Wu Guojin, Cheng Zhang Cheng
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Haematologica. 2021 Aug 1;106(8):2180-2190. doi: 10.3324/haematol.2019.243998.
Adult hematopoietic stem cells (HSCs) are quiescent most of the time, and how HSCs switch from quiescence to proliferation following hematopoietic stress is unclear. Here we demonstrate that upon stress the coxsackievirus and adenovirus receptor CAR (also known as CXADR) is upregulated in HSCs and critical for HSC entry into the cell cycle. WT HSCs were detected more rapid repopulation ability than the CAR cKO counterparts. After 5-FU treatment, CAR cKO HSCs had lower levels of Notch1 expression and elevated protein level of Numb, a Notch antagonist. The Notch signaling inhibitor DAPT, dominant negative form of MAML (a transcriptional coactivator of Notch), or dominant negative mutant of LNX2 (an E3 ligase that acts on Numb and binds to CAR), all were capable of abrogating the function of CAR in HSCs. We conclude that CAR activates Notch1 signaling by downregulating Numb protein expression to facilitate entry of quiescent HSCs into the cell cycle during regeneration.
成年造血干细胞（HSCs）大部分时间处于静止状态，目前尚不清楚造血干细胞在造血应激后如何从静止状态转变为增殖状态。在此，我们证明在应激状态下，柯萨奇病毒和腺病毒受体CAR（也称为CXADR）在造血干细胞中上调，并且对于造血干细胞进入细胞周期至关重要。野生型造血干细胞比CAR基因敲除（cKO）的对应细胞具有更快的再增殖能力。5-氟尿嘧啶（5-FU）处理后，CAR基因敲除的造血干细胞中Notch1表达水平较低，而Notch拮抗剂Numb的蛋白水平升高。Notch信号抑制剂DAPT、Notch转录共激活因子MAML的显性负性形式或LNX2（一种作用于Numb并与CAR结合的E3连接酶）的显性负性突变体，均能够消除CAR在造血干细胞中的功能。我们得出结论，CAR通过下调Numb蛋白表达来激活Notch1信号，以促进静止造血干细胞在再生过程中进入细胞周期。
