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 ParkSang Hun Lee

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
JournalCell Death and Differentiation
DOIs
Publication statusAccepted/In press - 2021

Bibliographical note

Funding Information:
This work was supported by the grants 2017R1A5A2015395, 2020M3A9D8039925, 2017M3A9B4062415, and 2018R1C1B6003436 funded by the National Research Foundation of Korea (NRF) of the Ministry of Science and ICT, Republic of Korea.

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

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