Mechanisms and rescue of craniosynostosis associated with gene-environment interaction

Craniosynostosis is a craniofacial disorder characterized by the premature fusion and loss of cranial sutures with defective mesenchymal stem cells (MSCs). Patients with severe craniosynostosis often have intellectual disability (ID)-like neurocognitive dysfunctions. Meninges represent the interface between the skull and the brain and play an essential role in maintaining suture patency. We propose establishing novel mechanisms and a potential therapeutic strategy through which implanted MSCs reprogram and interact with meningeal cells to rescue both skull deformities and neurological deficits in craniosynostosis. This is innovative and significant because the only current treatment option for craniosynostosis is complex surgery, which is invasive and often requires re-operation due to the calvarial bones fusing again (resynostosing). Our MSC-based cranial suture regeneration approach is less invasive, avoids calvarial bone re-fusion, corrects skull dysmorphology, restores elevated intracranial pressure, and reduces neurocognitive dysfunctions later in life in a clinically relevant Twist1+/- mouse model of craniosynostosis. These exciting discoveries were made through the collaborative efforts of two accomplished investigators with complementary craniofacial biology and neuroscience expertise. Yang Chai pioneered the identification of a population of Gli1+ stem cells in the suture that was lost before the premature fusion of cranial sutures in Twist1+/- mice. Chai lab further developed a novel formula in which Gli1+ MSCs and innovative modified GelMA scaffolds support cranial suture regeneration in Twist1+/- mice with craniosynostosis. Jian-Fu Chen then used his neuroscience background to develop a Twist1+/- model of neurological abnormalities associated with craniosynostosis patients. Importantly, collaborative efforts discovered that MSC-mediated suture regeneration mitigates skull deformities and neurocognitive dysfunctions in the Twist1+/- mice with craniosynostosis. To reveal the underlying mechanisms and improve the efficacy of this therapeutic approach, this research team will define a novel MSC implantation formula with optimal therapeutic outcomes. We will determine the roles and interactions of exogenous and dura-derived endogenous MSCs in suture regeneration. Furthermore, we will investigate the underlying cellular and molecular mechanisms by which implanted exogenous MSCs interact with endogenous MSCs, promoting suture regeneration. It is crucial to confirm that this strategy can be extended to different etiologies of craniosynostosis. Therefore, we will focus on Twist1’s partner Tcf12, mutations of which also lead to coronal synostosis. We will establish Tcf12 mutant mouse models with skull abnormalities and attempt to rescue these abnormalities using Gli1+ MSC-mediated suture regeneration. Collectively, our proposed studies build upon our previous discoveries, and our findings will be highly significant for improving our understanding of the disease mechanism; they offer a unique opportunity for improving the treatment of infants with craniosynostosis.