WNT1 Function in Stem Cells in Osteogenesis Imperfecta and Craniofacial-Skeletal Tissues

项目摘要 骨骼干细胞（SSC）是骨和软骨的稳态和修复所必需的。在颅颌面 骨、骨膜骨骼干/祖细胞（P-SSC）和缝间充质细胞在 骨稳态和再生。然而，由于分布有限和缺乏特异性标记， 关于颅面P-SSCs的功能及其在神经系统中的特异性调节机制， 稳态和对骨损伤的反应。成骨不全（OI）患者存在骨细胞生长调节障碍， 颅面和骨骼的骨稳态。WNT 1突变导致隐性OI和早发性OI 我们的初步数据支持颅面干细胞功能改变。因此，主 这项研究的目的是确定在体内的特点和独特的调节机制， 颅面P-SSC，并测试Wnt 1和α-sclerostin抗体增强Wnt信号传导是否通常被 对于这些P-SSC对骨损伤的反应至关重要。我们假设颅面P-SSC具有独特的 与长骨P-SSCs相比，这些P-SSCs的分子特征，以及Wnt 1对这些P-SSCs的调节是 对颅面骨的平衡再生和修复至关重要与先前已知的SSC相结合 标记，我们新鉴定了P-SSCs的选择性标记，使我们能够分离高度纯化的 小鼠P-SSCs，分析其基因表达谱，并通过以下方法测试其骨形成能力： 将这些P-SSC移植到颅骨缺损中。因此，我们建议回答以下问题， 实现具体目标：具体目标1：颅面P的独特特征和功能是什么？ 与长骨P-SSC相比。具体目标2：Wnt 1信号传导如何调节维持 和颅面P-SSC的功能具体目标3：丧失或获得 Wnt 1和α-sclerostin对颅面骨再生的影响这些研究将确定 调节来自不同颅骨和长骨来源的SSC的规格以及Wnt 1的贡献 以及α-Sost处理在调节骨形成、增殖、迁移和分化中的作用 神经嵴来源的缝与骨膜SSCs的稳态和修复。

PROJECT SUMMARY Skeletal stem cells (SSCs) are necessary for the homeostasis and repair of bone and cartilage. In craniofacial bones, periosteal skeletal stem/progenitor cells (P-SSCs) and suture mesenchymal cells play a critical role in bone homeostasis and regeneration. However, due to the restricted distribution and lack of specific markers, little is known about the function of craniofacial P-SSCs and about their specific regulatory mechanisms in homeostasis and response to bone injury. Patients with Osteogenesis Imperfecta (OI) have dysregulation of craniofacial and skeletal bone homeostasis. WNT1 mutations cause recessive OI and early onset osteoporosis and our preliminary data support altered craniofacial stem cell function. Therefore, the main objective of this research proposal is to define the in vivo characteristics and unique regulatory mechanisms of craniofacial P-SSCs, and to test if Wnt1 and α-sclerostin antibody augmentation of Wnt signaling in general are critical for these P-SSCs' response to bone injury. We hypothesize that craniofacial P-SSCs have unique molecular characteristics compared to long bone P-SSCs and that the regulation of these P-SSCs by Wnt1 is critical for craniofacial bone homeostasis, regeneration and repair. In combination with previously known SSC markers, we have newly identified selective markers for P-SSCs that enables us to isolate highly purified mouse P-SSCs and to analyze their gene expression profiles and to test their bone forming ability by transplantation of these P-SSCs into calvarial defects. We thus propose to answer the below questions in achieving the specific aims: Specific Aim 1: What are unique characteristics and function of craniofacial P- SSCs compared to long-bone P-SSCs. Specific Aim 2: How does Wnt1 signaling regulate the maintenance and function of craniofacial P-SSCs? Specific Aim 3: What are the functional consequences of loss or gain of Wnt1, and α-sclerostin therapy on craniofacial bone regeneration? These studies will identify factors that regulate the specification of SSC from different calvarial and long bone sources and the contribution of Wnt1 and effects of α-Sost treatment in regulating bone formation, and the proliferation, migration, and differentiation of neural crest derived-sutural vs. periosteal SSCs in homeostasis and repair.