Matrix metalloprotease-mediated cleavage of neural glial-related cell adhesion molecules activates quiescent olfactory stem cells via EGFR
Matrix metalloprotease-mediated cleavage of neural glial-related cell adhesion molecules activates quiescent olfactory stem cells via EGFR
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基质金属蛋白酶介导的神经胶质相关细胞粘附分子的裂解通过 EGFR 激活静止的嗅觉干细胞
DOI：
10.1016/j.mcn.2020.103552
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发表时间：
2020-10-01
影响因子：
3.5
通讯作者：
Huang, Liquan
中科院分区：
文献类型：
--
作者：
Chen, Zhen-huang;Luo, Xiao-cui;Huang, Liquan
在多个成体器官中发现了静止的干细胞，这些干细胞的激活对于受损组织响应损伤或压力的恢复至关重要。现有证据表明，来自细胞外基质或各种干细胞生态位的支持细胞的外在信号可能与内在成分相互作用以启动干细胞分化，但调节其激活的分子和细胞机制尚不完全清楚。在本研究中，我们发现嗅觉水平基底细胞（HBC）受到神经胶质相关细胞粘附分子（NrCAM）的刺激。 NrCAM 激活需要基质金属蛋白酶 (MMP) 和表皮生长因子受体 (EGFR)。抑制MMP活性或EGFR激活不仅可以阻断培养的嗅类器官中HBC的增殖，而且还可以严重抑制甲巯咪唑引起的损伤后嗅上皮细胞中HBC的增殖，导致受损小鼠嗅粘膜重建和功能恢复的延迟。 NrCAM 和 EGFR 均由 HBC 表达，并且它们的表达在损伤时增加。我们的数据表明，MMP 介导的 NrCAM 裂解作为自分泌或旁分泌信号，激活 HBC 上的 EGFR，从而触发 HBC 增殖和分化，从而在损伤后重建整个嗅觉上皮。
Quiescent stem cells have been found in multiple adult organs, and activation of these stem cells is critical to the restoration of damaged tissues in response to injury or stress. Existing evidence suggests that extrinsic cues from the extracellular matrix or supporting cells of various stem cell niches may interact with intrinsic components to initiate stem cell differentiation, but the molecular and cellular mechanisms regulating their activation are not fully understood. In the present study, we find that olfactory horizontal basal cells (HBCs) are stimulated by neural glial-related cell adhesion molecules (NrCAMs). NrCAM activation requires matrix metalloproteases (MMPs) and epidermal growth factor receptors (EGFRs). Inhibiting MMP activity or EGFR activation not only blocks HBC proliferation in the cultured olfactory organoids, but also severely suppresses HBC proliferation in the olfactory epithelium following methimazole-induced injury, resulting in a delay of olfactory mucosa reconstitution and functional recovery of the injured mice. Both NrCAMs and EGFR are expressed by the HBCs and their expression increases upon injury. Our data indicate that MMP-mediated cleavage of NrCAMs serves as an autocrine or paracrine signal that activates EGFRs on HBCs to trigger HBC proliferation and differentiation to reconstruct the entire olfactory epithelium following injury.