角质细胞生长因子在脂肪源间充质干细胞修复放化疗相关胸腺损伤中的作用机制研究

Thymic injury from radiation and chemotherapy precludes normal thymopoiesis, which leads to immune deficiency, as a consequence of general infectious diseases and diverse malignancies. It has been indicated from our clinical trials that MSCs administration was safe and effective in reducing disease activity for a long period in patients with active rheumatoid arthritis by anti-inflammation along with the improved immune-modulation and the induced immune tolerance. Moreover, thymus dysfunction is involved in the pathogenesis of rheumatoid arthritis. Our latest study suggested that well-organized cortex-medulla architecture and an obvious improvement in the maturation of thymus epithelial cells (TECs) appeared in newly developed thymus rudiment in Foxn1-/- mice after MSCs administration, and the thymopoiesis improved along with the T regulatory cells increase in peripheral blood. Furthermore, we found that MSCs can express many cytokines, especially Keratinocyte Growth Factor (KGF) and CD248, which was essential for the thymus development. This study is designed to investigate the therapeutic potential of adipose tissue-derived mesenchymal stem cells（ADSCs） on damaged thymus, and to explore the role of the KGF signaling pathway in the mechanisms of ADSCs on thymus reconstitution and thymopoiesis. This study may elicit an effective and persistent therapeutic method for thymus reconstitution after accepting radiation and chemotherapy.

接受放疗、化疗的患者胸腺急剧退化，妨碍了胸腺的T细胞生成能力，导致患者免疫功能低下，极易发生各种感染，甚至肿瘤。我们的临床试验表明，间充质干细胞（Mesenchymal stem cells，MSCs）通过抗炎、免疫调节及增加患者外周血中的调节性T细胞来治疗类风湿性关节炎，而类风湿性关节炎患者存在胸腺功能的异常；动物试验表明，MSCs能够促进Foxn1-/-的小鼠胸腺残基的结构发育及胸腺上皮细胞成熟，增强胸腺的输出功能及外周血中的调节性T细胞，并且，我们发现MSCs能够表达多种促进胸腺发育的因子，尤其是角质细胞生长因子（keratinocyte growth factor，KGF）和CD248。本研究旨在探索MSCs对放化疗所致损伤胸腺的结构和功能的修复作用，并进一步研究其修复作用的机制是否是通过KGF信号途径来实现，以期为临床治疗中接受放化疗患者的损伤胸腺寻找快速有效的修复方法。

临床工作中，接受放疗、化疗的患者胸腺急剧退化，胸腺的T细胞生成能力严重受损，其免疫系统的自我修复能力显著降低，导致患者感染的发生率和肿瘤复发的机率明显增高，极易发生各种严重感染，甚至发生二次肿瘤。本研究建立了放化疗所致胸腺损伤的小鼠模型，并应用脂肪源间充质干细胞（Adipose tissue-Derived Mesenchymal Stem Cells, ADSCs）对放射/环磷酰胺或地塞米松所致的损伤胸腺进行修复，并探讨了其发挥作用的机制是ADSCs向受损胸腺的迁移并分泌多种与胸腺发育相关的细胞因子和生长因子（如角质细胞生长因子（Keratinocyte Growth Factor, KGF）、Ghrelin、IL-15）。本研究证明ADSCs能够修复放化疗所致的受损胸腺的组织结构，提高受损胸腺向外周免疫系统输出成熟T细胞能力，增加外周血调节性T细胞的数量，并探讨了ADSCs修复作用的机制主要是通过分泌KGF实现的。通过输注ADSCs，能够快速修复受损胸腺的结构与功能，缩短放化疗后小鼠免疫功能低下的时间，减少感染发生的机率，延长小鼠的生存时间。因此，本研究为临床接受放化疗后免疫功能低下的患者寻找一种快速恢复自身免疫功能的治疗方法提供了理论依据。