Endotome as an Unrecognized Source of Human Peri-Aortic Brown Adipocytes

Mechanistically, we show that TGF-β-induced epithelial-to-mesenchymal transition (EMT) is required for endotome commitment, and that sequential BMP inhibition followed by WNT activation, rather than the BMP activation and WNT inhibition used for dermomyotome-derived BAs, fully potentiates a BA fate. Consequently, endotome-derived BAs resemble in vivo peri-aortic BAT. The developmental authenticity of these endotome precursors is further validated by differentiation into smooth muscle and vascular endothelial cells in response to HGF and VEGFA, respectively.

Collectively, we demonstrate that recapitulating the developmental sequence of signaling cues governing endotome plasticity enables efficient brown adipocyte production from human pluripotent stem cells. Our work identifies a novel source of BAT and establishes a streamlined, rapid, and cost-efficient method to generate metabolic active brown adipocytes, with broad implications for regenerative medicine.