基于多模态磁共振成像评估定向移植骨髓间充质干细胞治疗大鼠放射性唾液腺损伤疗效的机制研究

Radiotherapy induced salivary gland damage is a common complication in the patients with head and neck cancer after radiotherapy. It makes a heavy influence on the quality of life of these patients. Transplantation therapy of bone marrow mesenchymal stem cell (BMSC) could improve the functional outcome, but some problem still existed, including: 1) the relationship between the transplantation window, number of transplanted stem cell and the therapeutic effect has not been clarified; 2) therapeutic effect of stem cell therapy was assessed by using pathological methods, effective and intravital assessing method is still lacked. Therefore, based on the successfully established rat model of radiotherapy induced salivary gland damage, our study plans to transplant different numbers of BMSC at different time windows, so as to clarify the relationship between the transplantation window, number of transplanted stem cell and the therapeutic effect for radiotherapy induced salivary gland damage. Meanwhile, our study plans to use multimodal MR imaging (DWI、IVIM、DKI、DCE-MRI、DSC-PWI and ASL) to evaluate the therapeutic effect of stem cell therapy in vitro, to correlate the MR imaging findings with nascent acinar cell, ductal epithelial cells and vessels, and to clarify the potential mechanism of BMSC therapy for radiotherapy induced salivary gland damage. Our study may provide a theoretical basis for the clinical usage of BMSC therapy for radiotherapy induced salivary gland damage, and for the usage of multimodal MR imaging for intravital assessment.

放射性唾液腺损伤是头颈部肿瘤患者放疗后常见的并发症，严重影响患者生活质量。骨髓间充质干细胞移植治疗可促进唾液腺功能修复，但仍存在一些问题：①干细胞移植治疗放射性唾液腺损伤的时效和量效规律未得到明确阐述。②干细胞移植治疗的疗效评估多采取病理学手段，缺乏有效的活体评估手段。因此，本研究拟在成功建立大鼠放射性唾液腺损伤模型的基础上，在不同时间窗移植不同数量的骨髓间充质干细胞治疗放射性唾液腺损伤，以明确骨髓间充质干细胞移植治疗放射性唾液腺损伤的时效和量效规律；拟采用多模态MR成像（DWI、IVIM、DKI、DCE-MRI、DSC-PWI和ASL）活体评估移植治疗疗效，与病理学中可能出现的新生腺泡细胞、导管上皮细胞和新生血管对照，探讨骨髓间充质干细胞移植治疗放射性唾液腺损伤的机制，为临床应用骨髓间充质干细胞移植治疗放射性唾液腺损伤并采用多模态MR成像进行活体评估提供理论依据。

放射性唾液腺损伤是头颈部肿瘤患者放疗后最常见的并发症，其引起的持续性口干严重影响了患者的生活质量。目前，已有多个MRI技术被应用于放射性唾液腺损伤的活体无创评估，但尚缺乏组织学验证。本课题的主要研究内容是：建立大鼠放射性唾液腺损伤模型，探讨损伤前、后（照射后1、2、4、8、12、24周）唾液腺多参数MRI（mp-MRI）结果的纵向变化，及其与组织病理学结果之间的相关性。通过研究，我们发现：1）对大鼠颌下腺区行单剂量15Gy X线照射可成功建立大鼠放射性唾液腺损伤模型，照射后大鼠颈部照射区出现明显放射性皮损，颌下腺组织病理学显示：①腺泡细胞相对面积（AC%）在照射后呈缓慢下降趋势，差异显著；②微血管密度（MVD）于照射后前2周显著增高，于第4到24周呈下降趋势；③纤维化程度（F%）亦变化显著，但仅于24周时出现显著增高。2）放射性损伤后唾液腺的mp-MRI（本课题包括弥散加权成像（DWI）、体素内不相干运动MR成像（IVIM-MRI）、T1mapping和T2mapping）定量参数变化显著，其与相应病理参数相关性显示：①弥散参数（ADC＆D）与AC%呈高度负相关（p<0.001；ADC，r=-0.728；D，r=-0.773）；②IVIM-MRI的灌注分数f值与MVD呈中度正相关（r=0.496，p=0.022）；③T1弛豫时间与F%呈高度正相关（r=0.714，p<0.001）；④T2弛豫时间与AC%呈中度负相关（r=-0.600，p=0.004）。综上，本课题发现mp-MRI可无创、定量评估放射性损伤后唾液腺的动态病理变化，为临床采用MRI技术无创活体评估唾液腺损伤程度提供依据，为采用MRI技术对唾液腺损伤预防或治疗效果进行活体评估奠定基础。