Generation of Functional Brown Adipocytes from Human Pluripotent Stem Cells via Progression through a Paraxial Mesoderm State

• Published in: Cell stem cell Vol. 27; no. 5; pp. 784 - 797.e11
• Main Authors: Zhang, Liang, Avery, John, Yin, Amelia, Singh, Amar M., Cliff, Timothy S., Yin, Hang, Dalton, Stephen
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.11.2020
• Subjects: brown adipocytes; metabolic disease; pluripotent stem cells; thermogenic adipocytes; thermogenic adipocytes; pluripotent stem cells; metabolic disease; brown adipocytes
• ISSN: 1934-5909; 1875-9777; 1875-9777
• DOI: 10.1016/j.stem.2020.07.013

Brown adipocytes (BAs) are a potential cell source for the treatment of metabolic disease, including type 2 diabetes. In this report, human pluripotent stem cells (hPSCs) are subject to directed differentiation through a paraxial mesoderm progenitor state that generates BAs at high efficiency. Molecular analysis identifies potential regulatory networks for BA development, giving insight into development along this lineage. hPSC-derived BAs undergo elevated rates of glycolysis, uncoupled respiration, and lipolysis that are responsive to changes in cyclic AMP (cAMP)-dependent signaling, consistent with metabolic activity in BA tissue depots. Transplanted human BAs engraft into the inter-scapular region of recipient mice and exhibit thermogenic activity. Recipient animals have elevated metabolic activity, respiratory exchange ratios, and whole-body energy expenditure. Finally, transplanted BAs reduce circulating glucose levels in hyperglycemic animals. These data provide a roadmap for brown adipocyte development and indicate that BAs generated from hPSCs have potential as a tool for therapeutic development. [Display omitted] •Serum-free, directed differentiation strategy for generating functional BAs•Identification of a potential network of regulators that control BA development•Transplanted BAs improve whole body energy metabolism and blood glucose disposal Zhang et al. describe a system for the generation of human brown adipocytes (BAs) from pluripotent stem cells and identify potential regulatory networks for developmental commitment and specification of this lineage. Transplantation of BAs increases whole-body energy expenditure and improves glucose homeostasis, suggesting potential utility for treatment of metabolic disease.