Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
Yusang Zhang
Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
Peiyun Wang
Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
Qiyu Tang
Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
Yating Liu
Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
Fan Lu
Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
Mengting Han
Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
Miaojin Zhou
Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
Qian Hu
Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China
Mai Feng
Hunan Key Laboratory of Animal Models for Human Diseases, School of Life Sciences, Central South University, Changsha 410078, China
Desheng Liang
Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China; Corresponding author
Summary: Mesenchymal stem cells (MSCs) hold potential in cancer therapy; however, insufficient tumor homing ability and heterogeneity limit their therapeutic benefits. Obviously, the homogeneous induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells (iMSCs) with enhanced ability of tumor targeting could be the solution. In this study, a CAR containing the NKG2D extracellular domain was targeted at the B2M locus of iPSCs to generate NKG2D-CAR-iPSCs, which were subsequently differentiated into NKG2D-CAR-iMSCs. In vitro, NKG2D-CAR significantly enhanced migration and adhesion of iMSCs to a variety of solid tumor cells expressing NKG2D ligands. RNA sequencing (RNA-seq) revealed significant upregulation of genes related to cell adhesion, migration, and binding in NKG2D-CAR-iMSCs. In A549 xenograft model, NKG2D-CAR-iMSCs demonstrated a 57% improvement in tumor-homing ability compared with iMSCs. In conclusion, our findings demonstrate enhanced targeting specificity of NKG2D-CAR-iMSCs to tumor cells expressing NKG2D ligands in vitro and in vivo, facilitating future investigation of iMSCs as an off-the-shelf living carrier for targeted delivery of anti-tumor agents.
