Craniosynostosis results from premature fusion of the cranial suture(s), which contain mesenchymal stem cells (MSCs) that are crucial for calvarial expansion in coordination with brain growth. Infants with craniosynostosis have skull dysmorphology, increased intracranial pressure, and complications such as neurocognitive impairment that compromise quality of life. Animal models recapitulating these phenotypes are lacking, hampering development of urgently needed innovative therapies. Here, we show that Twist1^+/− mice with craniosynostosis have increased intracranial pressure and neurocognitive behavioral abnormalities, recapitulating features of human Saethre-Chotzen syndrome. Using a biodegradable material combined with MSCs, we successfully regenerated a functional cranial suture that corrects skull deformity, normalizes intracranial pressure, and rescues neurocognitive behavior deficits. The regenerated suture creates a niche into which endogenous MSCs migrated, sustaining calvarial bone homeostasis and repair. MSC-based cranial suture regeneration offers a paradigm shift in treatment to reverse skull and neurocognitive abnormalities in this devastating disease.

颅缝早闭是由于颅骨缝过早融合造成的，其中含有间充质干细胞（MSC），对于颅骨扩张与大脑生长协调至关重要。患有颅缝早闭的婴儿会出现颅骨畸形、颅内压升高以及神经认知障碍等并发症，从而影响生活质量。缺乏概括这些表型的动物模型，阻碍了急需的创新疗法的开发。在这里，我们发现患有颅缝早闭的Twist1 ^+/-小鼠颅内压升高且神经认知行为异常，再现了人类 Saethre-Chotzen 综合征的特征。使用可生物降解材料与间充质干细胞相结合，我们成功地再生了一种功能性颅骨缝合线，可以纠正颅骨畸形，使颅内压正常化，并挽救神经认知行为缺陷。再生缝线创造了一个供内源性 MSC 迁移的生态位，维持颅骨骨稳态和修复。基于间充质干细胞的颅缝再生为扭转这种毁灭性疾病中的颅骨和神经认知异常提供了治疗范式转变。