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Reprogramming roadmap reveals route to human induced trophoblast stem cells

Reprogramming roadmap reveals route to human induced trophoblast stem cells
Reprogramming roadmap reveals route to human induced trophoblast stem cells

The reprogramming of human somatic cells to primed or naive induced pluripotent stem cells recapitulates the stages of early embryonic development 1–6. The molecular mechanism that underpins these reprogramming processes remains largely unexplored, which impedes our understanding and limits rational improvements to reprogramming protocols. Here, to address these issues, we reconstruct molecular reprogramming trajectories of human dermal fibroblasts using single-cell transcriptomics. This revealed that reprogramming into primed and naive pluripotency follows diverging and distinct trajectories. Moreover, genome-wide analyses of accessible chromatin showed key changes in the regulatory elements of core pluripotency genes, and orchestrated global changes in chromatin accessibility over time. Integrated analysis of these datasets revealed a role for transcription factors associated with the trophectoderm lineage, and the existence of a subpopulation of cells that enter a trophectoderm-like state during reprogramming. Furthermore, this trophectoderm-like state could be captured, which enabled the derivation of induced trophoblast stem cells. Induced trophoblast stem cells are molecularly and functionally similar to trophoblast stem cells derived from human blastocysts or first-trimester placentas 7. Our results provide a high-resolution roadmap for the transcription-factor-mediated reprogramming of human somatic cells, indicate a role for the trophectoderm-lineage-specific regulatory program during this process, and facilitate the direct reprogramming of somatic cells into induced trophoblast stem cells.

0028-0836
101-107
Liu, Xiaodong
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Ouyang, John F.
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Rossello, Fernando J.
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Tan, Jia Ping
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Davidson, Kathryn C.
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Valdes, Daniela S.
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Schröder, Jan
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Sun, Yu B. Y.
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Chen, Joseph
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Knaupp, Anja S.
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Sun, Guizhi
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Chy, Hun S.
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Huang, Ziyi
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Pflueger, Jahnvi
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Firas, Jaber
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Tano, Vincent
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Buckberry, Sam
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Paynter, Jacob M.
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Larcombe, Michael R.
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Poppe, Daniel
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Choo, Xin Yi
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O’Brien, Carmel M.
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Pastor, William A.
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Chen, Di
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Leichter, Anna L.
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Naeem, Haroon
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Tripathi, Pratibha
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Das, Partha P.
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Grubman, Alexandra
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Powell, David R.
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Laslett, Andrew L.
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David, Laurent
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Nilsson, Susan K.
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Clark, Amander T.
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Lister, Ryan
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Nefzger, Christian M.
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Martelotto, Luciano G.
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Rackham, Owen J. L.
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Polo, Jose M.
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Liu, Xiaodong
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Ouyang, John F.
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Rossello, Fernando J.
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Tan, Jia Ping
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Davidson, Kathryn C.
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Valdes, Daniela S.
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Schröder, Jan
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Sun, Yu B. Y.
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Chen, Joseph
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Knaupp, Anja S.
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Sun, Guizhi
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Chy, Hun S.
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Huang, Ziyi
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Pflueger, Jahnvi
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Firas, Jaber
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Tano, Vincent
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Buckberry, Sam
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Paynter, Jacob M.
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Larcombe, Michael R.
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Poppe, Daniel
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Choo, Xin Yi
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O’Brien, Carmel M.
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Pastor, William A.
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Chen, Di
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Leichter, Anna L.
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Naeem, Haroon
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Tripathi, Pratibha
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Das, Partha P.
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Grubman, Alexandra
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Powell, David R.
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Laslett, Andrew L.
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David, Laurent
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Nilsson, Susan K.
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Clark, Amander T.
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Lister, Ryan
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Nefzger, Christian M.
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Martelotto, Luciano G.
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Rackham, Owen J. L.
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Polo, Jose M.
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Liu, Xiaodong, Ouyang, John F., Rossello, Fernando J., Tan, Jia Ping, Davidson, Kathryn C., Valdes, Daniela S., Schröder, Jan, Sun, Yu B. Y., Chen, Joseph, Knaupp, Anja S., Sun, Guizhi, Chy, Hun S., Huang, Ziyi, Pflueger, Jahnvi, Firas, Jaber, Tano, Vincent, Buckberry, Sam, Paynter, Jacob M., Larcombe, Michael R., Poppe, Daniel, Choo, Xin Yi, O’Brien, Carmel M., Pastor, William A., Chen, Di, Leichter, Anna L., Naeem, Haroon, Tripathi, Pratibha, Das, Partha P., Grubman, Alexandra, Powell, David R., Laslett, Andrew L., David, Laurent, Nilsson, Susan K., Clark, Amander T., Lister, Ryan, Nefzger, Christian M., Martelotto, Luciano G., Rackham, Owen J. L. and Polo, Jose M. (2020) Reprogramming roadmap reveals route to human induced trophoblast stem cells. Nature, 586 (7827), 101-107. (doi:10.1038/s41586-020-2734-6).

Record type: Article

Abstract

The reprogramming of human somatic cells to primed or naive induced pluripotent stem cells recapitulates the stages of early embryonic development 1–6. The molecular mechanism that underpins these reprogramming processes remains largely unexplored, which impedes our understanding and limits rational improvements to reprogramming protocols. Here, to address these issues, we reconstruct molecular reprogramming trajectories of human dermal fibroblasts using single-cell transcriptomics. This revealed that reprogramming into primed and naive pluripotency follows diverging and distinct trajectories. Moreover, genome-wide analyses of accessible chromatin showed key changes in the regulatory elements of core pluripotency genes, and orchestrated global changes in chromatin accessibility over time. Integrated analysis of these datasets revealed a role for transcription factors associated with the trophectoderm lineage, and the existence of a subpopulation of cells that enter a trophectoderm-like state during reprogramming. Furthermore, this trophectoderm-like state could be captured, which enabled the derivation of induced trophoblast stem cells. Induced trophoblast stem cells are molecularly and functionally similar to trophoblast stem cells derived from human blastocysts or first-trimester placentas 7. Our results provide a high-resolution roadmap for the transcription-factor-mediated reprogramming of human somatic cells, indicate a role for the trophectoderm-lineage-specific regulatory program during this process, and facilitate the direct reprogramming of somatic cells into induced trophoblast stem cells.

Text
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Accepted/In Press date: 24 June 2020
e-pub ahead of print date: 16 September 2020
Published date: 16 September 2020

Identifiers

Local EPrints ID: 445289
URI: http://eprints.soton.ac.uk/id/eprint/445289
ISSN: 0028-0836
PURE UUID: 246158b6-d0c3-434f-a0cd-00d00f232742

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Date deposited: 01 Dec 2020 17:31
Last modified: 04 Dec 2020 17:31

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Contributors

Author: Xiaodong Liu
Author: John F. Ouyang
Author: Fernando J. Rossello
Author: Jia Ping Tan
Author: Kathryn C. Davidson
Author: Daniela S. Valdes
Author: Jan Schröder
Author: Yu B. Y. Sun
Author: Joseph Chen
Author: Anja S. Knaupp
Author: Guizhi Sun
Author: Hun S. Chy
Author: Ziyi Huang
Author: Jahnvi Pflueger
Author: Jaber Firas
Author: Vincent Tano
Author: Sam Buckberry
Author: Jacob M. Paynter
Author: Michael R. Larcombe
Author: Daniel Poppe
Author: Xin Yi Choo
Author: Carmel M. O’Brien
Author: William A. Pastor
Author: Di Chen
Author: Anna L. Leichter
Author: Haroon Naeem
Author: Pratibha Tripathi
Author: Partha P. Das
Author: Alexandra Grubman
Author: David R. Powell
Author: Andrew L. Laslett
Author: Laurent David
Author: Susan K. Nilsson
Author: Amander T. Clark
Author: Ryan Lister
Author: Christian M. Nefzger
Author: Luciano G. Martelotto
Author: Jose M. Polo

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