PMID- 34556809 OWN - NLM STAT- MEDLINE DCOM- 20220419 LR - 20230302 IS - 1476-5403 (Electronic) IS - 1350-9047 (Print) IS - 1350-9047 (Linking) VI - 29 IP - 3 DP - 2022 Mar TI - LIN28A enhances regenerative capacity of human somatic tissue stem cells via metabolic and mitochondrial reprogramming. PG - 540-555 LID - 10.1038/s41418-021-00873-1 [doi] AB - 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. CI - (c) 2021. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare. FAU - Pieknell, Kelvin AU - Pieknell K AD - Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea. AD - Hanyang Biomedical Research Institute, Hanyang University, Seoul, South Korea. FAU - Sulistio, Yanuar Alan AU - Sulistio YA AUID- ORCID: 0000-0002-6701-6133 AD - Hanyang Biomedical Research Institute, Hanyang University, Seoul, South Korea. sulistio@hanyang.ac.kr. FAU - Wulansari, Noviana AU - Wulansari N AD - Hanyang Biomedical Research Institute, Hanyang University, Seoul, South Korea. FAU - Darsono, Wahyu Handoko Wibowo AU - Darsono WHW AD - Hanyang Biomedical Research Institute, Hanyang University, Seoul, South Korea. FAU - Chang, Mi-Yoon AU - Chang MY AD - Hanyang Biomedical Research Institute, Hanyang University, Seoul, South Korea. FAU - Ko, Ji-Yun AU - Ko JY AD - Research Institute for Integrative Regenerative Biomedical Engineering, Dongguk University, Goyang-si, South Korea. FAU - Chang, Jong Wook AU - Chang JW AD - Samsung Medical Center, Stem Cell and Regenerative Medicine Institute, Seoul, 06351, South Korea. FAU - Kim, Min-Jeong AU - Kim MJ AD - Samsung Medical Center, Stem Cell and Regenerative Medicine Institute, Seoul, 06351, South Korea. FAU - Lee, Man Ryul AU - Lee MR AD - Soonchunhyang Institute of Medibioscience (SIMS), Soonchunhyang University, Cheonan, Chungcheongnam-do, 31151, South Korea. FAU - Lee, Sang A AU - Lee SA AD - Soonchunhyang Institute of Medibioscience (SIMS), Soonchunhyang University, Cheonan, Chungcheongnam-do, 31151, South Korea. FAU - Lee, Hyunbeom AU - Lee H AUID- ORCID: 0000-0001-6954-7520 AD - Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul, 02792, South Korea. FAU - Lee, Gakyung AU - Lee G AD - Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul, 02792, South Korea. FAU - Jung, Byung Hwa AU - Jung BH AUID- ORCID: 0000-0002-7504-7132 AD - Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul, 02792, South Korea. AD - Division of Bio-Medical Science and Technology, KIST-School, Korea University of Science and Technology, Seoul, 02792, South Korea. FAU - Park, Hyunbum AU - Park H AD - Department of Chemistry, Hanyang University, Seoul, 04763, South Korea. FAU - Kim, Geun-Ho AU - Kim GH AD - Department of Chemistry, Hanyang University, Seoul, 04763, South Korea. FAU - Kim, Doory AU - Kim D AD - Department of Chemistry, Hanyang University, Seoul, 04763, South Korea. FAU - Cho, Gayoung AU - Cho G AD - Paean Biotechnology, Inc, Seoul, 04552, South Korea. FAU - Kim, Chun-Hyung AU - Kim CH AD - Paean Biotechnology, Inc, Seoul, 04552, South Korea. FAU - Ly, Dat Da AU - Ly DD AD - Mitohormesis Research Center, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do, 26426, South Korea. FAU - Park, Kyu-Sang AU - Park KS AUID- ORCID: 0000-0003-0322-9807 AD - Mitohormesis Research Center, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju, Gangwon-do, 26426, South Korea. FAU - Lee, Sang-Hun AU - Lee SH AUID- ORCID: 0000-0001-7553-8188 AD - Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, South Korea. leesh@hanyang.ac.kr. AD - Hanyang Biomedical Research Institute, Hanyang University, Seoul, South Korea. leesh@hanyang.ac.kr. AD - Department of Biochemistry and Molecular Biology, College of Medicine, Hanyang University, Seoul, South Korea. leesh@hanyang.ac.kr. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210923 PL - England TA - Cell Death Differ JT - Cell death and differentiation JID - 9437445 SB - IM MH - *Adult Stem Cells/metabolism MH - Cell Differentiation MH - Cellular Reprogramming MH - Glycolysis MH - Humans MH - *Mitochondria/metabolism MH - Oxidative Phosphorylation PMC - PMC8901931 COIS- The authors declare no competing interests. EDAT- 2021/09/25 06:00 MHDA- 2022/04/20 06:00 PMCR- 2023/03/01 CRDT- 2021/09/24 06:57 PHST- 2021/05/24 00:00 [received] PHST- 2021/09/08 00:00 [accepted] PHST- 2021/09/08 00:00 [revised] PHST- 2021/09/25 06:00 [pubmed] PHST- 2022/04/20 06:00 [medline] PHST- 2021/09/24 06:57 [entrez] PHST- 2023/03/01 00:00 [pmc-release] AID - 10.1038/s41418-021-00873-1 [pii] AID - 873 [pii] AID - 10.1038/s41418-021-00873-1 [doi] PST - ppublish SO - Cell Death Differ. 2022 Mar;29(3):540-555. doi: 10.1038/s41418-021-00873-1. Epub 2021 Sep 23.