凯斯西储大学医学院Paul J. Tesar研究组近日取得一项新成果。他们发现缺氧诱导因子（HIFs）的非经典靶标削弱少突胶质细胞祖细胞（OPCs）功能。这一研究成果于2020年10月22日发表在国际顶尖学术期刊《细胞-干细胞》上。
使用在多能干细胞来源的少突胶质细胞祖细胞（OPCs）中的慢性HIF1a积累模型，他们证明了HIF1a激活非经典靶标以减少OPC少突胶质细胞的产生。HIF1a通过与OPC特异性转录因子OLIG2相互作用激活了OPC中的一组特异基因。包括Ascl2和Dlx3在内的非经典靶标通过抑制少突胶质细胞调节子Sox10足以阻止分化。
化学筛选显示，通过恢复Sox10表达而不影响经典HIF1a活性，对MEK / ERK信号的抑制作用克服了HIF1a介导的少突胶质细胞生成的阻滞作用。 MEK / ERK抑制作用还导致人少皮层球体缺氧区域少突胶质细胞的形成。这项工作定义了HIF1a减弱少突胶质细胞形成的机制，并确定了细胞类型特异性HIF1a会针对低氧而扰动细胞功能。
据了解，哺乳动物细胞通过称为HIFs的转录调节因子对氧气不足做出反应。尽管具有短暂的保护作用，但延长的HIF活性会在不同组织中驱动不同的病理反应。
附：英文原文
Title: Non-canonical Targets of HIF1a Impair Oligodendrocyte Progenitor Cell Function
Author: Kevin C. Allan, Lucille R. Hu, Marissa A. Scavuzzo, Andrew R. Morton, Artur S. Gevorgyan, Erin F. Cohn, Benjamin L.L. Clayton, Ilya R. Bederman, Stevephen Hung, Cynthia F. Bartels, Mayur Madhavan, Paul J. Tesar
Issue&Volume: 2020-10-21
Abstract: Mammalian cells respond to insufficient oxygen through transcriptional regulatorscalled hypoxia-inducible factors (HIFs). Although transiently protective, prolongedHIF activity drives distinct pathological responses in different tissues. Using amodel of chronic HIF1a accumulation in pluripotent-stem-cell-derived oligodendrocyteprogenitors (OPCs), we demonstrate that HIF1a activates non-canonical targets to impairgeneration of oligodendrocytes from OPCs. HIF1a activated a unique set of genes inOPCs through interaction with the OPC-specific transcription factor OLIG2. Non-canonicaltargets, including Ascl2 and Dlx3, were sufficient to block differentiation through suppression of the oligodendrocyteregulator Sox10. Chemical screening revealed that inhibition of MEK/ERK signaling overcame the HIF1a-mediatedblock in oligodendrocyte generation by restoring Sox10 expression without affecting canonical HIF1a activity. MEK/ERK inhibition also droveoligodendrocyte formation in hypoxic regions of human oligocortical spheroids. Thiswork defines mechanisms by which HIF1a impairs oligodendrocyte formation and establishesthat cell-type-specific HIF1a targets perturb cell function in response to low oxygen.
DOI: 10.1016/j.stem.2020.09.019
Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30494-X
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
