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

摘要 每年，超过50万的头颈癌患者接受放射治疗，这导致 严重的口干综合症，口干症，由健康唾液腺的共同辐射引起。中国的生活质量很差 这类患者是口干症的结果，如口干症、龋齿、真菌 感染，腐烂的牙齿，味觉和咀嚼功能障碍。目前拯救肾功能不全的治疗方法 提供暂时的缓解，在很大程度上是无效的；因此，永久组织修复的新疗法 需要的。我们的实验室在尖端唾液腺干细胞研究方面拥有深厚的专业知识，并是第一个 证明KIT+(c-Kit，CD117)干/祖细胞在挽救肾功能不全方面的临床潜力。 然而，这种干细胞/祖细胞的数量随着年龄的增长而减少，目前损害了我们 有效地利用这些细胞进行治疗。我们目前的工作表明，转录因子Sox10在 在KIT+细胞增殖分化潜能中的作用。例如，Sox10上皮细胞的耗尽 结果Kit+和腺泡前细胞在胎儿期丢失。然而，目前还不清楚Sox10是否 KIT+细胞扩增和多能性所必需的，即分化为所有上皮细胞类型的能力 一直到成年。根据现有证据，我们假设Sox10在 所有KIT+细胞的扩增和分化。为了验证这一假设，我们将对微量上皮细胞进行谱系分析 Kit+Sox10+细胞在颌下腺中使用可诱导小鼠系统。我们还将评估强制 过表达Sox10以扩增KIT+细胞。总体而言，这些研究将阐明Sox10标志着 多能KIT+干细胞，并可应用于扩增KIT+干细胞。这里提出的科学思想 将扩大我们对唾液腺干细胞的知识，并将显著改善未来的淋巴功能低下 挽救以干细胞为基础的疗法。

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.