest to the first pharyngeal arch but also to the occipital somites (OSs). In the OSs, the CNCCs induce the commitment of mesodermal cells to the myogenic lineage by expressing Shh-Wnt. The committed cells migrate (brown arrow) toward the first pharyngeal arch (steps 1 and 2). The CNCCs in the tongue bud start to express Scx and will form the intramuscular connective tissue and the tendons. These Scx-positive precursors secrete TGFB1 and BMP to induce the differentiation of the committed cells. The committed cells then differentiate into myoblasts under control of MRFs and form the myofibers (step 3). Notch expressed by proliferating myoblasts controls their differentiation into myofibers. This figure is available in color online.

Figure 4.

Promoting orofacial muscle regeneration. Enhancement of satellite cell (SC) differentiation is key to improve the regeneration of orofacial muscles. Growth factors that can stimulate SC differentiation are fibroblast growth factor (FGF), hepatocyte growth factor (HGF), insulin-like growth factor (IGF), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and stromal cell–derived factor (SDF). Targeting transforming growth factor β1 (TGFβ1) is the main strategy to reduce fibrosis. Aligned scaffolds (gray lines) are required to deliver growth factors and antifibrotic factors into the wound site and to guide myofiber orientation.