小柯机器人

美国威尔·康奈尔医学院Matthew B. Greenblatt等研究人员合作揭示颅骨畸形和颅骨矿化的多干细胞基础。相关论文于2023年9月20日在线发表在《自然》杂志上。

研究人员发现，颅骨发育不全症的生理性颅骨矿化和病理性颅骨融合反映了两个独立干细胞系的相互作用；一个是先前确定的cathepsin K（CTSK）谱系颅骨干细胞（CTSK⁺ CSC），另一个是研究人员确定的单独的含盘状结构域受体2（DDR2）谱系干细胞（DDR2⁺ CSC）。仅在CTSK⁺ CSC中缺失Twist1（与人类颅骨畸形相关的基因）就足以导致小鼠颅骨畸形，但注定要融合的部位却出现了意想不到的CTSK⁺ CSC耗竭和相应的DDR2⁺ CSC扩增，DDR2⁺ CSC扩增是对CTSK⁺ CSC耗竭的直接不良反应。DDR2⁺ CSC显示出完整的干性特征，这些研究结果确定了缝中存在两种不同的干细胞系，这两种细胞群都有助于生理性钙化。DDR2⁺干细胞介导了一种不同形式的软骨内骨化，而没有典型的造血骨髓形成。将DDR2⁺造血干细胞植入缝合部位足以诱导融合，同时移植CTSK⁺造血干细胞可防止这种表型。最后，DDR2⁺干细胞和CTSK⁺干细胞的人类对应物在异种移植实验中显示出一致的功能特性。这两种干细胞群之间的相互作用为调节颅骨矿化和缝合通畅提供了一个新的生物界面。

据介绍，颅骨发育不全症是一组颅骨缝过早融合的疾病。在颅骨发育不全症中，颅骨干细胞（CSC）产生融合驱动成骨细胞，但人们对其身份仍知之甚少。

附：英文原文

Title: A multi-stem cell basis for craniosynostosis and calvarial mineralization

Author: Bok, Seoyeon, Yallowitz, Alisha R., Sun, Jun, McCormick, Jason, Cung, Michelle, Hu, Lingling, Lalani, Sarfaraz, Li, Zan, Sosa, Branden R., Baumgartner, Tomas, Byrne, Paul, Zhang, Tuo, Morse, Kyle W., Mohamed, Fatma F., Ge, Chunxi, Franceschi, Renny T., Cowling, Randy T., Greenberg, Barry H., Pisapia, David J., Imahiyerobo, Thomas A., Lakhani, Shenela, Ross, M. Elizabeth, Hoffman, Caitlin E., Debnath, Shawon, Greenblatt, Matthew B.

Issue&Volume: 2023-09-20

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.

DOI: 10.1038/s41586-023-06526-2

Source: https://www.nature.com/articles/s41586-023-06526-2

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html