Illuminating adipo-osteoprogenitors in the bone marrow

照亮骨髓中的脂肪骨祖细胞

基本信息

批准号：
10590788
负责人：
Fanxin Long
金额：
$ 46.19万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10590788
关键词：
ANXA5 gene Adipocytes Adult Age Aging Animals Apoptosis Binding Blood Cells Bone Diseases Bone Marrow Bone Marrow Cells Bone Surface Cell Lineage Cells Data Diabetes Mellitus Diabetic mouse Doxycycline Fatty acid glycerol esters Female Forteo Functional disorder Genetic Genotype Hematological Disease Hematopoiesis Hematopoietic Hematopoietic System Heterogeneity Homeostasis Image Impairment Knowledge Label Life Link Lipids Mammals Marrow Mesenchymal Molecular Monitor Mus Myeloproliferative disease Names Non-Insulin-Dependent Diabetes Mellitus Osteoblasts Osteogenesis Osteoporosis Pathogenesis Pharmaceutical Preparations Phenotype Physiologic pulse Physiological Physiology Production Proliferating Reticular Cell Role Source Stromal Cell-Derived Factor 1 Stromal Cells Tamoxifen Technology Testing adipocyte differentiation adiponectin age related aged bone bone aging bone cell bone loss bone mass chemokine diabetic imaging study improved in vivo leptin receptor male osteoblast differentiation osteogenic osteoprogenitor cell perilipin progenitor response single-cell RNA sequencing skeletal stem cell stem cells tibia

项目摘要

Abstract The bone marrow in mammals house both hematopoietic and mesenchymal cells that are responsible for sustaining blood and bone cell production, respectively, throughout adult life. Although the hematopoietic system is well understood, the molecular identities, hierarchy of the marrow mesenchymal cells and their respective contribution to bone homeostasis are just beginning to be unraveled. Elucidation of the organization and functions of the bone marrow mesenchymal cells is fundamental to understanding the pathogenesis of both myeloid and bone diseases. By employing single-cell RNA sequencing (scRNA-seq) technology, we have discovered a subset of bone marrow mesenchymal cells co-expressing adiponectin (Adipoq) and osterix (Osx) which are traditionally considered adipocyte or osteoblast markers, respectively. Trajectory analyses predict the Adipoq+Osx+ bi-marker cells to be common progenitors for osteoblasts and marrow adipogenic lineage cells. Lineage tracing with Osx-CreERT2 or Adipoq-CreERT2 supports that the bi-marker cells give rise to both osteoblasts and adipocytes in vivo. Imaging studies localize the bi-marker cells to the endosteal bone niche. The data therefore support the hypothesis that Adipoq+Osx+ bi-marker cells are adipo-osteoprogenitors attuned to the physiological milieu in the bone marrow. To test the hypothesis, we will first determine the number and fate of the bi-marker cells in young, mature and aged mice to uncover potential age-dependent changes (aim 1). We will then investigate the functional contribution of the bi-marker progenitors to bone formation both under basal conditions and in response to the main bone anabolic drug teriparatide in mature adult mice (aim2). We will finally examine the effect of diabetes on the fate of the bi-marker cells in an experimentally induced type II diabetes mouse model. The studies are expected to shed light on the role of the adipo- osteoprogenitors in bone physiology and pathophysiology.

抽象的哺乳动物的骨髓中含有造血细胞和间充质细胞，负责在整个成年过程中分别维持血液和骨细胞的产生。虽然造血系统很好理解，骨髓间充质细胞的分子特性、层次结构及其各自对骨稳态的贡献才刚刚开始被揭示。组织的阐明骨髓间充质细胞的功能和功能是了解骨髓间质瘤发病机制的基础骨髓疾病和骨疾病。通过采用单细胞 RNA 测序 (scRNA-seq) 技术，我们发现了共表达脂联素 (Adipoq) 和 osterix (Osx) 的骨髓间充质细胞子集传统上分别被认为是脂肪细胞或成骨细胞标记物。轨迹分析预测 Adipoq+Osx+ 双标记细胞是成骨细胞和骨髓成脂谱系的共同祖细胞细胞。使用 Osx-CreERT2 或 Adipoq-CreERT2 进行谱系追踪支持双标记细胞产生体内的成骨细胞和脂肪细胞。成像研究将双标记细胞定位于骨内膜骨生态位。因此，数据支持 Adipoq+Osx+ 双标记细胞是脂肪-骨祖细胞协调的假设到骨髓中的生理环境。为了检验假设，我们首先确定数量和年轻、成熟和老年小鼠中双标记细胞的命运，以揭示潜在的年龄依赖性变化（目的 1).然后我们将研究双标记祖细胞对骨形成的功能贡献在基础条件下以及对成熟成年小鼠中主要骨合成代谢药物特立帕肽的反应（目标2）。我们最终将在实验中检查糖尿病对双标记细胞命运的影响诱导II型糖尿病小鼠模型。这些研究有望揭示脂肪的作用骨生理学和病理生理学中的骨祖细胞。