Natural killer cells act as an extrinsic barrier for in vivo reprogramming

The ectopic expression of the transcription factors OCT4, SOX2, KLF4 and MYC (OSKM) enables reprogramming of differentiated cells into pluripotent embryonic stem cells. Methods based on partial and reversible in vivo reprogramming are a promising strategy for tissue regeneration and rejuvenation. Ho...

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Autores: Melendez, Elena, Chondronasiou, Dafni, Mosteiro, Lluc, Martínez de Villarreal, Jaime, Fernández-Alfara, Marcos, Lynch, Cian J., Grimm, Dirk, Real, Francisco X., Alcamí, José, Climent, Núria, Pietrocola, Federico, Serrano, Manuel
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/53527
Acceso en línea:http://hdl.handle.net/10230/53527
http://dx.doi.org/10.1242/dev.200361
Access Level:acceso abierto
Palabra clave:Immune system
Mouse
NK receptor ligands
Natural killer cells
Organoids
Plasticity
Pluripotency
Reprogramming
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spelling Natural killer cells act as an extrinsic barrier for in vivo reprogrammingMelendez, ElenaChondronasiou, DafniMosteiro, LlucMartínez de Villarreal, JaimeFernández-Alfara, MarcosLynch, Cian J.Grimm, DirkReal, Francisco X.Alcamí, JoséCliment, NúriaPietrocola, FedericoSerrano, ManuelImmune systemMouseNK receptor ligandsNatural killer cellsOrganoidsPlasticityPluripotencyReprogrammingThe ectopic expression of the transcription factors OCT4, SOX2, KLF4 and MYC (OSKM) enables reprogramming of differentiated cells into pluripotent embryonic stem cells. Methods based on partial and reversible in vivo reprogramming are a promising strategy for tissue regeneration and rejuvenation. However, little is known about the barriers that impair reprogramming in an in vivo context. We report that natural killer (NK) cells significantly limit reprogramming, both in vitro and in vivo. Cells and tissues in the intermediate states of reprogramming upregulate the expression of NK-activating ligands, such as MULT1 and ICAM1. NK cells recognize and kill partially reprogrammed cells in a degranulation-dependent manner. Importantly, in vivo partial reprogramming is strongly reduced by adoptive transfer of NK cells, whereas it is significantly increased by their depletion. Notably, in the absence of NK cells, the pancreatic organoids derived from OSKM-expressing mice are remarkably large, suggesting that ablating NK surveillance favours the acquisition of progenitor-like properties. We conclude that NK cells pose an important barrier for in vivo reprogramming, and speculate that this concept may apply to other contexts of transient cellular plasticity.E.M. was funded by an IRB Future Fellowship from the Institute for Research in Biomedicine (IRB Barcelona). F.P. was funded by a European Molecular Biology Organization Long Term Fellowship (EMBO-ALTF-358-2017). Work in the laboratory of F.P. was funded by a Starting Grant from the Swedish Research Council (Vetenskapsrådet) (VR MH 2019-02050) and by a starting grant from Karolinska Institutet. Work by N.C. was funded by a grant from Fondo de Investigaciones Sanitarias (FIS) (PI20/00676). Work in the laboratory of F.X.R. was funded by a grant from the Ministerio de Ciencia e Innovación co-funded by the European Regional Development Fund (RTI2018-101071-B-I00). Work in the laboratory of J.A. at Hospital Clínic was funded by “la Caixa” Foundation. Work in the laboratory of M.S. was funded by the Institute for Research in Biomedicine and “la Caixa” Foundation, and by grants from the Ministerio de Ciencia e Innovación co-funded by the European Regional Development Fund (SAF2017-82613-R), European Research Council (ERC-2014-AdG/669622), and Secretaria d'Universitats i Recerca del Departament d'Empresa i Coneixement, Generalitat de Catalunya (Grup de Recerca consolidat 2017 SGR 282). Open Access funding provided by Institute for Research in Biomedicine (IRB Barcelona). Deposited in PMC for immediate release.Company of Biologists202220222022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/53527http://dx.doi.org/10.1242/dev.200361reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésDevelopment. 2022 Apr 15;149(8):dev200361info:eu-repo/grantAgreement/EC/H2020/669622info:eu-repo/grantAgreement/ES/2PE/RTI2018-101071-B-I00info:eu-repo/grantAgreement/ES/2PE/SAF2017-82613-R© 2022. Published by The Company of Biologists Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.https://creativecommons.org/licenses/by/4.0info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/535272026-06-12T07:21:37Z
dc.title.none.fl_str_mv Natural killer cells act as an extrinsic barrier for in vivo reprogramming
title Natural killer cells act as an extrinsic barrier for in vivo reprogramming
spellingShingle Natural killer cells act as an extrinsic barrier for in vivo reprogramming
Melendez, Elena
Immune system
Mouse
NK receptor ligands
Natural killer cells
Organoids
Plasticity
Pluripotency
Reprogramming
title_short Natural killer cells act as an extrinsic barrier for in vivo reprogramming
title_full Natural killer cells act as an extrinsic barrier for in vivo reprogramming
title_fullStr Natural killer cells act as an extrinsic barrier for in vivo reprogramming
title_full_unstemmed Natural killer cells act as an extrinsic barrier for in vivo reprogramming
title_sort Natural killer cells act as an extrinsic barrier for in vivo reprogramming
dc.creator.none.fl_str_mv Melendez, Elena
Chondronasiou, Dafni
Mosteiro, Lluc
Martínez de Villarreal, Jaime
Fernández-Alfara, Marcos
Lynch, Cian J.
Grimm, Dirk
Real, Francisco X.
Alcamí, José
Climent, Núria
Pietrocola, Federico
Serrano, Manuel
author Melendez, Elena
author_facet Melendez, Elena
Chondronasiou, Dafni
Mosteiro, Lluc
Martínez de Villarreal, Jaime
Fernández-Alfara, Marcos
Lynch, Cian J.
Grimm, Dirk
Real, Francisco X.
Alcamí, José
Climent, Núria
Pietrocola, Federico
Serrano, Manuel
author_role author
author2 Chondronasiou, Dafni
Mosteiro, Lluc
Martínez de Villarreal, Jaime
Fernández-Alfara, Marcos
Lynch, Cian J.
Grimm, Dirk
Real, Francisco X.
Alcamí, José
Climent, Núria
Pietrocola, Federico
Serrano, Manuel
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Immune system
Mouse
NK receptor ligands
Natural killer cells
Organoids
Plasticity
Pluripotency
Reprogramming
topic Immune system
Mouse
NK receptor ligands
Natural killer cells
Organoids
Plasticity
Pluripotency
Reprogramming
description The ectopic expression of the transcription factors OCT4, SOX2, KLF4 and MYC (OSKM) enables reprogramming of differentiated cells into pluripotent embryonic stem cells. Methods based on partial and reversible in vivo reprogramming are a promising strategy for tissue regeneration and rejuvenation. However, little is known about the barriers that impair reprogramming in an in vivo context. We report that natural killer (NK) cells significantly limit reprogramming, both in vitro and in vivo. Cells and tissues in the intermediate states of reprogramming upregulate the expression of NK-activating ligands, such as MULT1 and ICAM1. NK cells recognize and kill partially reprogrammed cells in a degranulation-dependent manner. Importantly, in vivo partial reprogramming is strongly reduced by adoptive transfer of NK cells, whereas it is significantly increased by their depletion. Notably, in the absence of NK cells, the pancreatic organoids derived from OSKM-expressing mice are remarkably large, suggesting that ablating NK surveillance favours the acquisition of progenitor-like properties. We conclude that NK cells pose an important barrier for in vivo reprogramming, and speculate that this concept may apply to other contexts of transient cellular plasticity.
publishDate 2022
dc.date.none.fl_str_mv 2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/53527
http://dx.doi.org/10.1242/dev.200361
url http://hdl.handle.net/10230/53527
http://dx.doi.org/10.1242/dev.200361
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Development. 2022 Apr 15;149(8):dev200361
info:eu-repo/grantAgreement/EC/H2020/669622
info:eu-repo/grantAgreement/ES/2PE/RTI2018-101071-B-I00
info:eu-repo/grantAgreement/ES/2PE/SAF2017-82613-R
dc.rights.none.fl_str_mv https://creativecommons.org/licenses/by/4.0
info:eu-repo/semantics/openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/4.0
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Company of Biologists
publisher.none.fl_str_mv Company of Biologists
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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