Update: Generation of a craniofacial muscle model of FSHD

Update by Dr. Guo
See also Generation of a craniofacial muscle model of FSHD

FSHD pathology includes weakness of pharyngeal arch-derived facial muscles and somite-derived muscles. Facial and somitic muscle development are controlled by different transcription factors: PITX2 for facial muscles, and PAX3 and PAX7 for somitic muscles, raising the possibility that the DUX4 is regulated and functions differently in facial and somitic muscles, and might be responsive to different therapeutics. Our goal is to develop a craniofacial muscle model of FSHD for investigations of disease mechanisms and therapeutic development. Our approach is to differentiate FSHD iPSCs into craniofacial muscles by mimicking in vivo craniofacial muscle development. qPCR assays show that craniofacial muscles differentiated from iPSCs express PITX2, TCF21, and MYOR, the hallmarks of craniofacial muscles, but the expression of DUX4 and its target genes were repressed, as we have reported for iPSC differentiated somitic muscles but not for iPSC iMyoblasts isolated by reserve cell selection (Guo et al., 2022). A maintainable PITX2+ FSHD craniofacial muscle cell line was generated using a modified craniofacial iPSC induction protocol and reserve cell selection. We are utilizing PITX2+ FSHD craniofacial muscle cell line for comparative investigations of the epigenetic and differentiation-specific regulation of DUX4 and its transcriptional target genes in craniofacial and somitic iMyoblast lineages. The craniofacial myogenesis iPSC protocol provides a novel model for cell and molecular investigations of FSHD pathology in craniofacial muscle.