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Cxcl12-Hedgehog signaling in cranial bone regeneration

颅骨再生中的 Cxcl12-Hedgehog 信号传导

基本信息

批准号：
10657799
负责人：
Yingzi Yang
金额：
$ 59.68万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-05 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10657799
关键词：
Address Biological Assay Bone Development Bone Injury Bone Marrow Bone Regeneration Brain CXCR4 Receptors Calvaria Cells Cephalic Cicatrix Coupled Craniofacial Abnormalities Critical Pathways Defect Erinaceidae Extracellular Matrix Failure Foundations G Protein-Coupled Receptor Signaling GNAS gene GTP-Binding Proteins Genetic Diseases Health Heterotopic Ossification Homeostasis Human Human Genetics Impairment Inflammation Injury Joints Label Link Maintenance Mediating Mesenchymal Differentiation Modeling Molecular Monoclonal Antibodies Morbidity - disease rate Mus Natural regeneration Operative Surgical Procedures Osteoblasts Osteogenesis Pathway interactions Patients Play Population Progressive osseous heteroplasia Publishing Regulation Research Personnel Role SHH gene Shapes Signal Induction Signal Transduction Site Skeletal system Skeleton Solid Stromal Cell-Derived Factor 1 Surgical sutures Testing Therapeutic Tissues Trauma bone bone cell bone repair cell behavior cell motility craniofacial craniofacial bone cranium healing in vivo injury and repair intramembranous bone formation migration mortality mouse model novel osteoblast differentiation receptor reconstruction skeletal disorder skeletal dysplasia skeletal regeneration skeletal stem cell smoothened signaling pathway stem cell expansion stem cell migration stem cell niche stem cell proliferation stem cells tissue repair

项目摘要

Abstract: How skeletal stem cells are activated to expand, migrate to the injury site, and become osteoblast cells to restore damaged bone are central questions in skeletal regeneration, which is key for the maintenance of a functional skeletal system. Craniofacial bones mainly form through intramembranous ossification with limited bone marrow space and skeletal stem cells that reside in the suture, a special fibrous joint that connects calvarial bones of the skull together, have been identified as a major cell population that are required for craniofacial bone homeostasis and injury repair. Numerous studies in both human and mice have highlighted the importance of stem cell niche, a microenvironment where stem cells reside and also regulate stem cell behaviors. As the craniofacial skeleton encases the brain and protects it, calvarial bone defects in the skull, if failed to heal with bony tissue and consequently fibrous non-unions occur, are associated with high morbidity and mortality. Therefore, reconstruction and regeneration of calvarial defects, in particular critical-size defects, continuously poses as an unmet therapeutic challenge. The G protein stimulatory α-subunit (Gas), encoded by GNAS gene, transduces signals from G protein coupled receptors (GPCRs) and has emerged as a critical regulator of osteoblast differentiation by inhibiting Hedgehog (Hh) signaling. Studies in both mouse models and human genetic diseases supports the critical roles of both Gas and Hh signaling in regulating skeletal stem cells in multiple contexts. Having showed that activation of Hh signaling by loss of Gas is a common pathway that critically regulates intramembranous ossification in calvarial bone formation as in heterotopic ossification (HO), we have also made novel findings in unpublished preliminary studies in an calvarial bone injury model that directed suture stem cells (SuSCs) migration to the injury site correlates with upregulated expression of chemokine (C-X-C motif) ligand 12 (Cxcl12) and Sonic Hedgehog (Shh), to a less extent Indian Hedgehog (Ihh), in SuSC niche. Further, inhibition of the Cxcl12 cognate receptor Cxcr4, which is coupled to Gai that counteracts Gas signaling, severely impaired calvarial bone regeneration. Loss of Gas enhanced Shh expression, which induced osteoblast differentiation. We therefore hypothesize that Cxcl12 and Shh are critical niche factors that are induced by calvarial injury and coordinately promote SuSC migration, expansion and osteoblast differentiation, all of which are essential for calvarial bone injury repair. This hypothesis will be tested in three specific aims: 1) To better define SuSCs and determine the roles of Cxcl12 and Gai/Gas signaling in directing SuSC migration to the injury site during calvarial bone regeneration; 2) To determine the roles of Gai/Gas and Shh signaling in SuSC expansion and osteoblast differentiation during calvarial bone regeneration; 3) To determine the interaction of Cxcl12 and Shh signaling during bone regeneration after calvarial injury. We expect to identify novel interactive Cxcl12 and Shh signaling to harness intrinsic regulatory circuitry between niche and SuSCs to promote calvarial bone regeneration and treat calvarial defects.

摘要：骨骼干细胞如何被激活以扩增、迁移到损伤部位并成为成骨细胞，修复受损的骨是骨骼再生的中心问题，这是维持骨骼健康的关键。功能性骨骼系统颅面骨主要通过膜内骨化形成，骨髓空间和骨骼干细胞驻留在缝合线，一个特殊的纤维关节，连接颅骨的头盖骨在一起，已被确定为一个主要的细胞群，所需的颅面骨稳态和损伤修复。在人类和小鼠身上的大量研究都强调了干细胞小生境是干细胞驻留并调节干细胞微环境，行为。由于颅面骨骼包裹着大脑并对其进行保护，如果未能与骨组织愈合，因此发生纤维性骨不连，与高发病率相关 and mortality.因此，颅骨缺损，特别是临界尺寸缺损的重建和再生，一直是一个未解决的治疗挑战。G蛋白刺激性α亚基（Gas），由 GNAS基因，从G蛋白偶联受体（GPCR）转导信号，并已成为一个关键的通过抑制Hedgehog（Hh）信号传导调节成骨细胞分化。两种小鼠模型中的研究和人类遗传疾病支持Gas和Hh信号在调节骨骼干细胞中的关键作用细胞在多种环境中。已经表明，通过Gas丢失激活Hh信号传导是一种常见的途径，与异位骨化一样，严格调节颅骨形成中的膜内骨化 (HO)我们还在未发表的颅骨损伤模型的初步研究中取得了新的发现引导缝合干细胞（SuSC）迁移到损伤部位与以下基因的表达上调相关：趋化因子（C-X-C基序）配体12（Cxcl 12）和Sonic Hedgehog（Shh），在较小程度上是Indian Hedgehog (Ihh)在SuSC niche中。此外，抑制与Gai偶联的Cxc 112同源受体Cxcr 4，抵消气体信号，严重损害颅骨骨再生。气体损失增强Shh 表达，诱导成骨细胞分化。因此，我们假设Cxcl 12和Shh是关键的，由颅骨损伤诱导的生态位因子协同促进SuSC迁移、扩张和成骨细胞分化，所有这些都是颅骨损伤修复所必需的。这一假设将是在三个具体目标中进行测试：1）更好地定义SuSC并确定Cxcl 12和Gai/Gas的作用在颅骨骨再生过程中指导SuSC迁移到损伤部位的信号传导; 2）为了确定 Gai/Gas和Shh信号在颅骨发育过程中SuSC扩增和成骨细胞分化中的作用 3）确定Cxcl 12和Shh信号在骨再生过程中的相互作用，颅骨损伤我们希望能够识别新的相互作用的Cxcl 12和Shh信号转导，以利用内在的调控机制，在niche和SuSCs之间建立回路，以促进颅骨骨再生和治疗颅骨缺损。