MRC Centre for Regenerative Medicine & Cancer Research UK Edinburgh Centre, University of Edinburgh, Edinburgh, UK.
Samantha Dickson Brain Cancer Unit, UCL Cancer Institute, University College London, London, UK.
Nat Commun. 2021 May 10;12(1):2594. doi: 10.1038/s41467-021-22813-w.
Adult neural stem cells (NSCs) must tightly regulate quiescence and proliferation. Single-cell analysis has suggested a continuum of cell states as NSCs exit quiescence. Here we capture and characterize in vitro primed quiescent NSCs and identify LRIG1 as an important regulator. We show that BMP-4 signaling induces a dormant non-cycling quiescent state (d-qNSCs), whereas combined BMP-4/FGF-2 signaling induces a distinct primed quiescent state poised for cell cycle re-entry. Primed quiescent NSCs (p-qNSCs) are defined by high levels of LRIG1 and CD9, as well as an interferon response signature, and can efficiently engraft into the adult subventricular zone (SVZ) niche. Genetic disruption of Lrig1 in vivo within the SVZ NSCs leads an enhanced proliferation. Mechanistically, LRIG1 primes quiescent NSCs for cell cycle re-entry and EGFR responsiveness by enabling EGFR protein levels to increase but limiting signaling activation. LRIG1 is therefore an important functional regulator of NSC exit from quiescence.
成体神经干细胞 (NSCs) 必须严格调控静息和增殖。单细胞分析表明，当 NSCs 退出静息状态时，存在细胞状态的连续体。在这里，我们捕获并表征了体外诱导的静息 NSCs，并鉴定出 LRIG1 是一个重要的调节因子。我们表明，BMP-4 信号诱导休眠的非循环静息状态（d-qNSCs），而 BMP-4/FGF-2 信号的联合诱导处于细胞周期重新进入准备状态的特化静息状态。诱导的静息 NSCs (p-qNSCs) 的特征是高水平的 LRIG1 和 CD9，以及干扰素反应特征，并且可以有效地植入成年侧脑室下区 (SVZ) 龛位。体内 SVZ NSCs 中 Lrig1 的遗传破坏导致增殖增强。从机制上讲，LRIG1 通过使 EGFR 蛋白水平增加但限制信号激活，为静息 NSCs 重新进入细胞周期和 EGFR 反应性做好准备。因此，LRIG1 是 NSCs 退出静息状态的一个重要功能调节因子。
