Dai Pengxiu, Qi Guixiang, Zhu Mingde, Du Qingjie, Wang Keyi, Gao Yaxin, Li Mengnan, Feng Xiancheng, Zhang Xinke
The College of Veterinary Medicine, Northwest Agriculture and Forestry University, Yangling, China.
Front Vet Sci. 2024 Oct 9;11:1465879. doi: 10.3389/fvets.2024.1465879. eCollection 2024.
The immunogenicity of allogeneic mesenchymal stem cells (MSCs) is significantly enhanced after transplantation or differentiation, and these cells can be recognized and cleared by recipient immune cells. Graft rejection has become a major obstacle to improving the therapeutic effect of allogeneic MSCs or, after their differentiation, transplantation in the treatment of diabetes and other diseases. Solving this problem is helpful for prolonging the time that cells play a role in the recipient body and for significantly improving the clinical therapeutic effect.
In this study, canine adipose-derived mesenchymal stem cells (ADSCs) were used as seed cells, and gene editing technology was used to knock out the B2M gene in these cells and cooperate with the overexpression of the PD-L1 gene. Gene-edited ADSCs (GeADSCs), whose biological characteristics and safety are not different from those of normal canine ADSCs, have been obtained.
The immunogenicity of GeADSCs is reduced, the immune escape ability of GeADSCs is enhanced, and GeADSCs can remain in the body for a longer time. Using the optimized induction program, the efficiency of the differentiation of GeADSCs into new islet β-cells was increased, and the maturity of the new islet β-cells was increased. The immunogenicity of new islet β-cells decreased, and their immune escape ability was enhanced after the cells were transplanted into diabetic dogs (the graft site was prevascularized by the implantation of a scaffold to form a vascularized pouch). The number of infiltrating immune cells and the content of immune factors were decreased at the graft site.
New islet β-cell transplantation, which has low immunogenicity, can reverse diabetes in dogs, and the therapeutic effect of cell transplantation is significantly enhanced. This study provides a new method for prolonging the survival and functional time of cells in transplant recipients and significantly improving the clinical therapeutic effect.
同种异体间充质干细胞（MSCs）在移植或分化后免疫原性显著增强，可被受体免疫细胞识别并清除。移植物排斥已成为提高同种异体MSCs或其分化后移植治疗糖尿病等疾病疗效的主要障碍。解决这一问题有助于延长细胞在受体体内发挥作用的时间，并显著提高临床治疗效果。
本研究以犬脂肪间充质干细胞（ADSCs）为种子细胞，利用基因编辑技术敲除这些细胞中的B2M基因，并与PD-L1基因过表达协同作用。已获得基因编辑后的ADSCs（GeADSCs），其生物学特性和安全性与正常犬ADSCs无异。
GeADSCs的免疫原性降低，免疫逃逸能力增强，能在体内停留更长时间。采用优化的诱导方案，GeADSCs向新胰岛β细胞的分化效率提高，新胰岛β细胞的成熟度增加。将新胰岛β细胞移植到糖尿病犬体内（通过植入支架使移植部位预先血管化以形成血管化囊袋）后，其免疫原性降低，免疫逃逸能力增强。移植部位浸润免疫细胞数量和免疫因子含量减少。
免疫原性低的新胰岛β细胞移植可使犬糖尿病逆转，细胞移植治疗效果显著增强。本研究为延长移植受体中细胞的存活和功能时间以及显著提高临床治疗效果提供了一种新方法。
