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

项目总结 骨骼干细胞(SSCs)对于骨和软骨的动态平衡和修复是必不可少的。在头面部 骨、骨膜干/祖细胞(P-SSCs)和缝合间充质细胞在 骨骼动态平衡和再生。然而，由于分布有限，缺乏特异的标记， 关于颅面部P-SSCs的功能及其特定的调控机制，目前还知之甚少。 动态平衡与骨骼损伤反应。成骨不全(OI)患者存在骨发育不全 头面部和骨骼的动态平衡。WNT1基因突变导致隐性OI和早发 骨质疏松症和我们的初步数据支持颅面干细胞功能的改变。因此，主要的 这项研究的目的是确定在体内的特征和独特的调控机制 并检测Wnt1和α-skerostin抗体对WnT信号的增强作用 对这些P-SSCs对骨损伤的反应至关重要。我们假设颅面部P-SSCs具有独特的 与长骨P-SSCs的分子特征比较，以及WNT1对这些P-SSCs的调节是 对头面部骨骼的动态平衡、再生和修复至关重要。与先前已知的SSC相结合 标记物，我们新发现了P-SSCs的选择性标记物，使我们能够分离出高度纯化的 并对其基因表达谱进行分析，检测其成骨能力。 将这些P-SSCs移植到颅骨缺损区。因此，我们建议在#年回答以下问题 实现特定目标：特定目标1：颅面P-P的独特特征和功能是什么 SSCs与长骨P-SSCs的比较。具体目标2：WNT1信号如何调节维护 和颅面P-SSCs的功能？具体目标3：损失或收益的功能后果是什么 WNT1和α-skerostin治疗对颅面骨再生的影响？这些研究将确定以下因素 调节不同颅骨和长骨来源SSC的特性及WNT1的作用 以及α-SoST治疗对骨形成、增殖、迁移和分化的调节作用 神经冠源性缝合干细胞与骨膜干细胞在动态平衡和修复方面的比较。

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.