自噬在干细胞更新和分化中的作用

2020/9/15 15:52:13 本站原创 佚名 【字体:

 

廖联明   编译

宾夕法尼亚大学医学研究人员在发表在《科学》杂志上的一项新研究中表示,胚胎干细胞中的自噬过程,即所谓的分子伴侣介导的自噬(CMA),以及相关的代谢产物,可能成为有望修复或再生受损细胞和器官的新治疗靶点。

 

人体含有200多种不同类型的特化细胞。所有这些细胞都可以从胚胎干细胞(ES)中衍生出来,在成年动物中,ES细胞可以不断地自我更新,同时保持分化为任何细胞类型的能力,这种状态被称为多能性。研究人员已经知道,细胞的新陈代谢在细胞的自噬过程起着一定的作用;然而,目前还不清楚干细胞的内部是如何保持这种多能状态并最终决定干细胞的分化的。

 

这项新的研究首次展示了干细胞如何将CMA保持在较低的水平以促进自我更新,当干细胞准备分化时,它会改变低水平抑制状态,以增强CMA的活性水平,以及其他活性,并分化为专门的细胞。

 

我们揭示了两种潜在地操纵干细胞自我更新和分化的新方式:CMA和一种由CMA调控的被称为α-酮戊二酸代谢物。合理干预或引导这些功能可能是提高再生医学方法效率的有效途径。高级研究员、宾夕法尼亚大学佩雷尔曼医学院癌症生物学教授Xiaolu Yang说。

 

自噬是一种吞噬细胞的机制,是大多数生物体生存和发挥功能所必需的。当细胞自噬时,细胞内的物质被转移到溶酶体,溶酶体是帮助分解这些物质的细胞器。自噬有几种形式。然而,与其他存在于所有真核细胞中的形式不同,CMA是哺乳动物所特有的。到目前为止,CMA的生理作用尚不清楚。

 

研究人员利用小鼠胚胎干细胞的代谢组学和遗传学实验室技术,试图更好地理解干细胞在多能性状态和随后的分化过程中发生的重要变化。

 

他们发现,CMA的活性之所以保持在最低水平,是因为两个对多能性至关重要的细胞因子-Oct4Sox2-这两个因子抑制了一种名为LAMP2A的基因,LAMP2ACMA所需的一种名为溶酶体相关膜蛋白-2的蛋白的合成提供指令。最低的CMA活性水平使干细胞维持高水平的α-酮戊二酸,这是一种对增强细胞的多潜能状态重要的代谢物。

当细胞分化时,由于Oct4Sox2的减少,细胞开始上调CMACMA活性的增强会导致产生α-酮戊二酸的关键酶发生降解。这会导致α-酮戊二酸的水平降低,以及其他细胞活性的增加从而促进分化。这些发现揭示了CMAα-酮戊二酸决定胚胎干细胞的分化。

 

这一干细胞自噬作用新发现是深入研究的开始,这可能会导致研究人员和临床科学家找到更好的疗法来治疗各种疾病。

 

 

New roles of autophagy in stem cell renewal and differentiation uncovered

 

The self-eating process in embryonic stem cells known as chaperone-mediated autophagy (CMA) and a related metabolite may serve as promising new therapeutic targets to repair or regenerate damaged cells and organs, Penn Medicine researchers show in a new study published in Science.

 

Human bodies contain over 200 different types of specialized cells. All of them can be derived from embryonic stem (ES) cells, which relentlessly self-renew while retaining the ability to differentiate into any cell type in adult animals, a state known as pluripotency. Researchers have known that the cells' metabolism plays a role in this process; however, it wasn't clear exactly how the cells' internal wiring works to keep that state and ultimately decide stem cell fate.

 

The new study, for the first time, shows how the stem cells keeps CMA at low levels to promote that self-renewal, and when the stem cell is ready, it switches that suppression off to enhance CMA, among other activities, and differentiate into specialized cells.

 

"We reveal two novel ways to potentially manipulate the self-renewal and differentiation of stem cells: CMA and a metabolite, known as alpha-ketoglutarate, that is regulated by CMA. Rationally intervening or guiding these functions could be a powerful way to increase the efficiency of regenerative medicine approaches." said senior author Xiaolu Yang, a professor of Cancer Biology in the Perelman School of Medicine at the University of Pennsylvania.

 

Autophagy is a cell-eating mechanism necessary for survival and function of most living organisms. When cells self-eat, the intracellular materials are delivered to lysosomes, which are organelles that help break down these materials. There are a few forms of autophagy. However, unlike the other forms, which are present in all eukaryotic cells, CMA is unique to mammals. To date, the physiological role of CMA remains unclear.

 

Using metabolomic and genetic laboratory techniques on the embryonic stem cells of mice, the researchers sought to better understand significant changes that took place during their pluripotent state and subsequent differentiation.

 

They found that CMA activity is kept at a minimum due to two cellular factors critical for pluripotency -- Oct4 and Sox2 -- that suppresses a gene known as LAMP2A, which provides instructions for making a protein called lysosomal associated membrane protein-2 necessary in CMA. The minimal CMA activity allows stem cells to maintain high levels of alpha-ketoglutarate, a metabolite that is crucial to reinforce a cell's pluripotent state

When it's time for differentiation, the cells begin to upregulate CMA due to the reduction in Oct4 and Sox2. Augmented CMA activity leads to the degradation of key enzymes responsible for the production of alpha-ketoglutarate. This leads to a reduction in alpha-ketoglutarate levels as well as an increases in other cellular activities to promote differentiation. These findings reveal that CMA and alpha-ketoglutarate dictate the fate of embryonic stem cells.

 

This newly discovered role of autophagy in the stem cell is the beginning of further investigations that could lead to researchers and physician-scientists to better therapies to treat various disorders.

 

 

Journal Reference:

Yi Xu, Yang Zhang, Juan C. García-Cañaveras, Lili Guo, Mengyuan Kan, Sixiang Yu, Ian A. Blair, Joshua D. Rabinowitz, Xiaolu Yang. Chaperone-mediated autophagy regulates the pluripotency of embryonic stem cells. Science, 2020 DOI: 10.1126/science.abb4467 分子伴侣介导的自噬调节胚胎干细胞的多能性。

 

 

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