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Generation of Functional Brown Adipocytes from Human Pluripotent Stem Cells via Progression through a Paraxial Mesoderm State.
Cell Stem Cell ( IF 19.8 ) Pub Date : 2020-08-11 , DOI: 10.1016/j.stem.2020.07.013
Liang Zhang 1 , John Avery 1 , Amelia Yin 1 , Amar M Singh 1 , Timothy S Cliff 1 , Hang Yin 1 , Stephen Dalton 1
Affiliation  

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.



中文翻译:

从人多能干细胞通过近轴中胚层状态的进展生成功能性棕色脂肪细胞。

棕色脂肪细胞(BAs)是治疗包括2型糖尿病在内的代谢疾病的潜在细胞来源。在此报告中,人类多能干细胞(hPSC)通过近轴中胚层祖细胞状态进行定向分化,该状态可高效生成BA。分子分析确定了BA发展的潜在监管网络,从而深入了解了该谱系的发展。源自hPSC的BA经历了较高的糖酵解,解偶联呼吸和脂解速率,这些速率响应于环状AMP(cAMP)依赖性信号传导的变化,与BA组织贮库中的代谢活性一致。移植的人BA移植到受体小鼠的肩cap骨间区域,并显示产热活性。收件人动物的代谢活动,呼吸交换率,和全身能量消耗。最后,移植的BAs降低了高血糖动物的循环葡萄糖水平。这些数据为褐色脂肪细胞的发展提供了路线图,并表明从hPSC产生的BA具有作为治疗发展工具的潜力。

更新日期:2020-08-11
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