Unravelling the developmental roadmap towards human brown adipose tissue
Unravelling the developmental roadmap towards human brown adipose tissue
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DOI：
10.1101/2020.07.09.194886
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发表时间：
2020-07
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通讯作者：
S. Carobbio;Anne-Claire Guénantin;M. Bahri;I. Samuelson;Floris Honig;S. Rodríguez-Fdez;Kathleen Long;Ioannis Kamzolas;Sherine Awad;D. Lukovic;S. Erceg;Andrew R. Bassett;Sasha Mendjan;L. Vallier;B. Rosen;Davide Chiarugi;A. Vidal-Puig
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作者：
S. Carobbio;Anne-Claire Guénantin;M. Bahri;I. Samuelson;Floris Honig;S. Rodríguez-Fdez;Kathleen Long;Ioannis Kamzolas;Sherine Awad;D. Lukovic;S. Erceg;Andrew R. Bassett;Sasha Mendjan;L. Vallier;B. Rosen;Davide Chiarugi;A. Vidal-Puig
增加棕色脂肪组织（BAT）的质量和激活已被提出作为一种潜在的治疗策略，以治疗肥胖症和相关的心脏代谢并发症。鉴于肥胖和糖尿病患者拥有少量的BAT，如果BAT是有用的，则需要一种有效的方法来扩大其BAT质量。目前，关于人类BAT如何发展、分化和最佳激活的知识有限。此外，由于人类最佳可得技术的数量少，而且在解剖学上分散，因此获得人类最佳可得技术具有挑战性。这些限制使得与BAT在人类中的发育和功能相关的详细机制研究几乎是不可能的。为了克服这些局限性，我们开发了一种与人类相关的新方案，用于将人类多能干细胞（hPSC）分化为棕色脂肪细胞（BA）。该方案的独特之处在于，它是化学定义的，以概括BAT的生理逐步发育路径，其捕获短暂的近轴中胚层和BAT祖细胞状态，最终到达脂肪细胞阶段。这些hPSC衍生的BA表达棕色脂肪细胞和产热标志物，是胰岛素敏感性的，并对β-肾上腺素能刺激有反应。这个新的协议是一个可扩展的工具，在开发过程中研究人类BA。
Increasing brown adipose tissue (BAT) mass and activation has been proposed as a potential therapeutic strategy to treat obesity and associated cardiometabolic complications. Given that obese and diabetic patients possess low amounts of BAT, an efficient way to expand their BAT mass would be necessary if BAT is to be useful. Currently, there is limited knowledge about how human BAT develops, differentiates, and is optimally activated. Moreover, to have access to human BAT is challenging, given its low volume and being anatomically dispersed. These constrain makes detailed mechanistic studies related to BAT development and function in humans virtually impossible. To overcome these limitations, we have developed a human-relevant new protocol for the differentiation of human pluripotent stem cells (hPSCs) into brown adipocytes (BAs). Unique to this protocol is that it is chemically-defined to recapitulate a physiological step-by-step developmental path of BAT that captures transient paraxial mesoderm and BAT progenitor states, on its way to reaching the adipocyte stage finally. These hPSC-derived BAs express brown adipocyte and thermogenic markers, are insulin sensitive, and respond to β-adrenergic stimuli. This new protocol is a scalable tool to study human BAs during development.