HIF1a非經典靶標削弱OPC功能
作者：
小柯機器人發布時間：2020/10/25 21:34:10
凱斯西儲大學醫學院Paul J. Tesar研究組近日取得一項新成果。他們發現缺氧誘導因子（HIFs）的非經典靶標削弱少突膠質細胞祖細胞（OPCs）功能。這一研究成果於2020年10月22日發表在國際頂尖學術期刊《細胞-幹細胞》上。
使用在多能幹細胞來源的少突膠質細胞祖細胞（OPCs）中的慢性HIF1a積累模型，他們證明了HIF1a激活非經典靶標以減少OPC少突膠質細胞的產生。HIF1a通過與OPC特異性轉錄因子OLIG2相互作用激活了OPC中的一組特異基因。包括Ascl2和Dlx3在內的非經典靶標通過抑制少突膠質細胞調節子Sox10足以阻止分化。
化學篩選顯示，通過恢復Sox10表達而不影響經典HIF1a活性，對MEK / ERK信號的抑制作用克服了HIF1a介導的少突膠質細胞生成的阻滯作用。 MEK / ERK抑制作用還導致人少皮層球體缺氧區域少突膠質細胞的形成。這項工作定義了HIF1a減弱少突膠質細胞形成的機制，並確定了細胞類型特異性HIF1a會針對低氧而擾動細胞功能。
據了解，哺乳動物細胞通過稱為HIFs的轉錄調節因子對氧氣不足做出反應。儘管具有短暫的保護作用，但延長的HIF活性會在不同組織中驅動不同的病理反應。
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