Illuminating adipo-osteoprogenitors in the bone marrow

照亮骨髓中的脂肪骨祖细胞

• 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
• 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

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.

摘要 哺乳动物的骨髓中既有造血细胞，也有间充质细胞，它们负责 在整个成年生活中，分别维持血液和骨骼细胞的产生。虽然是造血剂 系统已被熟知，骨髓间充质细胞的分子特性、层级和它们的 各自对骨骼稳态的贡献才刚刚开始被解开。对该组织的说明 而骨髓间充质细胞的功能是了解其发病机制的基础。 包括骨髓性疾病和骨质疏松症。通过使用单细胞RNA测序(scRNA-seq)技术，我们已经 发现骨髓间充质细胞亚群共表达脂联素(ADIPOQ)和骨钙素(OSX) 传统上分别被认为是脂肪细胞或成骨细胞的标志物。弹道分析预测 ADIPOQ+OSX+双标记细胞是成骨细胞和骨髓成脂细胞的共同祖细胞 细胞。OSX-CreERT2或ADIPOQ-CreERT2的谱系追踪支持双标记细胞产生两者 体内成骨细胞和脂肪细胞。影像研究将双标记细胞定位于骨内膜骨龛。 因此，这些数据支持ADIPOQ+OSX+双标记细胞是经过调谐的脂肪骨祖细胞的假设 骨髓中的生理环境。为了检验这一假设，我们将首先确定数字和 年轻、成熟和老年小鼠双标记细胞的命运以揭示潜在的年龄相关性变化(目的 1)。然后，我们将研究双标记前体细胞对骨形成的功能贡献 基础条件下成年小鼠对主要骨合成药物特瑞帕泰的反应 (AIM2)。我们最终将在实验中检验糖尿病对双标记细胞命运的影响。 诱导小鼠II型糖尿病模型。这些研究有望阐明脂肪的作用-- 骨生理学和病理生理学中的骨祖细胞。