Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
Flow Cytometry Core Facility, Weill Cornell Medicine, New York, NY, USA.
Nature. 2023 Sep;621(7980):804-812. doi: 10.1038/s41586-023-06526-2. Epub 2023 Sep 20.
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.
颅缝早闭是一种颅缝过早融合的疾病。在颅缝早闭中，产生融合驱动成骨细胞的颅盖干细胞（CSC）的身份仍知之甚少。本文研究表明，生理颅盖骨矿化和颅缝早闭中的病理颅缝融合都反映了两个独立的干细胞谱系之间的相互作用；我们在这项研究中鉴定了一个先前确定的组织蛋白酶 K（CTSK）谱系 CSC（CTSK CSC）和一个单独的盘状结构域受体 2（DDR2）谱系干细胞（DDR2 CSC）。仅在 CTSK CSCs 中缺失与人类颅缝早闭相关的基因 Twist1，足以在小鼠中驱动颅缝早闭，但注定要融合的部位显示出 CTSK CSCs 的意外耗竭和 DDR2 CSCs 的相应扩张，而 DDR2 CSC 的扩张是 CTSK CSCs 耗竭的直接适应性反应。DDR2 CSCs 显示出完整的干细胞特征，我们的结果确立了在缝中存在两个不同的干细胞谱系，这两个群体都有助于生理颅盖骨矿化。DDR2 CSCs 介导了一种独特的软骨内骨化形式，而没有典型的造血骨髓形成。将 DDR2 CSCs 植入缝部位足以诱导融合，而将 CTSK CSCs 共移植可预防这种表型。最后，在异种移植实验中，DDR2 CSCs 和 CTSK CSCs 的人类对应物显示出保守的功能特性。这两个干细胞群体之间的相互作用为调节颅盖骨矿化和缝通畅性提供了一个新的生物学界面。
