LIN28A enhances regenerative capacity of human somatic tissue stem cells via metabolic and mitochondrial reprogramming

Kelvin Pieknell; Yanuar Alan Sulistio; Noviana Wulansari; Wahyu Handoko Wibowo Darsono; Mi-Yoon Chang; Ji-Yun Ko; Jong Wook Chang; Min-Jeong Kim; Man Ryul Lee; Sang A Lee; Hyunbeom Lee; Gakyung Lee; Byung Hwa Jung; Hyunbum Park; Geun-Ho Kim; Doory Kim; Gayoung Cho; Chun-Hyung Kim; Dat Da Ly; Kyu-Sang Park; Sang-Hun Lee

doi:10.1038/s41418-021-00873-1

LIN28A enhances regenerative capacity of human somatic tissue stem cells via metabolic and mitochondrial reprogramming

Cell Death Differ. 2022 Mar;29(3):540-555. doi: 10.1038/s41418-021-00873-1. Epub 2021 Sep 23.

Authors

Kelvin Pieknell^#^{1

2}, Yanuar Alan Sulistio^#³, Noviana Wulansari², Wahyu Handoko Wibowo Darsono², Mi-Yoon Chang², Ji-Yun Ko⁴, Jong Wook Chang⁵, Min-Jeong Kim⁵, Man Ryul Lee⁶, Sang A Lee⁶, Hyunbeom Lee⁷, Gakyung Lee⁷, Byung Hwa Jung^{7

8}, Hyunbum Park⁹, Geun-Ho Kim⁹, Doory Kim⁹, Gayoung Cho¹⁰, Chun-Hyung Kim¹⁰, Dat Da Ly¹¹, Kyu-Sang Park¹¹, Sang-Hun Lee^{12

13

14}

Affiliations

¹ Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea.
² Hanyang Biomedical Research Institute, Hanyang University, Seoul, South Korea.
³ Hanyang Biomedical Research Institute, Hanyang University, Seoul, South Korea. [email protected].
⁴ Research Institute for Integrative Regenerative Biomedical Engineering, Dongguk University, Goyang-si, South Korea.
⁵ Samsung Medical Center, Stem Cell and Regenerative Medicine Institute, Seoul, 06351, South Korea.
⁶ Soonchunhyang Institute of Medibioscience (SIMS), Soonchunhyang University, Cheonan, Chungcheongnam-do, 31151, South Korea.
⁷ Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul, 02792, South Korea.
⁸ Division of Bio-Medical Science and Technology, KIST-School, Korea University of Science and Technology, Seoul, 02792, South Korea.
⁹ Department of Chemistry, Hanyang University, Seoul, 04763, South Korea.
¹⁰ Paean Biotechnology, Inc, Seoul, 04552, South Korea.
¹¹ Mitohormesis Research Center, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do, 26426, South Korea.
¹² Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea. [email protected].
¹³ Hanyang Biomedical Research Institute, Hanyang University, Seoul, South Korea. [email protected].
¹⁴ Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, South Korea. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult Stem Cells* / metabolism
Cell Differentiation
Cellular Reprogramming
Glycolysis
Humans
Mitochondria* / metabolism
Oxidative Phosphorylation