Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
EPITERNA SA, Epalinges, Switzerland.
Nat Aging. 2023 Dec;3(12):1509-1520. doi: 10.1038/s43587-023-00528-5. Epub 2023 Nov 27.
The induction of cellular reprogramming via expression of the transcription factors Oct4, Sox2, Klf4 and c-Myc (OSKM) can drive dedifferentiation of somatic cells and ameliorate age-associated phenotypes in multiple tissues and organs. However, the benefits of long-term in vivo reprogramming are limited by detrimental side-effects. Here, using complementary genetic approaches, we demonstrated that continuous induction of the reprogramming factors in vivo leads to hepatic and intestinal dysfunction resulting in decreased body weight and contributing to premature death (within 1 week). By generating a transgenic reprogrammable mouse strain, avoiding OSKM expression in both liver and intestine, we reduced the early lethality and adverse effects associated with in vivo reprogramming and induced a decrease in organismal biological age. This reprogramming mouse strain, which allows longer-term continuous induction of OSKM with attenuated toxicity, can help better understand rejuvenation, regeneration and toxicity during in vivo reprogramming.
通过表达转录因子 Oct4、Sox2、Klf4 和 c-Myc（OSKM）来诱导细胞重编程，可以驱动体细胞去分化，并改善多种组织和器官与年龄相关的表型。然而，长期体内重编程的益处受到有害副作用的限制。在这里，我们使用互补的遗传方法证明，体内持续诱导重编程因子会导致肝脏和肠道功能障碍，导致体重下降，并导致过早死亡（在 1 周内）。通过生成一种可重编程的转基因小鼠品系，避免 OSKM 在肝脏和肠道中的表达，我们降低了与体内重编程相关的早期致死率和不良反应，并诱导了机体生物年龄的下降。这种重编程小鼠品系可以允许更长时间的持续诱导 OSKM，同时降低毒性，有助于更好地理解体内重编程过程中的 rejuvenation、regeneration 和毒性。
