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Weill Cornell Medicine

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Nature, 20 September 2023 | https://doi.org/10.1038/s41586-023-06526-2 A multi-stem cell basis for craniosynostosis and calvarial mineralization

Seoyeon Bok ¹, Alisha R. Yallowitz ¹, Jun Sun ¹, Jason McCormick ², Michelle Cung ¹, Lingling Hu ³, Sarfaraz Lalani ¹, Zan Li ¹, Branden R. Sosa ¹, Tomas Baumgartner ², Paul Byrne2,Tuo Zhang ⁴, Kyle W. Morse ³, Fatma F. Mohamed ⁵, Chunxi Ge ⁵, Renny T. Franceschi ⁵, Randy T. Cowling ⁶, Barry H. Greenberg ⁶, David J. Pisapia ¹, Thomas A. Imahiyerobo ⁷, Shenela Lakhani ⁸, M. Elizabeth Ross ⁸, Caitlin E. Hoffman ⁹, Shawon Debnath ^1,* & Matthew B. Greenblatt ^1,10 ,*

¹Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
²Flow Cytometry Core Facility, Weill Cornell Medicine, New York, NY, USA.
³Department of Orthopedic Surgery, Hospital for Special Surgery, New York, NY, USA.
⁴Genomics Resources Core Facility, Weill Cornell Medicine, New York, NY, USA.
⁵Department of Periodontics, Prevention and Geriatrics, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.
⁶Division of Cardiovascular Medicine, Department of Medicine, University of California, San Diego, CA, USA.
⁷Division of Plastic Surgery, Department of Surgery, New York-Presbyterian Hospital and Columbia University Medical Center, New York, NY, USA.
⁸Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
⁹Department of Neurological Surgery, Weill Cornell Medicine and New York-Presbyterian Hospital, New York, NY, USA.
¹⁰Research Division, Hospital for Special Surgery, New York, NY, USA.

^*Corresponding author: correspondence to Shawon Debnath or Matthew B. Greenblatt

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 CSC (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, 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.

논문정보

형식Research article
게재일2023년 09월 (BRIC 등록일 2023-09-22)
연구진국외 연구진
분야 생명과학 > 세포생물학

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