Salivary gland homeostasis and regeneration after radiotherapy depend significantly on progenitor cells. However, the lineage of submandibular gland (SMG) progenitor cells remains less defined compared with other normal organs. Here, using a mouse strain expressing regulated CreERT2 recombinase from the endogenous Tert locus, we identify a distinct telomerase-expressing (Tert^High) cell population located in the ductal region of the adult SMG. These Tert^High cells contribute to ductal cell generation during SMG homeostasis and to both ductal and acinar cell renewal 1 year after radiotherapy. Tert^High cells maintain self-renewal capacity during in vitro culture, exhibit resistance to radiation damage, and demonstrate enhanced proliferative activity after radiation exposure. Similarly, primary human SMG cells with high Tert expression display enhanced cell survival after radiotherapy, and CRISPR-activated Tert in human SMG spheres increases proliferation after radiation. RNA sequencing reveals upregulation of “cell cycling” and “oxidative stress response” pathways in Tert^High cells following radiation. Mechanistically, Tert appears to modulate cell survival through ROS levels in SMG spheres following radiation damage. Our findings highlight the significance of Tert^High cells in salivary gland biology, providing insights into their response to radiotherapy and into their use as a potential target for enhancing salivary gland regeneration after radiotherapy.

中文翻译：

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表达 Tert 的细胞有助于放射治疗后唾液腺稳态和组织再生


放疗后唾液腺的稳态和再生很大程度上取决于祖细胞。然而，与其他正常器官相比，颌下腺（SMG）祖细胞的谱系仍然不太明确。在这里，使用表达来自内源性 Tert 位点的受调节 CreERT2 重组酶的小鼠品系，我们鉴定了位于成年 SMG 导管区域的独特的端粒酶表达 (Tert ^High ) 细胞群。这些 Tert ^High 细胞有助于 SMG 稳态期间导管细胞的生成，以及放射治疗后 1 年后导管和腺泡细胞的更新。 Tert ^High 细胞在体外培养过程中保持自我更新能力，表现出对辐射损伤的抵抗力，并在辐射暴露后表现出增强的增殖活性。同样，具有高 Tert 表达的原代人 SMG 细胞在放疗后显示出增强的细胞存活率，并且人 SMG 球体中 CRISPR 激活的 Tert 增加了放疗后的增殖。 RNA 测序揭示了辐射后 Tert ^High 细胞中“细胞周期”和“氧化应激反应”途径的上调。从机制上讲，Tert 似乎可以通过辐射损伤后 SMG 球体中的 ROS 水平来调节细胞存活。我们的研究结果强调了 Tert ^High 细胞在唾液腺生物学中的重要性，为了解它们对放疗的反应以及它们作为放疗后增强唾液腺再生的潜在靶点提供了见解。