Neuronal and Progenitor/Stem Cell Function During Salivary Gland Development

唾液腺发育过程中的神经元和祖细胞/干细胞功能

• 批准号: 9339234
• 负责人: Matthew Hoffman
• 金额: $ 109.13万
• 依托单位: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9339234
• 关键词: Acinar Cell; Adult; Apoptosis; Cell Communication; Cell Fate Control; Cell Maintenance; Cell Therapy; Cell physiology; Cells; Communication; Development; Epithelial; Epithelial Cells; Extracellular Matrix; Future; Genes; Gland; Growth; Head and Neck Cancer; Maintenance; Mesenchymal; Morphogenesis; Mus; Natural regeneration; Nerve; Neurons; Organ; Organogenesis; Parasympathectomy; Patients; Population; Radiation; Salivary Glands; Series; Staging; Stem cells; Therapeutic; Tissues; Undifferentiated; Viral Vector; Xerostomia; cell type; gland development; improved; improved functioning; in vivo; injured; irradiation; loss of function; nerve stem cell; nerve supply; neuron apoptosis; neurotrophic factor; neurturin; organ growth; organ regeneration; prevent; progenitor; regenerative therapy; repaired; stem

This project has two parts, one investigating the communication between parasympathetic nerve development and SMG epithelial morphogenesis, and the second identifying mouse salivary gland stem/progenitor cell populations within the gland. The maintenance of progenitors as a reservoir of undifferentiated cells is required for organ development and regeneration. Parasympathetic nerves are a vital component of the progenitor niche during development. Injured adult organs do not regenerate after parasympathectomy, and there are few treatments to improve organ regeneration or prevent damage, particularly that caused by therapeutic irradiation. Restoring parasympathetic function with the neurotrophic factor neurturin increases epithelial organ regeneration after irradiation. We used SMG explant culture and injured the tissue with irradiation. The progenitors survived, parasympathetic function was diminished, and epithelial apoptosis reduced expression of neurturin, which consequently increased neuronal apoptosis. Treatment with neurturin reduced neuronal apoptosis, restored parasympathetic function, and increased epithelial regeneration. Furthermore adult human salivary glands damaged by irradiation also had reduced parasympathetic innervation but an increase in sympathetic innervation. We propose that neurturin will protect the parasympathetic nerves from damage and improve regeneration. We continue to use viral vectors that express neurotrophic factors to infect salivary glands in vivo and ex vivo to improve the function of surviving nerves in repairing the gland.

该项目有两个部分，其中一个研究了副交感神经发育与SMG上皮形态发生之间的通信，以及第二个识别腺体内的小鼠唾液腺茎/祖细胞群。器官发育和再生需要维持祖细胞作为未分化细胞的储层。副交感神经是发育过程中祖细胞生态位的重要组成部分。受伤的成年器官在副交感神经切除术后不会再生，并且几乎没有治疗可改善器官再生或预防损害，尤其是由治疗辐射引起的损害。用神经营养因子神经蛋白恢复副交感神经功能会增加照射后上皮器官再生。我们使用了SMG外植体培养物，并通过辐照损害了组织。祖细胞幸存下来，副交感神经功能降低，上皮凋亡降低了神经毒素的表达，从而增加了神经元凋亡。神经蛋白的治疗减少了神经元凋亡，恢复了副交感神经功能和上皮再生。此外，受辐射受损的成年人类唾液腺也减少了副交感神经，但交感神经神经的增加。我们建议神经蛋白会保护副交感神经免受损害并改善再生。我们继续使用表达神经营养因子的病毒载体在体内和体内感染唾液腺，以改善存活神经在修复腺体中的功能。