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 Axin2LacZ/+ 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.
Highlights
Cranial sutures are major growth centers for the calvarial vault, and their premature fusion leads to a pathologic condition called craniosynostosis
We initiated our study by confirming the presence of skeletal stem/ progenitor cells, defined by the following immunophenotype: CD51+, CD200+, CD45−, Fig. 1 Temporal Fluorescence assisted cell sorting (FACS) profiling of CD51+;CD200+ cells in patent and fusing cranial sutures. a Outline of calvarial suture harvesting and processing. b Time-course profiling of skeletal stem/progenitor cells isolated in vivo by flow cytometric analysis from freshly harvested posterior frontal (PF), sagittal (SAG), and coronal (COR) sutures
CD51+;CD200+ cells were analyzed in the posterior-frontal suture (PF), SAG, and coronal suture (COR) sutures between postnatal day 3 (pN3) and pN17 (n = 60 mice/time-point), a time frame spanning the period of physiological PF suture closure[10] (Fig. 1c)
Summary
Cranial sutures are major growth centers for the calvarial vault, and their premature fusion leads to a pathologic condition called craniosynostosis. Crossing Axin2LacZ/+ mouse, endowing enhanced Wnt activation, to a Twist1+/− mouse model of coronal craniosynostosis enriches skeletal stem/progenitor cells in sutures restoring patency. Cotransplantation 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. Cranial sutures are fibrous joints that comprise two approaching osteogenic bone fronts separated by intervening proliferative mesenchymal tissue They represent the major sites of cranial morphogenesis and grow in close coordination with the rapidly developing brain[1,2,3,4,5]. Fueled by our prior isolation of skeletal stem cells and progenitors from long bone[31,32], long bone fractures[33,34], and mandibles[35,36], we aimed to examine cranial suture biology through the lens of these cells
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