Abstract
Craniosynostosis is a group of disorders of premature calvarial sutural fusion. An incomplete understanding of the calvarial stem cells (CSCs) that produce fusion-driving osteoblasts has limited the development of non-surgical therapeutic approaches for craniosynostosis. Here we show that both physiologic calvarial mineralization and pathologic calvarial fusion in craniosynostosis reflect the interaction of two separate stem cell lineages; a recently reported CathepsinK (CTSK) lineage CSC (CTSK+ CSC)1 and a separate Discoidin domain-containing receptor 2 (DDR2) lineage stem cell (DDR2+ CSC) identified in this study. Deletion of Twist1, a gene associated with human craniosynostosis2,3, solely in CTSK+ CSCs is sufficient to drive craniosynostosis, however the sites destined to fuse surprisingly display a marked depletion of CTSK+ CSCs and a corresponding expansion of DDR2+ CSCs. This DDR2+ CSC expansion is a direct maladaptive response to CTSK+ CSC depletion, as partial suture fusion occurred after genetic ablation of CTSK+ CSCs. This DDR2+ CSC is a specific fraction of DDR2+ lineage cells that displayed full stemness features, establishing the presence of two distinct stem cell lineages in the sutures, with each population contributing to physiologic calvarial mineralization. DDR2+ CSCs mediate a distinct form of endochondral ossification where an initial cartilage template is formed but the recruitment of hematopoietic marrow is absent. Direct implantation of DDR2+ CSCs into suture sites was sufficient to induce fusion, and this phenotype was prevented by co-transplantation of CTSK+ CSCs. Lastly, the human counterparts of DDR2+ CSCs and CTSK+ CSCs are present in calvarial surgical specimens and display conserved functional properties in xenograft assays. The interaction between these two stem cell populations provides a new biologic interface to modulate calvarial mineralization and suture patency.
The Cancer Stem Cell in Hepatocellular Carcinoma
