A multi-stem cell basis for craniosynostosis and calvarial mineralization.

TitleA multi-stem cell basis for craniosynostosis and calvarial mineralization.
Publication TypeJournal Article
Year of Publication2023
AuthorsBok S, Yallowitz AR, Sun J, McCormick J, Cung M, Hu L, Lalani S, Li Z, Sosa BR, Baumgartner T, Byrne P, Zhang T, Morse KW, Mohamed FF, Ge C, Franceschi RT, Cowling RT, Greenberg BH, Pisapia DJ, Imahiyerobo TA, Lakhani S, M Ross E, Hoffman CE, Debnath S, Greenblatt MB
Date Published2023 Sep
KeywordsAnimals, Cell Lineage, Craniosynostoses, Humans, Mice, Osteogenesis, Phenotype, Stem Cells

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 CSC1 (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 humans2,3, 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.

Alternate JournalNature
PubMed ID37730988
PubMed Central ID6193396
Grant ListP30 AR069620 / AR / NIAMS NIH HHS / United States
R01 DE029465 / DE / NIDCR NIH HHS / United States
R21 DE029012 / DE / NIDCR NIH HHS / United States