Pieknell Kelvin, Sulistio Yanuar Alan, Wulansari Noviana, Darsono Wahyu Handoko Wibowo, Chang Mi-Yoon, Ko Ji-Yun, Chang Jong Wook, Kim Min-Jeong, Lee Man Ryul, Lee Sang A, Lee Hyunbeom, Lee Gakyung, Jung Byung Hwa, Park Hyunbum, Kim Geun-Ho, Kim Doory, Cho Gayoung, Kim Chun-Hyung, Ly Dat Da, Park Kyu-Sang, Lee Sang-Hun
Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea.
Hanyang Biomedical Research Institute, Hanyang University, Seoul, South Korea.
Cell Death Differ. 2022 Mar;29(3):540-555. doi: 10.1038/s41418-021-00873-1. Epub 2021 Sep 23.
Developing methods to improve the regenerative capacity of somatic stem cells (SSCs) is a major challenge in regenerative medicine. Here, we propose the forced expression of LIN28A as a method to modulate cellular metabolism, which in turn enhances self-renewal, differentiation capacities, and engraftment after transplantation of various human SSCs. Mechanistically, in undifferentiated/proliferating SSCs, LIN28A induced metabolic reprogramming from oxidative phosphorylation (OxPhos) to glycolysis by activating PDK1-mediated glycolysis-TCA/OxPhos uncoupling. Mitochondria were also reprogrammed into healthy/fused mitochondria with improved functional capacity. The reprogramming allows SSCs to undergo cell proliferation more extensively with low levels of oxidative and mitochondrial stress. When the PDK1-mediated uncoupling was untethered upon differentiation, LIN28A-SSCs differentiated more efficiently with an increase of OxPhos by utilizing the reprogrammed mitochondria. This study provides mechanistic and practical approaches of utilizing LIN28A and metabolic reprogramming in order to improve SSCs utility in regenerative medicine.
开发提高体干细胞（SSCs）再生能力的方法是再生医学中的一项重大挑战。在此，我们提出强制表达LIN28A作为一种调节细胞代谢的方法，这反过来又能增强各种人类SSCs移植后的自我更新、分化能力和植入能力。从机制上讲，在未分化/增殖的SSCs中，LIN28A通过激活PDK1介导的糖酵解 - TCA/氧化磷酸化解偶联，诱导代谢重编程从氧化磷酸化（OxPhos）转变为糖酵解。线粒体也被重编程为功能能力得到改善的健康/融合线粒体。这种重编程使SSCs能够在低水平的氧化和线粒体应激下更广泛地进行细胞增殖。当分化时PDK1介导的解偶联被解除时，LIN28A - SSCs通过利用重编程的线粒体，以增加OxPhos的方式更有效地分化。本研究提供了利用LIN28A和代谢重编程的机制和实用方法，以提高SSCs在再生医学中的效用。
