Identification of a mesenchymal progenitor cell hierarchy in adipose tissue

脂肪组织中间充质祖细胞层次结构的鉴定

• 批准号: 10394270
• 负责人: David M Merrick
• 金额: $ 16.79万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394270
• 关键词: Adipocytes; Adipose tissue; Adult; Anatomy; Biology; Candidate Disease Gene; Cell Differentiation process; Cell Maintenance; Cell Therapy; Cells; Cellular biology; Chronic; Complex; Connective Tissue; Coupled; Development; Elements; Environment; Equilibrium; Fibrosis; Foundations; Growth; High Fat Diet; Homeostasis; Hypertrophy; ICAM1 gene; Immunohistochemistry; Implant; In Vitro; Inflammation; Insulin Resistance; Investigation; Label; Lead; Lipids; Liver; Location; Maintenance; Mesenchymal; Mesenchymal Stem Cells; Metabolic; Metabolic syndrome; Multipotent Stem Cells; Mus; Muscle; Myofibroblast; Natural regeneration; Nature; Nutrient; Obesity; Organ; Organogenesis; Pathologic; Pathway interactions; Phenotype; Physiological; Play; Population; Property; Public Health; RNA; Regenerative capacity; Reporter; Reporting; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Specificity; Stimulus; Structure; Techniques; Testing; Tissue Expansion; Tissues; Training; Transforming Growth Factor beta; Transplantation; WNT Signaling Pathway; adipocyte differentiation; cell type; diet-induced obesity; exhaustion; experimental study; in silico; in vivo; insight; interstitial; lipid biosynthesis; mouse model; multipotent cell; novel; novel therapeutics; progenitor; prospective; pup; response; self-renewal; stem; stem cells; therapeutically effective; transcriptome; transcriptome sequencing; transcriptomics; transplant model

PROJECT TITLE Characterization of a novel adipogenic mesenchymal progenitor population inhabiting a unique interstitial tissue niche. ABSTRACT Obesity and the associated metabolic syndrome represent a profound public health challenge for which there are few effective therapeutics. Fundamentally, obesity arises in the setting of nutrient excess, which stimulates adipose tissue expansion. The healthy growth of adipose tissue depends on the capacity of progenitor cells to undergo de novo adipogenesis. However, the cellular hierarchy and mechanisms governing adipocyte progenitor differentiation are poorly understood. Adipose mesenchymal progenitors represent a complex pool of highly diverse cell types, and previous attempts to characterize these populations using candidate gene approaches have been significantly limited by lack of specificity and loss of spatial information. Using unbiased single-cell RNA transcriptomics coupled with immunohistochemistry, we identified a novel progenitor population which we term Interstitial Progenitor Cells (IPCs). IPCs are multipotent progenitors, marked by expression of Dpp4 and Wnt2, which can give rise to committed preadipocytes and mature adipocytes. Importantly, we show that IPCs inhabit the Reticular Interstitium (RI), a fibrous tissue that envelops many organs including adipose depots and represents a previously unrecognized anatomical niche for multipotent mesenchymal progenitors. The scientific objectives of this proposal are to determine the in vivo contribution of IPCs to adipose tissue biology and define the niche elements that maintain IPC identity and direct lineage allocation. The Aims of the proposal are: 1) Trace the in vivo lineage allocation of IPCs during early adipose organogenesis and adult stimulated adipogenesis. 2) Investigate the role of TGFβ and Wnt signaling in IPC maintenance and differentiation. In addition to the scientific contributions of the proposed aims, this proposal outlines a structured, focused training plan that will equip me with the techniques and expertise in progenitor cell biology that will serve as the foundation of a successful transition to independence.

项目名称 一种新的成脂间充质祖细胞群体的特征 纸巾利基。 摘要 肥胖和相关的代谢综合征是一个深刻的公共卫生挑战， 几乎没有有效的治疗方法。从根本上说，肥胖是在营养过剩的背景下产生的，营养过剩会刺激 脂肪组织扩张。脂肪组织的健康生长依赖于祖细胞的能力 接受新的成脂作用。然而，控制脂肪细胞的细胞层次和机制 对祖细胞的分化知之甚少。 脂肪间充质祖细胞代表高度多样化的细胞类型的复杂池，并且以前 使用候选基因方法刻画这些人群的特征的尝试受到以下因素的严重限制 缺乏特异性和空间信息的丢失。使用无偏倚的单细胞RNA转录转录结合 免疫组织化学，我们鉴定了一种新的祖细胞群体，我们称之为间质祖细胞 (IPCS)。IPC是多能祖细胞，以DPP4和WNT2的表达为标志，可导致 承诺的前脂肪细胞和成熟的脂肪细胞。重要的是，我们证明了IPC居住在网状结构中 间质(RI)，一种包裹包括脂肪库在内的许多器官的纤维组织，代表着 先前未知的多潜能间充质祖细胞的解剖学定位。 这项建议的科学目标是确定体内IPC对脂肪组织的贡献。 生物学，并定义维持IPC身份和直接血统分配的利基元素。该计划的目标是 建议如下：1)追踪早期脂肪器官形成和成年期间IPC的体内谱系分配 刺激脂肪生成。2)研究转化生长因子β和Wnt信号转导在IPC维持和发展中的作用 差异化。除了拟议目标的科学贡献外，本提案还概述了 有组织、有重点的培训计划，将使我掌握祖细胞生物学方面的技术和专业知识 这将成为成功过渡到独立的基础。