Therapeutic Effects of Hematopoietic Stem Cell Derived From Gene-Edited Mice on β654-Thalassemia

作者：Lu, Dan; Gong, Xiuli; Guo, Xinbing; Chen, Yanwen; Zhu, Yiwen; Fang, Yudan; Cai, Qin; Xu, Miao; Yang, Hua; Li, Dali^*; Zeng, Yitao; Zeng, Fanyi^*

来源：Stem Cells, 2023.

DOI：10.1093/stmcls/sxad096

• hematopoietic stem cell
• stem cell transplantation
• beta-thalassemia
• gene-edited mice
• cell therapy

beta-thalassemia is an inherited blood disease caused by reduced or inadequate beta-globin synthesis due to beta-globin gene mutation. Our previous study developed a gene-edited mice model (beta 654-ER mice) by CRISPR/Cas9-mediated genome editing, targeting both the beta IVS2-654 (C > T) mutation site and the 3MODIFIER LETTER PRIME splicing acceptor site at 579 and corrected abnormal beta-globin mRNA splicing in the beta 654-thalassemia mice. Herein, we further explored the therapeutic effect of the hematopoietic stem cells (HSCs) from beta 654-ER mice on beta-thalassemia by consecutive HSC transplantation. The results indicated that HSC transplantation derived from gene-edited mice can significantly improve the survival rate of mice after lethal radiation doses and effectively achieve hematopoietic reconstruction and long-term hematopoiesis. Clinical symptoms, including hematologic parameters and tissue pathology of transplanted recipients, were significantly improved compared to the non-transplanted beta 654 mice. The therapeutic effect of gene-edited HSC transplantation demonstrated no significant difference in hematological parameters and tissue pathology compared with wild-type mouse-derived HSCs. Our data revealed that HSC transplantation from gene-edited mice completely recovered the beta-thalassemia phenotype. Our study systematically investigated the therapeutic effect of HSCs derived from beta 654-ER mice on beta-thalassemia and further confirmed the efficacy of our gene-editing approach. Altogether, it provided a reference and primary experimental data for the clinical usage of such gene-edited HSCs in the future. [Graphical Abstract]

• 单位
  河北医科大学; 上海交通大学