A novel long-term intravenous combined with local treatment with human amnion-derived mesenchymal stem cells for a multidisciplinary rescued uremic calciphylaxis patient and the underlying mechanism

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作者：Qin Lianju, Zhang Jing, Xiao Yujie, Liu Kang, Cui Yugui, Xu Fangyan, Ren Wenkai, Yuan Yanggang, Jiang Chunyan, Ning Song, Ye Xiaoxue, Zeng Ming, Qian Hanyang, Bian Anning, Li Fan, Yang Guang, Tang Shaowen, Zhang Zhihong, Dai Juncheng, Guo Jing, Wang Qiang, Sun Bin, Ge Yifei, Ouyang Chun, Xu Xueqiang, Wang Jing, Huang Yaoyu, Cui Hongqing, Zhou Jing, Wang Meilian, Su Zhonglan, Lu Yan, Wu Di, Shi Jingping, Liu Wei, Dong Li, Pan Yinbing, Zhao Baiqiao, Cui Ying, Gao Xueyan, Gao Zhanhui, Ma Xiang, Chen Aiqin, Wang Jie, Cao Meng, Cui Qian, Chen Li, Chen Feng, Yu Youjia, Ji Qiang, Zhang Zhiwei, Gu Mufeng, Zhuang Xiaojun, Lv Xiaolin, Wang Hui, Pan Yanyan, Wang Ling, Xu Xianrong, Zhao Jing, Wang Xiuqin, Liu Cuiping, Liang Ningxia, Xing Changying, Liu Jiayin, Wang Ningning
期刊：Journal of Molecular Cell Biology
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Calciphylaxis is a rare disease characterized histologically by microvessel calcification and microthrombosis, with high mortality and no proven therapy. Here, we reported a severe uremic calciphylaxis patient with progressive skin ischemia, large areas of painful malodorous ulcers, and mummified legs. Because of the worsening symptoms and signs refractory to conventional therapies, treatment with human amnion-derived mesenchymal stem cells (hAMSCs) was approved. Preclinical release inspections of hAMSCs, efficacy, and safety assessment, including cytokine secretory ability, immunocompetence, tumorigenicity, and genetics analysis in vitro, were introduced. We further performed acute and long-term hAMSC toxicity evaluations in C57BL/6 mice and rats, abnormal immune response tests in C57BL/6 mice, and tumorigenicity tests in neonatal Balbc-nu nude mice. After the preclinical research, the patient was treated with hAMSCs by intravenous and local intramuscular injection and external supernatant application to the ulcers. When followed up to 15 months, the blood-based markers of bone and mineral metabolism improved, with skin soft tissue regeneration and a more favorable profile of peripheral blood mononuclear cells. Skin biopsy after 1-month treatment showed vascular regeneration with mature noncalcified vessels within the dermis, and 20 months later, the re-epithelialization restored the integrity of the damaged site. No infusion or local treatment-related adverse events occurred. Thus, this novel long-term intravenous combined with local treatment with hAMSCs warrants further investigation as a potential regenerative treatment for uremic calciphylaxis due to effects of inhibiting vascular calcification, stimulating angiogenesis and myogenesis, anti-inflammatory and immune modulation, multidifferentiation, re-epithelialization, and restoration of integrity.