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 TGF? 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.

Public Health Relevance

Obesity and the metabolic syndrome are thought to arise in the setting of inadequate preadipocyte differentiation to accommodate chronic energy surplus and there are no current therapies that specifically target this pathway. I have discovered a novel mesenchymal progenitor cell that contributes to adipogenesis and that inhabits a previously unrecognized tissue niche present throughout the body. I am working to identify signaling pathways that regulate the function of these progenitors, the understanding of which may open new avenues of investigation into novel therapeutics for obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08DK122099-01
Application #
9806725
Study Section
Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
Program Officer
Haft, Carol R
Project Start
2019-07-15
Project End
2024-04-30
Budget Start
2019-07-15
Budget End
2020-04-30
Support Year
1
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104