Hagey Laboratory for Pediatric Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Division of Plastic and Reconstructive Surgery, Stanford University School of Medicine, Stanford, CA, USA.
Nat Commun. 2021 Jul 30;12(1):4640. doi: 10.1038/s41467-021-24801-6.
Cranial sutures are major growth centers for the calvarial vault, and their premature fusion leads to a pathologic condition called craniosynostosis. This study investigates whether skeletal stem/progenitor cells are resident in the cranial sutures. Prospective isolation by FACS identifies this population with a significant difference in spatio-temporal representation between fusing versus patent sutures. Transcriptomic analysis highlights a distinct signature in cells derived from the physiological closing PF suture, and scRNA sequencing identifies transcriptional heterogeneity among sutures. Wnt-signaling activation increases skeletal stem/progenitor cells in sutures, whereas its inhibition decreases. Crossing Axin2 mouse, endowing enhanced Wnt activation, to a Twist1 mouse model of coronal craniosynostosis enriches skeletal stem/progenitor cells in sutures restoring patency. Co-transplantation of these cells with Wnt3a prevents resynostosis following suturectomy in Twist1 mice. Our study reveals that decrease and/or imbalance of skeletal stem/progenitor cells representation within sutures may underlie craniosynostosis. These findings have translational implications toward therapeutic approaches for craniosynostosis.
颅骨缝是颅顶的主要生长中心，其过早融合会导致一种称为颅缝早闭的病理状况。本研究探讨了颅缝中是否存在骨骼干/祖细胞。通过 FACS 进行前瞻性分离，发现融合与未融合的颅骨缝之间存在明显的时空差异。转录组分析突出了源自生理闭合 PF 缝的细胞的独特特征，单细胞 RNA 测序确定了缝之间的转录异质性。Wnt 信号激活增加了骨骼干/祖细胞在缝中的数量，而抑制则减少了其数量。将 Axin2 小鼠（赋予增强的 Wnt 激活）与冠状颅缝早闭的 Twist1 小鼠模型杂交，增加了骨骼干/祖细胞在缝中的数量，恢复了其开放性。将这些细胞与 Wnt3a 共移植可防止 Twist1 小鼠缝切除术后再融合。我们的研究表明，颅骨缝内骨骼干/祖细胞的减少和/或失衡可能是颅缝早闭的基础。这些发现对颅缝早闭的治疗方法具有转化意义。
