Single-cell transcriptomic analysis reveals dynamic activation of cellular signaling pathways regulating beige...

Area of Science:

• Cell Biology
• Metabolic Research
• Adipose Tissue Biology

Background:

• Platelet-derived growth factor receptor alpha (PDGFRA)+ cells are recognized as adipocyte stem cells (ASCs) capable of differentiating into beige adipocytes.
• Thermogenic stimuli, such as beta3 adrenergic receptor agonists, can induce beige adipocyte formation in white adipose tissue (WAT).

Purpose of the Study:

• To investigate the molecular heterogeneity of PDGFRA+ adipocyte stem cells (ASCs).
• To understand the differentiation pathways and lineage contributions during beige adipogenesis and obesity.

Main Methods:

• Single-cell transcriptomic profiling (scRNA-seq) of PDGFRA+ cells from mouse inguinal WAT (iWAT).
• Trajectory analysis to map molecular pathway activation during beige adipogenesis.
• Genetic lineage tracing and in vitro/in vivo differentiation assays.

Main Results:

• scRNA-seq identified nine distinct cell clusters within PDGFRA+ cells, categorized into resting, proliferating, differentiating, and adipogenic factor-expressing cells (AFECs).
• AFECs expressed Dipeptidyl peptidase-4 (DPP4) and did not differentiate into adipocytes under tested conditions.
• Lineage tracing showed DPP4+ cells did not contribute to beige adipogenesis but were recruited as adipocytes during high-fat diet-induced obesity.

Conclusions:

• Beige adipogenesis involves sequential activation of pathways like Hedgehog and Notch signaling.
• DPP4+ cells represent a distinct lineage within PDGFRA+ cells that does not contribute to thermogenic beige adipocyte formation.
• DPP4+ cells can contribute to white adipose tissue expansion in obesity, highlighting their role in metabolic disease pathogenesis.