In Vitro Modeling of the Craniofacial Disorders Using iPSCs/Organoids: Deciphering the Molecular and Genetic Mechanisms of Craniofacial Development

Dear Colleagues,

Congenital craniofacial disorders, e.g., craniosynostosis, hemifacial microsomia, vascular malformation, positional plagiocephaly, cleft lip, and cleft palate influence the development of the skull and facial bones. As a result, patients experience developmental delays, persistent head or facial deformities, seizures, neurodevelopmental disorders, hearing, speaking, eating, breathing difficulties, etc. Animal models, such as mice with targeted mutations in genes, have provided valuable insights into the congenital craniofacial anomalies (CFA) developmental processes. However, existing in vivo mouse models often fail to recapitulate the complexity of craniofacial developmental biology, limiting their utility in studying disease pathogenesis in human models. Therefore, there is a critical need for a relevant human cell model to elucidate the molecular and genetic basis of CFA and develop novel strategies for disease modeling and therapeutic intervention. One recent groundbreaking development in disease developmental biology is the advancement in iPSCs and organoid-based disease modeling. Organoids are miniature, simplified versions of organs grown in vitro from stem cells. They closely resemble real organs both structurally and functionally, making them valuable tools for studying disease mechanisms and testing potential therapies. Using iPSCs/ organoid disease models instead of traditional mouse models offers several advantages. These models reduce the need for animal experimentation, addressing ethical concerns associated with using animals in research. This approach aligns with the growing emphasis on animal welfare and the 3Rs (replacement, reduction, refinement) principle in research ethics. Human iPSCs can be generated from patient-derived cells, allowing for the creation of personalized disease models. This personalized approach enables researchers to study disease mechanisms and test potential treatments in a manner tailored to individual patients, potentially leading to more effective therapies. Further, iPSCs-based modeling provides a more accurate representation of human biology and disease compared to animal models. This human relevance increases the likelihood of findings translating to effective treatments in humans. More importantly, these iPSCs/organoids can be genetically manipulated using techniques such as CRISPR-Cas9 gene editing, allowing for the creation of precise disease models with specific genetic mutations. This capability enables researchers to study the effects of genetic alterations on disease development and test targeted therapeutic approaches. Overall, the use of iPSCs and organoids in craniofacial disease developmental biology has revolutionized our understanding of disease mechanisms and holds immense promise for personalized medicine.

This Special Issue provides an excellent platform to present and discuss iPSCs-based modeling for studying key signaling pathways, morphogens, cytokines, and their interactions, cell–cell interactions, neural crest-mesoderm interaction, extracellular matrix composition during craniofacial development, and how perturbations in these pathways lead to deformities. This issue also includes emerging therapeutic approaches for craniofacial abnormalities, such as gene therapy and CRISPR/Cas9-based gene editing, novel genomic and proteomic technologies for deciphering the molecular and cellular mechanisms of craniofacial development and abnormalities, case reports, clinical management, and outcomes of craniofacial abnormalities.

We welcome article types including original research, comprehensive reviews, case reports, short communications, and perspectives that cover a range of topics related to in vitro iPSCs/organoid-based modeling of craniofacial abnormalities with aims to provide a platform to guide future work in the craniofacial developmental biology area.

We look forward to receiving your contributions.

Dr. Md Shaifur Rahman
Dr. Quenten P. Schwarz
Guest Editors

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• human iPSCs
• ESCs
• organoid
• craniofacial disorders
• in vitro modeling
• craniosynostosis
• cleft palate
• craniofacial development
• neural crest
• paraxial mesoderm