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: 10212524
• 负责人: SOOSAN GHAZIZADEH
• 金额: $ 19.6万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212524
• 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.

项目概要/摘要： 唾液腺功能的丧失严重影响患者的口腔健康和整体生活质量。恢复 分泌单位和腺体功能，通过促进内源性愈合和再生， 腺泡细胞可能为唾液腺功能障碍患者提供一种有效和非侵入性治疗选择。 通过将遗传谱系追踪方法与严重和可逆的腺体损伤的经典模型相结合， 在成年小鼠的下颌下腺，我们询问了不同的实质细胞的能力， 群体经历谱系重编程向分泌腺泡细胞。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储备腺泡祖细胞， 再生腺泡。我们发现，肌上皮细胞和cKit+导管细胞的可塑性，包括逆转成一个 在再分化为前腺泡/腺泡细胞之前的双能祖细胞样状态是腺泡细胞分化的主要机制。 在这个损伤模型中再生。这些新的发现提供了第一个直接证据， 不同的上皮细胞向分泌唾液的腺泡细胞;并建立一个明确的运作基础 了解可用于诱导内源性再生的分子机制 退化的唾液腺中的腺泡是什么触发了上皮细胞的这种广泛谱系可塑性， 这些细胞如何重新编程它们的命运并获得增殖和双谱系分化能力， 未知我们假设来自伤口环境的线索引起了不同上皮细胞的谱系可塑性， 细胞群向腺泡细胞的方向发展。为了验证这一假设，我们将使用我们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 特定于促塑微环境的成分，然后在功能上评估这些成分的作用。 成分促进腺泡从头形成（目的1）。然后我们采用系统的方法来破译 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 逆转，并获得这两个相对丰富的细胞群重编程为 腺泡细胞（Aim 2）。这一探索性/发展性R21提案将产生重要信息， 作为基础，用于开发有效的靶向策略，用于腺泡细胞内源性再生， 受损、退化或老化的唾液腺，这是一种重要的治疗方法， 还可以鉴定抑制祖细胞样分化的上皮细胞分化的看门人， 正常情况下的特征。