Control of bone physiology by a novel type of adipose cells

新型脂肪细胞对骨生理学的控制

基本信息

批准号：
10577829
负责人：
Ling Qin
金额：
$ 46.24万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-15 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10577829
关键词：
3-Dimensional Ablation Address Adipocytes Adipose tissue Adult Age Aging Albers-Schonberg disease Angiogenic Factor Animal Model Bacterial Infections Biology Blood Vessels Blood capillaries Bone Development Bone Diseases Bone Marrow Bone Marrow Cells Bone Resorption Bone Resorption Inhibition Bone Surface CSF1 gene Cell Lineage Cell physiology Cells Chondrocytes Chronic Disease Clinical Coupled Coupling Data Development Disease Environment Fluorescent in Situ Hybridization Fracture Future Genetic study Health Care Costs Homeostasis Impairment Injections Intervention Knockout Mice Knowledge Label Lead Lipids LoxP-flanked allele Malignant Neoplasms Marrow Mesenchymal Mesenchymal Stem Cells Modeling Morbidity - disease rate Morphology Mus Names Nature Normal tissue morphology Obesity Osteoblasts Osteoclasts Osteocytes Osteogenesis Osteolysis Osteoporosis Ovariectomy Pathologic Pericytes Phenotype Physiologic pulse Physiology Play Population Postmenopausal Osteoporosis Process Proliferating Property Public Health RNA Radiation Reporter Research Role Route Skeletal Development Source Stromal Cell-Derived Factor 1 Stromal Cells Structure TNFSF11 gene Three-Dimensional Imaging Tissues VEGFA gene adiponectin bone bone loss bone mass bone repair cell type conditional knockout diabetic bone disease human old age (65+)improved in vivo injury and repair innovation long bone novel novel therapeutics osteogenic postnatal development response response to injury single nucleus RNA-sequencing skeletal disorder spatiotemporal spine bone structure transcriptome transcriptomics translational impact

项目摘要

Project Summary Osteoporosis and low bone mass are common chronic disorders associated with significant morbidity and substantial healthcare costs. Bone is a dynamic tissue that constantly undergoes coupled remodeling by osteoblasts and osteoclasts. Bone marrow (BM) adipocytes, arising from the same mesenchymal stem cells (MSCs) as osteoblasts, also play a crucial role in bone homeostasis. Therefore, advancing our knowledge on mesenchymal populations in bone and understanding their functions will reveal novel targets that address the unmet clinical need for improved treatments for skeletal diseases. By carrying out large scale single cell transcriptome analysis, we recently computationally defined the hierarchy of BM mesenchymal lineage cells and delineated the in vivo differentiation process of MSCs through multiple intermediate subpopulations. Interestingly, we identified a new subpopulation situated after proliferative mesenchymal progenitors and before classic lipid-laden adipocytes (LiLAs) along the adipogenic differentiation route, and thus named those cells marrow adipogenic lineage precursors (MALPs). These non-proliferative cells express mature adipocyte markers, including Adiponectin (Adipoq), but do not accumulate lipid. In young mice, MALPs, genetically labelled by Adipoq-Cre(ER), exist abundantly as BM stromal cells and capillary pericytes. Morphologically, they display many long cell processes that make contacts among themselves and with surrounding cells, as well as the bone surface, to establish a ubiquitous 3D network inside BM cavity. Cell ablation revealed that these Adipoq+ cells play critical roles in maintaining BM vasculature and in suppressing bone formation. Strikingly, MALPs are rapidly and transiently expanded after focal radiation, implying a reparative role during injury response. One important feature of MALPs is that they highly express many secreted factors, such as VEGFa, RANKL (Tnfsf11), CSF1, Cxcl12 etc, indicating regulatory actions on surrounding cells. These data lead to our central hypothesis that MALPs represent a novel adipose cell type with pivotal roles in regulating their BM environment during skeletal development, homeostasis, aging, and injury repair. Bone marrow adipose tissue (MAT) normally refers to LiLAs, and current MAT research centers on their energy and lipid-related roles. This proposal will expand the concept of MAT to include MALPs, a much more abundant cell population, and its non-lipid-associated actions. Our aims are to: 1) determine the in vivo fate and properties of MALPs; 2) elucidate the role of MALPs in regulating bone marrow vasculature; 3) determine the regulatory actions of MALPs on bone resorption. Innovative approaches, such as single nucleus RNA-sequencing (snRNA-seq), confocal 3D imaging, RNA FISH, genetically modified and reporter animal models, will be used throughout the proposal. Our project will comprehensively characterize a novel mesenchymal subpopulation and its multifaceted regulatory roles in bone. The data we gather here will shed new light on bone, adipose, and vascular biology and identify new targets of intervention on osteoporosis and bone repair.

项目概要骨质疏松症和低骨量是常见的慢性疾病，与显着的发病率和巨大的医疗费用。骨骼是一种动态组织，不断经历耦合重塑成骨细胞和破骨细胞。骨髓 (BM) 脂肪细胞，由相同的间充质干细胞产生（间充质干细胞）作为成骨细胞，在骨稳态中也发挥着至关重要的作用。因此，提高我们的知识骨中的间充质群并了解其功能将揭示解决该问题的新靶点对改善骨骼疾病治疗的临床需求尚未得到满足。通过进行大规模单细胞转录组分析，我们最近通过计算定义了 BM 间充质谱系细胞的层次结构并通过多个中间亚群描述了 MSC 的体内分化过程。有趣的是，我们发现了一个位于增殖间充质祖细胞之后的新亚群，并且沿着脂肪形成分化途径出现在经典的载脂脂肪细胞（LiLA）之前，因此将其命名为细胞骨髓成脂谱系前体（MALP）。这些非增殖细胞表达成熟的脂肪细胞标记物，包括脂联素（Adipoq），但不会积累脂质。在年轻小鼠中，MALPs 基因由 Adipoq-Cre(ER) 标记，以骨髓基质细胞和毛细血管周细胞的形式大量存在。从形态上来说，它们显示许多长的细胞突起，这些突起在它们之间以及与周围细胞之间进行接触，以及骨表面，在 BM 腔内建立无处不在的 3D 网络。细胞消融表明这些 Adipoq+ 细胞在维持 BM 脉管系统和抑制骨形成方面发挥着关键作用。引人注目的是， MALP 在局灶性放射后迅速且短暂地扩张，这意味着损伤期间的修复作用回复。 MALPs的一个重要特征是它们高度表达许多分泌因子，例如VEGFa、 RANKL（Tnfsf11）、CSF1、Cxcl12等，表明对周围细胞的调节作用。这些数据导致我们中心假设是 MALP 代表一种新型脂肪细胞类型，在调节 BM 方面发挥关键作用骨骼发育、体内平衡、衰老和损伤修复过程中的环境。骨髓脂肪组织 (MAT) 通常指 LiLA，目前 MAT 研究的重点是其与能量和脂质相关的作用。这该提案将扩展 MAT 的概念，将 MALP 包括在内，这是一种更加丰富的细胞群，及其非脂质相关的作用。我们的目标是：1）确定 MALP 的体内命运和特性； 2）阐明 MALP 在调节骨髓血管系统中的作用； 3）确定监管行动 MALP 对骨吸收的影响。创新方法，例如单核 RNA 测序 (snRNA-seq)、共焦 3D 成像、RNA FISH、转基因和报告动物模型将在整个过程中使用提议。我们的项目将全面描述一种新型间充质亚群及其特征骨骼中的多方面调节作用。我们在这里收集的数据将为骨骼、脂肪和骨骼提供新的线索血管生物学并确定骨质疏松和骨修复干预的新目标。