Salivary glands regenerate after radiation injury through SOX2-mediated secretory cell replacement.
Salivary glands regenerate after radiation injury through SOX2-mediated secretory cell replacement.
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DOI：
10.15252/emmm.201708051
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发表时间：
2018-03
影响因子：
11.1
通讯作者：
Knox SM
中科院分区：
文献类型：
--
作者：
Emmerson E;May AJ;Berthoin L;Cruz-Pacheco N;Nathan S;Mattingly AJ;Chang JL;Ryan WR;Tward AD;Knox SM
唾液腺腺泡细胞在头颈部癌症的放射治疗过程中通常会被破坏，导致终生的唾液分泌不足和合并症。替代受损组织的潜在再生策略是通过靶向治疗重新激活内源性干细胞。然而，这些细胞的身份，它们是否能够再生组织，以及它们被调节的机制是未知的。使用体内和离体模型，结合遗传谱系追踪和人体组织，我们发现了一个SOX 2+干细胞群，它对腺泡细胞的维持至关重要，能够在辐射后补充腺泡。此外，我们表明，腺泡细胞的替代是神经依赖性的，除了毒蕈碱模拟物是足以驱动再生。此外，我们表明，SOX 2减少照射人唾液腺，沿着与副交感神经，这表明组织变性是由于祖细胞及其调节剂的损失。因此，我们建立了一个新的范式，即唾液腺可以在遗传毒性休克后再生，并通过SOX 2神经依赖性机制实现。
Salivary gland acinar cells are routinely destroyed during radiation treatment for head and neck cancer that results in a lifetime of hyposalivation and co‐morbidities. A potential regenerative strategy for replacing injured tissue is the reactivation of endogenous stem cells by targeted therapeutics. However, the identity of these cells, whether they are capable of regenerating the tissue, and the mechanisms by which they are regulated are unknown. Using in vivo and ex vivo models, in combination with genetic lineage tracing and human tissue, we discover a SOX2+ stem cell population essential to acinar cell maintenance that is capable of replenishing acini after radiation. Furthermore, we show that acinar cell replacement is nerve dependent and that addition of a muscarinic mimetic is sufficient to drive regeneration. Moreover, we show that SOX2 is diminished in irradiated human salivary gland, along with parasympathetic nerves, suggesting that tissue degeneration is due to loss of progenitors and their regulators. Thus, we establish a new paradigm that salivary glands can regenerate after genotoxic shock and do so through a SOX2 nerve‐dependent mechanism.