Cellular plasticity in salivary gland regeneration.

唾液腺再生中的细胞可塑性。

基本信息

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
项目类别：
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

项目摘要

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.

抽象的放射治疗是头颈癌的主要治疗方法，会对人体造成不可逆转的损害唾液腺，由于分泌腺泡细胞的损失。我们实验室的最新数据表明人类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，受辐射腺体表现出的再生潜力意味着治疗策略可能会有所不同。被开发用于刺激辐射引起的损伤的修复。新出现的证据表明，细胞可塑性，定义为分化细胞重新进入细胞周期的能力，是一种供应手段组织再生的前体。最近才在唾液中报道了细胞可塑性的证据腺体。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。其中包括可以重新繁殖的存活再生细胞导管结扎腺，共表达导管和腺泡细胞标记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性腺泡细胞的导管细胞受辐射的腺体。细胞可塑性以及在体内转化来自另一个谱系的细胞的能力，提供了替代丢失的腺泡细胞的巨大潜力。然而，我们对机制的了解诱导、调节和限制这一过程的因素是有限的。我们建议比较不同的伤害模型，用于唾液腺细胞的反应，并定义诱导可塑性的条件。谱系追踪可遗传地标记细胞及其后代，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。单细胞 RNA 测序将用于表征所涉及的细胞类型再生，并深入了解参与的分子途径。刺激的可行性将探索通过引入外源因子来实现内源细胞的再生。这些研究将确定细胞可塑性和谱系转换如何参与损伤反应和唾液腺的再生。识别所涉及的细胞和驱动条件这些过程可能会产生用于开发再生方法来治疗的关键信息口干症。