Regulation of Lineage Plasticity and Acinar Regeneration in Adult Salivary Glands

成人唾液腺谱系可塑性和腺泡再生的调节

• 批准号: 10353421
• 负责人: SOOSAN GHAZIZADEH
• 金额: $ 23.59万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2024-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10353421
• 关键词: Acinar Cell; Acinus organ component; Adult; Affect; Aging; American; Autoimmune Diseases; Blood Vessels; Cell Differentiation process; Cell Lineage; Cells; Characteristics; Cues; Cytokeratin; Data; Development; Duct (organ) structure; Ductal Epithelial Cell; Elements; Ensure; Epithelial; Epithelial Cells; Fibroblasts; Foundations; Functional disorder; Future; Gatekeeping; Gene Expression Profiling; Gene Targeting; Genetic; Genetic Transcription; Gland; Goals; Homeostasis; Inflammatory; Inflammatory Infiltrate; Injury; Intercalated Duct; Laboratories; Mediator of activation protein; Modeling; Molecular; Molecular Profiling; Mus; Myoepithelial; Myoepithelial cell; Natural regeneration; Neurons; Obstruction; Oral health; Organoids; Pathway interactions; Patients; Population; Protocols documentation; Quality of life; Radiation induced damage; Regenerative capacity; Regulation; Role; Saliva; Salivary; Salivary Glands; Secretory Cell; Signal Transduction; Smooth Muscle Actin Staining Method; Submandibular gland; Testing; Therapeutic; Tissues; Transgenic Mice; Translational Research; Trauma; Xerostomia; base; cell type; cytotoxic; effective therapy; experimental study; healing; in vivo; injured; insight; mouse model; novel; oral tissue; patient population; progenitor; programs; regenerative; response; response to injury; restoration; severe injury; spatiotemporal; stem cell differentiation; stem cell population; stem cells; trait; transcriptome sequencing; transdifferentiation; wound; wound environment

Project Summary/Abstract: Loss of salivary gland function severely affects patient’s oral health and overall quality of life. Restoration of secretory units and gland function through promoting endogenous healing and regeneration of acinar cells may offer an effective and non-invasive treatment option for patient with salivary dysfunction. By combining genetic lineage tracing approaches with a classic model of severe and reversible glandular injury in the adult mouse submandibular gland, we have interrogated the capacity of diverse parenchymal cell populations to undergo lineage reprogramming toward secretory acinar cells. Our data revealed that following substantial loss of acinar cells, not only ductal stem cells but differentiated cell populations including myoepithelial and ductal cells serve as reserve acinar progenitors and contribute to more than 90% of regenerated acini. We found that plasticity of myoepithelial and cKit+ duct cells that involves reversion into a bipotent progenitor-like state before re-differentiation to proacinar/acinar cells is the major mechanism of acinar regeneration in this model of injury. These novel findings provide the first direct evidence for plasticity of diverse epithelial cells toward saliva-secreting acinar cells; and build the foundation for a clear operational understanding of the molecular mechanisms that could be harnessed to induce endogenous regeneration of acini in the degenerative salivary glands. What triggers this broad lineage plasticity in epithelial cells and how these cells reprogram their fate and acquire proliferative and bi-lineage differentiation capacity is currently unknown. We hypothesize that cues from the wound environment provoke lineage plasticity in diverse epithelial cell populations toward acinar cells. To test this hypothesis we will use our established transgenic mouse models and two models of mild and severe obstruction-induced injury to characterize inflammatory and stromal components that are specific to a pro-plastic microenvironment and then functionally assess the role of these components on promoting de novo formation of acini (Aim 1). We then take a systematic approach to decipher the unique and common molecular signature of myoepithelial cells and ductal cells as they undergo lineage reversion, and gain valuable insights into reprogramming of these two relatively abundant cell populations into acinar cells (Aim 2). This exploratory/developmental R21 proposal will yield important information that can be used as a foundation for developing effective targeted strategies for endogenous regeneration of acinar cells in damaged, degenerative or aging salivary glands, an important therapy for a large patient population suffering from hyposalivation and may also identify gatekeepers of epithelial differentiation that inhibit progenitor-like traits under normal condition.

项目摘要/摘要： 唾液腺功能丧失严重影响患者的口腔健康和整体生活质量。恢复 促进内源性修复和再生的分泌单位和腺体功能 腺泡细胞可能为涎腺功能障碍患者提供一种有效的非侵入性治疗选择。 通过将遗传谱系追踪方法与严重和可逆性腺体损伤的经典模型相结合 在成年小鼠的颌下腺中，我们询问了不同的实质细胞的能力 朝向分泌腺泡细胞进行谱系重编程的种群。我们的数据显示， 腺泡细胞的大量损失，不仅是导管干细胞，而且分化的细胞群包括 肌上皮细胞和导管细胞作为预备腺泡祖细胞，贡献了超过90%的 再生的腺泡。我们发现，肌上皮细胞和cKit+导管细胞的可塑性涉及逆转为 腺泡细胞再分化前的双能祖细胞样状态是腺泡细胞分化的主要机制 在这种损伤模型中再生。这些新的发现提供了第一个直接的证据来证明 不同的上皮细胞向分泌唾液的腺泡细胞转化；并为明确的手术操作奠定基础 了解可用于诱导内源性再生的分子机制 在退化的唾液腺中的腺泡。是什么触发了这种广泛的上皮细胞谱系可塑性 这些细胞如何重新编程其命运并获得增殖和双系分化能力目前尚不清楚 未知。我们假设创伤环境中的信号会刺激不同上皮细胞的谱系可塑性。 细胞向腺泡细胞聚集。为了验证这一假设，我们将使用我们已建立的转基因小鼠模型 以及两种轻度和重度梗阻诱导的损伤模型，以表征炎症和间质 特定于亲塑料微环境的组件，然后从功能上评估这些组件的作用 促进腺泡从头形成的成分(目标1)。然后我们采取系统的方法来破译 肌上皮细胞和导管细胞在经历谱系时的独特和共同的分子特征 恢复，并获得对将这两个相对丰富的细胞群重新编程为 腺泡细胞(目标2)。这份试探性/开发性的R21计划将产生重要的信息，可以 为制定有效的靶向内源性再生腺泡细胞策略奠定基础 唾液腺受损、退化或老化，是治疗大量患者的重要方法 也可能识别抑制祖细胞样分化的上皮分化的守门人 正常情况下的特征。