美国辛辛那提大学Marie-Dominique Filippi团队研究发现不对称分离线粒体为造血干细胞（HSC）的复制历史提供细胞记忆，并驱动HSC耗损。相关论文2020年2月13日在线发表在国际学术期刊《细胞—干细胞》上。

他们发现，线粒体激活并复制后，HSC不可逆地重塑了线粒体网络，并且与造血祖细胞相反，HSC重新进入静止状态后，该网络未得到修复。HSC通过主动分裂过程中的不对称分离来维持和积累功能异常的线粒体。从机制上讲，线粒体感受到压力后聚集并去极化，这是因为线粒体分离调控子Drp1在线粒体上的活性丧失。遗传学和药理学研究表明，在保持HSC静止时，Drp1失活会导致HSC再生潜能丧失。在分子水平上，携带功能异常的线粒体的HSC可以重新进入静止状态，但在随后的分裂中无法同步核心细胞周期和代谢成分的转录控制。因此，线粒体形态保真性和分离的丧失是HSC分离记忆的一种类型，并驱动HSC耗损。

研究人员表示，HSC的代谢要求随其细胞周期活性而变化。但是，线粒体的潜在作用仍不清楚。

附：英文原文

Title: Asymmetrically Segregated Mitochondria Provide Cellular Memory of Hematopoietic Stem Cell Replicative History and Drive HSC Attrition

Author: Ashwini Hinge, Jingyi He, James Bartram, Jose Javier, Juying Xu, Ellen Fjellman, Hiromi Sesaki, Tingyu Li, Jie Yu, Mark Wunderlich, James Mulloy, Matthew Kofron, Nathan Salomonis, H. Leighton Grimes, Marie-Dominique Filippi

Issue&Volume: February 13, 2020

Abstract: The metabolic requirements of hematopoietic stem cells (HSCs) change with their cellcycle activity. However, the underlying role of mitochondria remains ill-defined.Here we found that, after mitochondrial activation with replication, HSCs irreversiblyremodel the mitochondrial network and that this network is not repaired after HSCre-entry into quiescence, contrary to hematopoietic progenitors. HSCs keep and accumulatedysfunctional mitochondria through asymmetric segregation during active division.Mechanistically, mitochondria aggregate and depolarize after stress because of lossof activity of the mitochondrial fission regulator Drp1 onto mitochondria. Geneticand pharmacological studies indicate that inactivation of Drp1 causes loss of HSCregenerative potential while maintaining HSC quiescence. Molecularly, HSCs carryingdysfunctional mitochondria can re-enter quiescence but fail to synchronize the transcriptionalcontrol of core cell cycle and metabolic components in subsequent division. Thus,loss of fidelity of mitochondrial morphology and segregation is one type of HSC divisionalmemory and drives HSC attrition.

DOI: 10.1016/j.stem.2020.01.016

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(20)30016-3