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我国学者发现逆转骨质疏松患者来源骨髓间充质干细胞免疫调控能力异常的新策略
来源: | 作者:廖立 | 时间 :2018-01-29 | 587 次浏览 | 分享到:

基于骨髓间充质干细胞(BMSC)的细胞治疗被广泛应用于多种难愈性免疫疾病的治疗,具有良好的应用前景。但是越来越多的研究发现,多种疾病患者自身来源的BMSC往往在细胞治疗中效果不佳,严重阻碍了自体BMSC细胞治疗的临床应用。但是因为导致患者BMSC免疫调控能力异常的分子机制不清,导致目前尚无有效手段提高疾病BMSC的治疗能力。

来自第四军医大学组织工程中心和西安组织工程与再生医学研究所的学者金岩教授、廖立博士、于洋博士等人利用骨质疏松模型,证实了骨质疏松个体来源的BMSC免疫调控能力存在明显缺陷,主要表现为诱导T细胞凋亡的能力下降。进一步研究证实,BMSC表面Fas/FasL蛋白的缺失是其免疫调控功能异常的关键,Fas/FasL的缺失使得BMSC诱导辅助性T细胞迁移和凋亡的能力下降。结合前期研究结果,他们进一步揭示了雌激素缺乏后,炎症因子TNF-α水平升高引起特定微小RNAmicro RNA)异常表达,并最终通过转录后调控抑制Fas/FasL蛋白表达的分子机制。更重要的是,他们通过多种体内外模型证实,通过靶向抑制micro RNA let-7a的表达,可以逆转骨质疏松来源BMSC的免疫调控功能,恢复其对于免疫疾病的治疗能力。

上述研究在国际上率先揭示了骨质疏松患者来源BMSC免疫调控能力异常的分子机制,并提出了通过调节特定miRNA来恢复患者BMSC免疫治疗能力的新策略,为自体BMSC细胞治疗应用清除了一大障碍,有望进一步推动BMSC细胞治疗的临床应用。


Redundant let-7a suppresses the immunomodulatory properties of BMSCs by inhibiting Fas/FasL system in osteoporosis

 

Li Liao,1,2 Yang Yu,3,4,5 Bingyi Shao,3,4,5 Xiaoxia Su,6 Han Wang,7 Huijuan Kuang, 1,2 Huan Jing, 1,2 Yi Shuai,1,8 Deqin Yang, 3,4,5 Yan Jin1,2

Authorship: Li Liao and Yang Yu contributed equally to this work

 

1. State Key Laboratory of Military Stomatology & National Clinical Research Center for Oral Diseases & Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xian, Shaanxi 710032, China;

2. Xi'an Institute of Tissue Engineering and Regenerative Medicine, Shaanxi 710032, China;

3. Department of Endodontics, Stomatological Hospital of Chongqing Medical University, Chongqing 401147, Peoples Republic of China;

4. Chongqing key Laboratory of Oral Diseases and Biomedical Sciences, Chongqing 401147, Peoples Republic of China;

5. Chongqing Municipal Key Laboratory of Oral Biomedical Engineering of Higher Education, Chongqing 401147, Peoples Republic of China.

6. Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xian Jiaotong University, Xi'an, Shaanxi 710004, China;

7. Department of Stomatology, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong 510000, China;

8. Department of Stomatology, Nanjing General Hospital of Nanjing Military Command, PLA, Nanjing 210002, Jiangsu, China.

 

ABSTRACT: Bone marrowderived mesenchymal stem cell (BMSC) cytotherapy has emerged as a promising treatment strategy for refractory immune diseases; however, the influence of the pathologic conditions of donors on the immunomodulatory properties of BMSCs is still poorly understand. Here, we found that BMSCs that were derived from donors with osteoporosis were ineffective as cytotherapy for patients with experimental colitis and graft-vs.-host disease (GVHD). In vivo and in vitro assays revealed that the capacity of osteoporotic BMSCs to induce T-cell apoptosis declined as a result of decreased Fas and FasL protein. Additional analysis revealed that let-7a, a microRNA induced by TNF-a in osteoporosis, inhibited the expression of the Fas/FasL system via post-transcriptional regulation. By knocking down let-7a expression, we successfully recovered the immunosuppressive capacity of osteoporotic BMSCs and improved their therapy for experimental colitis and GVHD. Taken together, our study demonstrates that the immunomodulatory properties of BMSCs are suppressed in osteoporosis and illustrates the molecular mechanism that underlies this suppression. These findings might have important implications for the development of targeted strategies to improve BMSC cytotherapy.

 

文章链接

https://www.ncbi.nlm.nih.gov/pubmed/29203591