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: 10153769
• 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/10153769
• 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.

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