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

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

Physiology

Research output: Contribution to journal › Article › peer-review

14 Citations (Scopus)

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 language	English
Pages (from-to)	540-555
Number of pages	16
Journal	Cell Death and Differentiation
Volume	29
Issue number	3
DOIs	https://doi.org/10.1038/s41418-021-00873-1
Publication status	Published - 2022 Mar

Bibliographical note

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41418-021-00873-1

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Pieknell, K., Sulistio, Y. A., Wulansari, N., Darsono, W. H. W., Chang, M. Y., Ko, J. Y., Chang, J. W., Kim, M. J., Lee, M. R., Lee, S. A., Lee, H., Lee, G., Jung, B. H., Park, H., Kim, G. H., Kim, D., Cho, G., Kim, C. H., Ly, D. D., ... Lee, S. H. (2022). LIN28A enhances regenerative capacity of human somatic tissue stem cells via metabolic and mitochondrial reprogramming. Cell Death and Differentiation, 29(3), 540-555. https://doi.org/10.1038/s41418-021-00873-1

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title = "LIN28A enhances regenerative capacity of human somatic tissue stem cells via metabolic and mitochondrial reprogramming",

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.",

author = "Kelvin Pieknell and Sulistio, {Yanuar Alan} and Noviana Wulansari and Darsono, {Wahyu Handoko Wibowo} and Chang, {Mi Yoon} and Ko, {Ji Yun} and Chang, {Jong Wook} and Kim, {Min Jeong} and Lee, {Man Ryul} and Lee, {Sang A.} and Hyunbeom Lee and Gakyung Lee and Jung, {Byung Hwa} and Hyunbum Park and Kim, {Geun ho} and Doory Kim and Gayoung Cho and Kim, {Chun Hyung} and Ly, {Dat Da} and Park, {Kyu Sang} and Lee, {Sang Hun}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.",

year = "2022",

month = mar,

doi = "10.1038/s41418-021-00873-1",

language = "English",

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Pieknell, K, Sulistio, YA, Wulansari, N, Darsono, WHW, Chang, MY, Ko, JY, Chang, JW, Kim, MJ, Lee, MR, Lee, SA, Lee, H, Lee, G, Jung, BH, Park, H, Kim, GH, Kim, D, Cho, G, Kim, CH, Ly, DD, Park, KS & Lee, SH 2022, 'LIN28A enhances regenerative capacity of human somatic tissue stem cells via metabolic and mitochondrial reprogramming', Cell Death and Differentiation, vol. 29, no. 3, pp. 540-555. https://doi.org/10.1038/s41418-021-00873-1

TY - JOUR

T1 - LIN28A enhances regenerative capacity of human somatic tissue stem cells via metabolic and mitochondrial reprogramming

AU - Pieknell, Kelvin

AU - Sulistio, Yanuar Alan

AU - Wulansari, Noviana

AU - Darsono, Wahyu Handoko Wibowo

AU - Chang, Mi Yoon

AU - Ko, Ji Yun

AU - Chang, Jong Wook

AU - Kim, Min Jeong

AU - Lee, Man Ryul

AU - Lee, Sang A.

AU - Lee, Hyunbeom

AU - Lee, Gakyung

AU - Jung, Byung Hwa

AU - Park, Hyunbum

AU - Kim, Geun ho

AU - Kim, Doory

AU - Cho, Gayoung

AU - Kim, Chun Hyung

AU - Ly, Dat Da

AU - Park, Kyu Sang

AU - Lee, Sang Hun

PY - 2022/3

Y1 - 2022/3

N2 - 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.

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.

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U2 - 10.1038/s41418-021-00873-1

DO - 10.1038/s41418-021-00873-1

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AN - SCOPUS:85115401645

SN - 1350-9047

VL - 29

SP - 540

EP - 555

JO - Cell Death and Differentiation

JF - Cell Death and Differentiation

IS - 3

ER -

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

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

UN SDGs

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