Wnt/β-连环蛋白信号通路对 Tert 干细胞静息态的退出对于肠道再生是必不可少的。
Quiescence Exit of Tert Stem Cells by Wnt/β-Catenin Is Indispensable for Intestinal Regeneration.
机构信息
Department of Experimental Radiation Oncology, Division of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA.
Department of Experimental Radiation Oncology, Division of Radiation Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA; Graduate School of Biomedical Sciences, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA; Program in Genes and Development, The University of Texas MD, Anderson Cancer Center, Houston, TX 77030, USA.
出版信息
Cell Rep. 2017 Nov 28;21(9):2571-2584. doi: 10.1016/j.celrep.2017.10.118.
Fine control of stem cell maintenance and activation is crucial for tissue homeostasis and regeneration. However, the mechanism of quiescence exit of Tert intestinal stem cells (ISCs) remains unknown. Employing a Tert knockin (Tert) mouse model, we found that Tert cells are long-term label-retaining self-renewing cells, which are partially distinguished from the previously identified +4 ISCs. Tert cells become mitotic upon irradiation (IR) injury. Conditional ablation of Tert cells impairs IR-induced intestinal regeneration but not intestinal homeostasis. Upon IR injury, Wnt signaling is specifically activated in Tert cells via the ROS-HIFs-transactivated Wnt2b signaling axis. Importantly, conditional knockout of β-catenin/Ctnnb1 in Tert cells undermines IR-induced quiescence exit of Tert cells, which subsequently impedes intestinal regeneration. Our results that Wnt-signaling-induced activation of Tert ISCs is indispensable for intestinal regeneration unveil the underlying mechanism for how Tert stem cells undergo quiescence exit upon tissue injury.
精细控制干细胞的维持和激活对于组织稳态和再生至关重要。然而，Tert 肠道干细胞（ISCs）静止期退出的机制尚不清楚。利用 Tert 敲入（Tert）小鼠模型，我们发现 Tert 细胞是长期标记保留的自我更新细胞，部分与先前鉴定的+4 ISCs 不同。Tert 细胞在照射（IR）损伤后进入有丝分裂。Tert 细胞的条件性缺失会损害 IR 诱导的肠道再生，但不会损害肠道稳态。在 IR 损伤后，ROS-HIFs 转激活的 Wnt2b 信号轴通过 Wnt 信号在 Tert 细胞中特异性激活。重要的是，Tert 细胞中β-catenin/Ctnnb1 的条件性敲除会破坏 IR 诱导的 Tert 细胞静止期退出，进而阻碍肠道再生。我们的研究结果表明，Wnt 信号诱导的 Tert ISCs 激活对于肠道再生是必不可少的，揭示了 Tert 干细胞在组织损伤时如何退出静止期的潜在机制。
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