A multi-stem cell basis for craniosynostosis and calvarial mineralization

Seoyeon Bok, Alisha R. Yallowitz, Jun Sun, Jason McCormick, Michelle Cung, Lingling Hu, Sarfaraz Lalani, Zan Li, Branden R. Sosa, Tomas Baumgartner, Paul Byrne, Tuo Zhang, Kyle W. Morse, Fatma F. Mohamed, Chunxi Ge, Renny T. Franceschi, Randy T. Cowling, Barry H. Greenberg, David J. Pisapia, Thomas A. Imahiyerobo, Shenela Lakhani, M. Elizabeth Ross, Caitlin E. Hoffman, Shawon Debnath () and Matthew B. Greenblatt ()
Additional contact information
Seoyeon Bok: Weill Cornell Medicine
Alisha R. Yallowitz: Weill Cornell Medicine
Jun Sun: Weill Cornell Medicine
Jason McCormick: Weill Cornell Medicine
Michelle Cung: Weill Cornell Medicine
Lingling Hu: Hospital for Special Surgery
Sarfaraz Lalani: Weill Cornell Medicine
Zan Li: Weill Cornell Medicine
Branden R. Sosa: Weill Cornell Medicine
Tomas Baumgartner: Weill Cornell Medicine
Paul Byrne: Weill Cornell Medicine
Tuo Zhang: Weill Cornell Medicine
Kyle W. Morse: Hospital for Special Surgery
Fatma F. Mohamed: University of Michigan
Chunxi Ge: University of Michigan
Renny T. Franceschi: University of Michigan
Randy T. Cowling: University of California
Barry H. Greenberg: University of California
David J. Pisapia: Weill Cornell Medicine
Thomas A. Imahiyerobo: New York-Presbyterian Hospital and Columbia University Medical Center
Shenela Lakhani: Weill Cornell Medicine
M. Elizabeth Ross: Weill Cornell Medicine
Caitlin E. Hoffman: Weill Cornell Medicine and New York-Presbyterian Hospital
Shawon Debnath: Weill Cornell Medicine
Matthew B. Greenblatt: Weill Cornell Medicine

Nature, 2023, vol. 621, issue 7980, 804-812

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41586-023-06526-2

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