| First Author | Bok S | Year | 2023 |
| Journal | Nature | Volume | 621 |
| Issue | 7980 | Pages | 804-812 |
| PubMed ID | 37730988 | Mgi Jnum | J:349334 |
| Mgi Id | MGI:7647054 | Doi | 10.1038/s41586-023-06526-2 |
| Citation | Bok S, et al. (2023) A multi-stem cell basis for craniosynostosis and calvarial mineralization. Nature 621(7980):804-812 |
| abstractText | Craniosynostosis is a group of disorders of premature calvarial suture fusion. The identity of the calvarial stem cells (CSCs) that produce fusion-driving osteoblasts in craniosynostosis remains poorly understood. Here we show that both physiologic calvarial mineralization and pathologic calvarial fusion in craniosynostosis reflect the interaction of two separate stem cell lineages; a previously identified cathepsin K (CTSK) lineage CSC(1) (CTSK(+) CSC) and a separate discoidin domain-containing receptor 2 (DDR2) lineage stem cell (DDR2(+) CSC) that we identified in this study. Deletion of Twist1, a gene associated with craniosynostosis in humans(2,3), solely in CTSK(+) CSCs is sufficient to drive craniosynostosis in mice, but the sites that are destined to fuse exhibit an unexpected depletion of CTSK(+) CSCs and a corresponding expansion of DDR2(+) CSCs, with DDR2(+) CSC expansion being a direct maladaptive response to CTSK(+) CSC depletion. DDR2(+) CSCs display full stemness features, and our results establish the presence of two distinct stem cell lineages in the sutures, with both populations contributing to physiologic calvarial mineralization. DDR2(+) CSCs mediate a distinct form of endochondral ossification without the typical haematopoietic marrow formation. Implantation of DDR2(+) CSCs into suture sites is sufficient to induce fusion, and this phenotype was prevented by co-transplantation of CTSK(+) CSCs. Finally, the human counterparts of DDR2(+) CSCs and CTSK(+) CSCs display conserved functional properties in xenograft assays. The interaction between these two stem cell populations provides a new biologic interface for the modulation of calvarial mineralization and suture patency. |
