Cellular plasticity in salivary gland regeneration.

摘要 放射治疗是头颈部癌症的主要治疗方法，它会对 唾液腺，由于分泌腺泡细胞的丧失。我们实验室的最新数据 证明人和小鼠唾液腺在辐射后启动腺泡细胞再生 治疗，但与导管结扎造成的损伤相比，唾液腺的功能并未完全恢复。 然而，受辐射的腺体表现出的再生潜力意味着治疗策略可能 被开发来刺激辐射损伤的修复。新出现的证据表明，细胞 可塑性，定义为分化的细胞重新进入细胞周期的能力，是一种供应方式 组织再生的前体。细胞可塑性的证据最近才在唾液中被报道。 腺体。在对导管结扎或电离辐射损伤的腺体的研究中，我们发现了三种特定的 表现出可塑性的细胞群。包括存活的再生细胞，这些细胞可以重新填充 导管结扎腺，共表达导管和腺泡细胞标志物的异质细胞群 未知的命运，以及可以进行谱系转换以产生分泌腺泡细胞的导管细胞 受辐射的腺体。细胞的可塑性，以及在体内转换来自另一个谱系的细胞的能力，提供了 有相当大的潜力来替代丢失的腺泡细胞。然而，我们对这些机制的了解 诱导、调节和约束这一过程的能力是有限的。我们建议比较不同的损伤 模型，用于唾液腺细胞的反应，并确定诱导可塑性的条件。 世系追踪，遗传地标记细胞及其后代，将被用来研究细胞如何 表现出可塑性的有助于再生，以及这些细胞经历谱系的要求 转换。将使用单细胞RNA测序来表征所涉及的细胞类型 再生，并深入了解参与的分子途径。激励的可行性 将探索通过引入外源因子来再生内源细胞。这些 研究将确定细胞可塑性和谱系转换如何参与对损伤的反应。 和唾液腺的再生。对涉及的细胞和驱动条件的鉴定 这些过程可能会产生关键信息，用于开发再生治疗方法 口干燥症。

ABSTRACT Radiation therapy, the predominant treatment for head and neck cancers, causes irreversible damage to the salivary glands, due to the loss of secretory acinar cells. Recent data from our laboratory demonstrates that human and murine salivary glands initiate acinar cell regeneration after radiation treatment, but in contrast to injury by duct ligation, the salivary glands do not fully recover function. However, the regenerative potential exhibited in irradiated glands implies that therapeutic strategies may be developed to stimulate repair of radiation-induced damage. Emerging evidence suggests that cell plasticity, defined as the ability of differentiated cells to re-enter the cell cycle, is a means of supplying precursors for tissue regeneration. Evidence of cell plasticity has only recently been reported in salivary glands. In studies of glands injured by duct ligation or ionizing radiation, we have identified three specific cell populations that display plasticity. These include surviving regenerative cells that can repopulate duct-ligated glands, a heterogeneous population of cells co-expressing duct and acinar cell markers with unknown fate, and duct cells that can undergo lineage conversion to generate secretory acinar cells in irradiated glands. Cellular plasticity, and the ability to convert cells from another lineage in vivo, offer considerable potential for replacement of lost acinar cells. However, our knowledge of the mechanisms that induce, regulate, and constrain this process is limited. We propose to compare different injury models, for the response of salivary gland cells, and to define the conditions that induce plasticity. Lineage tracing, which heritably labels cells and their descendants, will be used to investigate how cells exhibiting plasticity contribute to regeneration, and the requirements for those cells to undergo lineage conversion. Single cell RNA sequencing will be used to characterize the cell types involved in regeneration, and gain insight into participating molecular pathways. The feasibility of stimulating regeneration of endogenous cells through the introduction of exogenous factors will be explored. These studies will determine how cellular plasticity and lineage conversion are involved in the response to injury and regeneration of the salivary glands. Identification of the cells involved and the conditions driving these processes may yield critical information for development of regenerative approaches to treat xerostomia.