The Role of SOX10 in Stemness of KIT+ Cells and Repairing Irradiated Salivary Glands

SOX10 在 KIT 细胞干细胞和修复辐照唾液腺中的作用

• 批准号: 10060741
• 负责人: Harleen Athwal
• 金额: $ 5.18万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10060741
• 关键词: Acinar Cell; Adenoviruses; Adherent Culture; Adult; Age; Biology; Cell Differentiation process; Cell Line; Cell Therapy; Cells; Clinical; Critical Thinking; Data; Dental caries; Dentists; Deposition; Development; Duct (organ) structure; Epithelial; Epithelial Cells; Faculty; Fetal Development; Follow-Up Studies; Functional disorder; Future; Goals; Grant; Homologous Transplantation; Human; Immune; In Vitro; Knowledge; Mediating; Modeling; Molecular; Morphology; Multipotent Stem Cells; Mus; Mycoses; Names; Natural regeneration; Oral health; Organ; Pain; Patients; Play; Population; Production; Proto-Oncogene Protein c-kit; Quality of life; Radiation; Radiation therapy; Receptor Protein-Tyrosine Kinases; Regenerative Medicine; Role; Saliva; Salivary Glands; Scientist; Signal Transduction; Stem Cell Research; Submandibular gland; Syndrome; System; Taste Perception; Technical Expertise; Testing; Tetanus Helper Peptide; Therapeutic; Tissues; Training; Transplant Recipients; Transplantation; Virus; Work; Xerostomia; base; career; cell type; effective therapy; fetal; fibroblast growth factor receptor 2b; head and neck cancer patient; improved; in vivo; irradiation; mouse genetics; multipotent cell; novel therapeutics; offspring; optimal treatments; oral infection; overexpression; progenitor; prospective; regeneration potential; repaired; skills; stem; stem cell population; stem cell therapy; stem cells; stemness; tissue repair; transcription factor

ABSTRACT Each year, over half a million head and neck cancer patients are treated with radiotherapy, which results in the severe dry mouth syndrome, xerostomia, due to co-radiation of healthy salivary glands. Poor quality of life in such patients is a result of conditions associated with xerostomia such as hyposalivation, dental caries, fungal infections, decaying teeth, and taste and masticatory dysfunctions. Current therapies to rescue hyposalivation provide temporary relief and are largely ineffective; thus, new therapies for permanent tissue repair are needed. Our lab has deep expertise in cutting-edge salivary glands stem cell research, and was the first to demonstrate the clinical potential of KIT+ (c-Kit, CD117) stem/progenitor cells in rescuing hyposalivation. However, this population of stem/progenitor cells decreases with age, currently compromising our ability to efficiently use these cells for therapy. Our current work shows that transcription factor SOX10 plays a major role in the proliferation and differentiation potential of KIT+ cells. For example, epithelial depletion of Sox10 results in loss of KIT+ and pro-acinar cells in the fetal stages. However, it is unclear whether SOX10 is required for expansion and multi-potency, i.e. the ability to differentiate into all epithelial cell types, of KIT+ cells through adulthood. Based on existing evidence, we hypothesize that SOX10 plays a central role in the expansion and differentiation of all KIT+ cells. To test this hypothesis, we will lineage trace epithelial KIT+SOX10+ cells in the submandibular gland using inducible mouse systems. We will also assess forced overexpression of SOX10 to expand KIT+ cells. Overall, these studies will elucidate whether SOX10 marks multi-potent KIT+ stem cells, and can be applied to expand KIT+ stem cells. The scientific ideas proposed here will expand our knowledge of salivary gland stem cells, and will significantly improve future hyposalivation rescue stem cell-based therapies.

摘要 每年，超过50万头颈部癌症患者接受放射治疗， 由于健康唾液腺的共辐射引起的严重口干综合征、口干症。生活质量差， 这些患者是与口腔干燥相关的病症的结果 感染、蛀牙、味觉和咀嚼功能障碍。目前挽救唾液分泌不足的治疗方法 提供暂时的缓解，并且在很大程度上是无效的;因此， needed.我们的实验室在尖端的唾液腺干细胞研究方面拥有深厚的专业知识，并且是第一个 证明了KIT+（c-Kit，CD 117）干/祖细胞在挽救唾液过少中的临床潜力。 然而，这种干/祖细胞群体随着年龄的增长而减少，目前损害了我们的能力， 将这些细胞用于治疗。我们目前的工作表明，转录因子SOX 10起着主要的作用， 在KIT+细胞的增殖和分化潜能中的作用。例如，Sox 10的上皮耗竭 导致胎儿期KIT+和前腺泡细胞的损失。目前尚不清楚SOX 10是否 KIT+细胞的扩增和多能性（即分化为所有上皮细胞类型的能力）所需 直到成年基于现有的证据，我们假设SOX 10在 所有KIT+细胞的扩增和分化。为了验证这一假设，我们将追踪上皮细胞 KIT+ SOX 10+细胞在下颌下腺使用诱导型小鼠系统。我们还将评估 过表达S 0X 10以扩增KIT+细胞。总之，这些研究将阐明SOX 10标志是否 多能KIT+干细胞，并可用于扩增KIT+干细胞。这里提出的科学观点 这将扩大我们对唾液腺干细胞的了解，并将显著改善未来的唾液不足 拯救基于干细胞的疗法。