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: 10614948
• 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/10614948
• 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; 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; 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的特征， 组织龛 摘要 肥胖和相关的代谢综合征代表了一个深刻的公共卫生挑战， 很少有有效的治疗方法。从根本上说，肥胖是在营养过剩的情况下产生的， 脂肪组织扩张术脂肪组织的健康生长取决于祖细胞的能力， 进行新生脂肪形成。然而，控制脂肪细胞的细胞层次和机制 祖细胞分化知之甚少。 脂肪间充质祖细胞代表了高度多样化的细胞类型的复杂池，并且先前的研究表明， 使用候选基因方法来表征这些群体的尝试受到了显著的限制， 缺乏特异性和空间信息丢失。使用无偏的单细胞RNA转录组学， 通过免疫组化，我们鉴定了一种新的祖细胞群，我们称之为间质祖细胞 （IPC）。IPC是多能祖细胞，以Dpp4和Wnt 2的表达为标志，其可以引起 定向前脂肪细胞和成熟脂肪细胞。重要的是，我们表明，IPC居住在网状 间质（RI）是一种纤维组织，包裹着包括脂肪库在内的许多器官，代表着一种 以前未被认识到的多能间充质祖细胞的解剖学生态位。 本提案的科学目标是确定IPC对脂肪组织的体内贡献 生物学和定义生态位元素，维持IPC身份和直接谱系分配。的目标 本研究的主要目的是：1）追踪早期脂肪器官形成和成年过程中IPC的体内谱系分布 刺激脂肪形成。2)研究TGFβ和Wnt信号在IPC维持中的作用， 分化除了拟议目标的科学贡献外，该提案还概述了 一个结构化的，有重点的培训计划，这将使我具备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。