Cellular plasticity in salivary gland regeneration.

唾液腺再生中的细胞可塑性。

• 批准号: 10356931
• 负责人: MELINDA LARSEN
• 金额: $ 46.63万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10356931
• 关键词: Acinar Cell; Adult; Affect; Automobile Driving; Cancer Patient; Cancer Survivor; Cell Cycle; Cell Differentiation process; Cell Lineage; Cell Transplantation; Cells; Chronic; Clinical; Data; Development; Duct (organ) structure; Ductal Epithelial Cell; Embryo; Exhibits; Exogenous Factors; Fibrosis; Genetic Transcription; Gland; Head and Neck Cancer; Heritability; Human; In Vitro; Inflammation; Inflammatory; Injury; Intervention; Investigation; Ionizing radiation; Knowledge; Label; Laboratories; Ligation; Modality; Modeling; Molecular; Mus; Natural regeneration; Organ; Organism; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Population; Population Heterogeneity; Process; Property; Quality of life; Radiation; Radiation Injuries; Radiation induced damage; Radiation therapy; Regenerative capacity; Reporting; Resolution; Role; Salivary Glands; Testing; Therapeutic; Tissues; Xerostomia; cell growth regulation; cell regeneration; cell type; experimental study; functional restoration; head and neck cancer patient; improved; in vivo; injured; injury and repair; insight; irradiation; paracrine; prevent; progenitor; programs; regeneration potential; regenerative; regenerative approach; regenerative cell; repaired; response; response to injury; senescence; single cell sequencing; single-cell RNA sequencing; success; tissue regeneration; tissue repair; trait

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.

摘要 放射治疗是头颈部癌症的主要治疗方法， 唾液腺，由于分泌腺泡细胞的损失。我们实验室的最新数据 证明人和鼠的唾液腺在辐射后启动腺泡细胞再生 治疗，但与导管结扎损伤相反，唾液腺不能完全恢复功能。 然而，在辐射腺体中表现出的再生潜力意味着治疗策略可能 以刺激辐射损伤的修复。新出现的证据表明， 可塑性，定义为分化细胞重新进入细胞周期的能力，是一种提供 组织再生的前体。细胞可塑性的证据最近才被报道在唾液 腺体在对导管结扎或电离辐射损伤的腺体的研究中，我们已经确定了三种特异性的 显示可塑性的细胞群。这些包括存活的再生细胞， 导管结扎腺体，共表达导管和腺泡细胞标记物的异质细胞群， 未知的命运，导管细胞可以经历谱系转换，以产生分泌腺泡细胞， 辐射过的腺体细胞的可塑性，以及在体内从另一个谱系转化细胞的能力， 相当大的潜力，以取代失去腺泡细胞。然而，我们对这些机制的了解 诱导、调节和约束这一过程的机制是有限的。我们建议比较不同的伤害 模型，唾液腺细胞的反应，并确定诱导可塑性的条件。 谱系追踪，遗传标记细胞及其后代，将用于研究细胞如何 表现出可塑性有助于再生，以及这些细胞经历谱系的要求， 转换.将使用单细胞RNA测序来表征参与以下过程的细胞类型： 再生，并深入了解参与分子途径。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 以及唾液腺的再生识别涉及的细胞和驱动条件 这些过程可能为开发再生方法提供关键信息， 口干症。