美国德克萨斯大学西南医学中心Sean J. Morrison研究组发现，天门冬氨酸的可用性限制造血干细胞在造血再生过程中的功能。这一研究成果于2021年8月26日在线发表在国际学术期刊《细胞—干细胞》上。
研究人员发现，小鼠造血干细胞（HSC）完全依赖于细胞自主的天门冬氨酸合成，而天门冬氨酸在造血干细胞激活时增加。过量表达谷氨酸/天门冬氨酸转运体Glast或敲除谷氨酸-氧乙酸转氨酶1（Got1）都会增加造血干细胞/祖细胞中的天门冬氨酸水平，并增加造血干细胞的功能，但不会增加集落形成祖细胞的功能。相反，Got2的缺失会降低天门冬氨酸水平和造血干细胞的功能，但不会降低集落形成祖细胞的功能。GOT1和GOT2的缺失会消除造血干细胞。
同位素追踪显示天门冬氨酸被用来合成天门冬氨酸和嘌呤。两者都有助于增加造血干细胞的功能，因为敲除天冬酰胺合成酶或用6-巯基嘌呤处理可减弱GLAST过表达造血干细胞的功能增加。因此，造血干细胞的功能在造血再生过程中受到天门冬氨酸、嘌呤和天冬酰胺的限制。
据了解，电子传输链促进天门冬氨酸的合成，而天门冬氨酸是癌细胞增殖所必需的。然而，目前还不清楚天门冬氨酸在正常干细胞中是否具有局限性。
附：英文原文
Title: Aspartate availability limits hematopoietic stem cell function during hematopoietic regeneration
Author: Le Qi, Misty S. Martin-Sandoval, Salma Merchant, Wen Gu, Matthias Eckhardt, Thomas P. Mathews, Zhiyu Zhao, Michalis Agathocleous, Sean J. Morrison
Issue&Volume: 2021-08-26
Abstract: The electron transport chain promotes aspartate synthesis, which is required for cancercell proliferation. However, it is unclear whether aspartate is limiting in normalstem cells. We found that mouse hematopoietic stem cells (HSCs) depend entirely oncell-autonomous aspartate synthesis, which increases upon HSC activation. Overexpressionof the glutamate/aspartate transporter, Glast, or deletion of glutamic-oxaloacetic transaminase 1 (Got1) each increased aspartate levels in HSCs/progenitor cells and increased the functionof HSCs but not colony-forming progenitors. Conversely, deletion of Got2 reduced aspartate levels and the function of HSCs but not colony-forming progenitors.Deletion of Got1 and Got2 eliminated HSCs. Isotope tracing showed aspartate was used to synthesize asparagineand purines. Both contributed to increased HSC function as deletion of asparaginesynthetase or treatment with 6-mercaptopurine attenuated the increased function ofGLAST-overexpressing HSCs. HSC function is thus limited by aspartate, purine, andasparagine availability during hematopoietic regeneration.
DOI: 10.1016/j.stem.2021.07.011
Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00296-4
Cell Stem Cell：《细胞—干细胞》，创刊于2007年。隶属于细胞出版社，最新IF：25.269
官方网址：https://www.cell.com/cell-stem-cell/home
投稿链接：https://www.editorialmanager.com/cell-stem-cell/default.aspx
本期文章：《细胞—干细胞》：Online/在线发表
