Skeletal stem and progenitor cells maintain cranial suture patency and prevent craniosynostosis
Siddharth Menon, Ankit Salhotra, Siny Shailendra, Ruth Tevlin, Ryan C. Ransom, Michael Januszyk, Charles K. F. Chan, Björn Behr, Derrick C. Wan, Michael T. Longaker, Natalina Quarto
Abstract
Abstract 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 LacZ/+ 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.