Yue Jiping, Gou Xuewen, Li Yuanyuan, Wicksteed Barton, Wu Xiaoyang
Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA.
Cell Stem Cell. 2017 Aug 3;21(2):256-263.e4. doi: 10.1016/j.stem.2017.06.016.
Somatic gene therapy is a promising approach for treating otherwise terminal or debilitating diseases. The human skin is a promising conduit for genetic engineering, as it is the largest and most accessible organ, epidermal autografts and tissue-engineered skin equivalents have been successfully deployed in clinical applications, and skin epidermal stem/progenitor cells for generating such grafts are easy to obtain and expand in vitro. Here, we develop skin grafts from mouse and human epidermal progenitors that were engineered by CRISPR-mediated genome editing to controllably release GLP-1 (glucagon-like peptide 1), a critical incretin that regulates blood glucose homeostasis. GLP-1 induction from engineered mouse cells grafted onto immunocompetent hosts increased insulin secretion and reversed high-fat-diet-induced weight gain and insulin resistance. Taken together, these results highlight the clinical potential of developing long-lasting, safe, and versatile gene therapy approaches based on engineering epidermal progenitor cells.
体细胞基因治疗是一种治疗终末期或使人衰弱疾病的有前景的方法。人类皮肤是基因工程的一个有前景的途径，因为它是最大且最易触及的器官，表皮自体移植和组织工程皮肤替代物已成功应用于临床，并且用于生成此类移植的皮肤表皮干细胞/祖细胞易于在体外获取和扩增。在此，我们利用经CRISPR介导的基因组编辑工程改造的小鼠和人类表皮祖细胞开发了皮肤移植体，使其能够可控地释放胰高血糖素样肽1（GLP-1），这是一种调节血糖稳态的关键肠促胰岛素。移植到具有免疫活性宿主上的经工程改造的小鼠细胞诱导产生的GLP-1增加了胰岛素分泌，并逆转了高脂饮食诱导的体重增加和胰岛素抵抗。综上所述，这些结果凸显了基于工程化表皮祖细胞开发持久、安全且通用的基因治疗方法的临床潜力。
