New Role for Growth/Differentiation Factor 15 in the Survival of Transplanted Brown Adipose Tissues in Cooperation with Interleukin-6
New Role for Growth/Differentiation Factor 15 in the Survival of Transplanted Brown Adipose Tissues in Cooperation with Interleukin-6
复制标题
生长/分化因子15与白细胞介素-6协同在褐色脂肪移植组织存活中的新作用
DOI：
10.3390/cells9061365
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发表时间：
2020-06-01
期刊：
影响因子：
6
通讯作者：
Saeki, Kumiko
中科院分区：
文献类型：
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作者：
Oka, Masako;Kobayashi, Norihiko;Saeki, Kumiko
为了确定参与人类胚胎干细胞（hESC）分化为棕色脂肪细胞（BA）的最早阶段的因素，我们进行了多时间点微阵列分析。我们发现，当未成熟 hESC 标记物的表达持续存在时，生长/分化因子 15 (GDF15) 的表达在分化三天内特异性上调。尽管GDF15表达在随后的分化阶段持续增加，但GDF15缺陷的hESC分化为成熟BA（第10天），没有明显异常。此外，GDF15缺陷的小鼠具有正常的棕色脂肪组织（BAT）并且代谢健康。出乎意料的是，我们发现GDF15(-/-)小鼠BAT中白细胞介素6(IL6)的表达显着降低。此外，GDF15(-/-)hESCs在分化后期（>第6天）表现出无效的IL6表达。有趣的是，GDF15的表达在IL6(-)(/-)hESCs分化为BA的整个过程中均受到显着抑制，表明IL6对于hESCs分化中诱导GDF15至关重要。最后，GDF15(-/-)供体小鼠腹腔移植的BAT移植物在GDF15(-/-)受体小鼠中无法长期存活(12周)，而野生型(WT)小鼠则不然。总的来说，GDF15 通过与 IL6 建立互基因诱导环，是 BAT 移植物长期存活所必需的。
To identify factors involved in the earliest phase of the differentiation of human embryonic stem cells (hESCs) into brown adipocytes (BAs), we performed multi-time point microarray analyses. We found that growth/differentiation factor 15 (GDF15) expressions were specifically upregulated within three days of differentiation, when expressions of immature hESC markers were sustained. Although GDF15 expressions continued to increase in the subsequent differentiation phases,GDF15-deficient hESCs differentiated into mature BAs (Day 10) without apparent abnormalities. In addition,GDF15-deficient mice had normal brown adipose tissue (BAT) and were metabolically healthy. Unexpectedly, we found that interleukin-6 (IL6) expression was significantly lowered in the BAT ofGDF15(-/-)mice. In addition,GDF15(-/-)hESCs showed abortive IL6 expressions in the later phase (>Day 6) of the differentiation. Interestingly, GDF15 expression was markedly repressed throughout the whole course of the differentiation ofIL6(-)(/-)hESCs into BAs, indicating IL6 is essential for the induction of GDF15 in the differentiation of hESCs. Finally, intraperitoneally transplanted BAT grafts ofGDF15(-/-)donor mice, but not those of wild-type (WT) mice, failed in the long-term survival (12 weeks) inGDF15(-/-)recipient mice. Collectively, GDF15 is required for long-term survival of BAT grafts by creating a mutual gene induction loop with IL6.