PNAS:甲状腺激素如何促成红细胞生成?
2017/09/12
我们一直都知道,甲状腺激素参与红细胞的生成。但是这背后的机制却并不清晰。来自于Whitehead研究所的科学家们试图打破未知,他们以细胞和动物为模型证实,甲状腺激素负责红细胞成熟的最后一步,并找到了调控这一过程的关键因子。


一个多世纪以来,医生们一直在强调,甲状腺功能障碍(多由碘缺乏引发)患者常常伴随有贫血。但是,甲状腺激素(TH)与红细胞之间存在怎样的联系?我们并不知道。

现在,《PNAS》期刊发表一篇文章揭示,来自于Whitehead研究所的科学家们正试图打破未知。他们以细胞和动物为模型证实,甲状腺激素负责红细胞成熟的最后一步,并找到了调控这一过程的关键因子。

红细胞造血祖细胞在调节因子的作用下会朝着红细胞的方向分化,它会启动血红蛋白及其他红细胞相关蛋白基因的表达,促成红细胞的最终成熟。之前已有研究证实,在血清中培养祖细胞有助于其表达所有必需蛋白质的编码基因。

在这一篇最新研究中,研究团队试图找到血清中控制红细胞生成的关键成分。为了缩小筛选范围,研究团队利用木炭(charcoal)作为过滤器,对血清进行处理。他们发现,一旦经过木炭过滤,血清将不再支持红细胞的生产。考虑到木炭能够吸收并保留疏水分子,所以他们推测,被木炭捕获的疏水分子是红细胞成熟最后一步的关键。

在血清(经过过滤)中添加甲状腺激素后,红系祖细胞会再次启动成熟过程。这意味着,甲状腺激素对于红细胞的成熟很重要。而且,如果在红细胞生成初期添加该激素,红细胞的正常发育过程会缩短(即加速红细胞的生成)。

随后,他们对“甲状腺激素影响红细胞成熟”背后的机制进行了解析:成熟红细胞表面有与甲状腺激素结合的特定受体——甲状腺技术受体β亚型(TRβ),负责催化祖细胞的分化,能够缓解小鼠的贫血症状。而且,TRβ会与核受体共激活因子4(NCOA4)共同协作,调控红细胞的成熟。

通过更好地了解甲状腺激素和红细胞成熟之间的关联,科学家们有望开发出新的治疗方法,用于催化特定贫血症患者体内红细胞的生成。

参考资料:

Mystery solved: How thyroid hormone prods red blood cell production

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  • Thyroid hormone receptor beta and NCOA4 regulate terminal erythrocyte differentiation

    An effect of thyroid hormone (TH) on erythropoiesis has been known for more than a century but the molecular mechanism(s) by which TH affects red cell formation is still elusive. Here we demonstrate an essential role of TH during terminal human erythroid cell differentiation; specific depletion of TH from the culture medium completely blocked terminal erythroid differentiation and enucleation. Treatment with TRβ agonists stimulated premature erythroblast differentiation in vivo and alleviated anemic symptoms in a chronic anemia mouse model by regulating erythroid gene expression. To identify factors that cooperate with TRβ during human erythroid terminal differentiation, we conducted RNA-seq in human reticulocytes and identified nuclear receptor coactivator 4 (NCOA4) as a critical regulator of terminal differentiation. Furthermore, Ncoa4−/− mice are anemic in perinatal periods and fail to respond to TH by enhanced erythropoiesis. Genome-wide analysis suggests that TH promotes NCOA4 recruitment to chromatin regions that are in proximity to Pol II and are highly associated with transcripts abundant during terminal differentiation. Collectively, our results reveal the molecular mechanism by which TH functions during red blood cell formation, results that are potentially useful to treat certain anemias.

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