CNRS UMR 7277, Nice, France.
University of Nice-Sophia Antipolis, Nice, France.
Stem Cells. 2015 Aug;33(8):2564-73. doi: 10.1002/stem.2016. Epub 2015 May 13.
Adipose tissue expansion is well-orchestrated to fulfill the energy demand. It results from adipocyte hypertrophy and hyperplasia due to adipose progenitor cell (APC) expansion and differentiation. Chronic low grade inflammation and hypoxia take place in obese adipose tissue microenvironment. Both of these events were shown to impact the APC pool by promoting increased self-renewal along with a decrease in the APC differentiation potential. However, no common target has been identified so far. Here we show that the immediate early response 3 gene (IER3) is preferentially expressed in APCs and is essential for APC proliferation and self-renewal. Experiments based on RNA interference revealed that impairing IER3 expression altered cell proliferation through ERK1/2 phosphorylation and clonogenicity. IER3 expression was induced by Activin A, which plays a crucial role in adipocyte differentiation as well as by a decrease in oxygen tension through HIF1-induced transcriptional activation. Interestingly, high levels of IER3 were detected in native APCs (CD34+/CD31- cells) isolated from obese patients and conditioned media from obese adipose tissue-macrophages stimulated its expression. Overall, these results indicate that IER3 is a key player in expanding the pool of APC while highlighting the role of distinct effectors found in an obese microenvironment in this process.
脂肪组织的扩张是经过精心协调以满足能量需求的。它是由于脂肪祖细胞（APC）的扩增和分化导致脂肪细胞肥大和增生的结果。肥胖脂肪组织微环境中存在慢性低度炎症和缺氧。这两个事件都被证明通过促进自我更新以及降低 APC 分化潜能来影响 APC 池。然而，迄今为止尚未确定共同的靶标。在这里，我们表明立即早期反应基因 3（IER3）在 APC 中优先表达，并且对于 APC 的增殖和自我更新至关重要。基于 RNA 干扰的实验表明，破坏 IER3 的表达会通过 ERK1/2 磷酸化和集落形成能力改变细胞增殖。IER3 的表达受激活素 A 的诱导，激活素 A 在脂肪细胞分化中起着至关重要的作用，并且通过 HIF1 诱导的转录激活降低氧张力。有趣的是，在从肥胖患者中分离出的天然 APC（CD34+/CD31-细胞）和肥胖脂肪组织-巨噬细胞的条件培养基中检测到高水平的 IER3，并能诱导其表达。总的来说，这些结果表明 IER3 是扩增 APC 池的关键因素，同时突出了在肥胖微环境中发现的不同效应物在该过程中的作用。
