Identification of a mesenchymal progenitor cell hierarchy in adipose tissue

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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.