한빛사 논문
Kelvin Pieknell1,2,12, Yanuar Alan Sulistio2,12,*, Noviana Wulansari2, Wahyu Handoko Wibowo Darsono2, Mi-Yoon Chang2, Ji-Yun Ko3, Jong Wook Chang4, Min-Jeong Kim4, Man Ryul Lee5, Sang A. Lee5, Hyunbeom Lee6, Gakyung Lee6, Byung Hwa Jung6,7, Hyunbum Park8, Geun-ho Kim8, Doory Kim8, Gayoung Cho9, Chun-Hyung Kim9, Dat Da Ly10, Kyu-Sang Park10 and Sang-Hun Lee1,2,11,*
1Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea. 2Hanyang Biomedical Research Institute, Hanyang University, Seoul, South Korea. 3Research Institute for Integrative Regenerative Biomedical Engineering, Dongguk University, Goyang-si, South Korea. 4Samsung Medical Center, Stem Cell and Regenerative Medicine Institute, Seoul 06351, South Korea. 5Soonchunhyang Institute of Medibioscience (SIMS), Soonchunhyang University, Cheonan, Chungcheongnam-do 31151, South Korea. 6Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul 02792, South Korea. 7Division of Bio-Medical Science and Technology, KIST-School, Korea University of Science and Technology, Seoul 02792, South Korea. 8Department of Chemistry, Hanyang University, Seoul 04763, South Korea. 9Paean Biotechnology, Inc, Seoul 04552, South Korea. 10Mitohormesis Research Center, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do 26426, South Korea. 11Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, South Korea. 12These authors contributed equally: Kelvin Pieknell, Yanuar Alan Sulistio.
*Correspondence to Yanuar Alan Sulistio or Sang-Hun Lee.
Abstract
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.
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