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

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

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

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dc.contributor.author Melendez, Elena
dc.contributor.author Chondronasiou, Dafni
dc.contributor.author Mosteiro, Lluc
dc.contributor.author Martínez de Villarreal, Jaime
dc.contributor.author Fernández-Alfara, Marcos
dc.contributor.author Lynch, Cian J.
dc.contributor.author Grimm, Dirk
dc.contributor.author Real, Francisco X.
dc.contributor.author Alcamí, José
dc.contributor.author Climent, Núria
dc.contributor.author Pietrocola, Federico
dc.contributor.author Serrano, Manuel
dc.date.accessioned 2022-06-20T05:55:39Z
dc.date.available 2022-06-20T05:55:39Z
dc.date.issued 2022
dc.description.abstract 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.
dc.description.sponsorship 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.
dc.format.mimetype application/pdf
dc.identifier.citation Melendez E, Chondronasiou D, Mosteiro L, Martínez de Villarreal J, Fernández-Alfara M, Lynch CJ, Grimm D, Real FX, Alcamí J, Climent N, Pietrocola F, Serrano M. Natural killer cells act as an extrinsic barrier for in vivo reprogramming. Development. 2022 Apr 15;149(8):dev200361. DOI: 10.1242/dev.200361
dc.identifier.doi http://dx.doi.org/10.1242/dev.200361
dc.identifier.issn 0950-1991
dc.identifier.uri http://hdl.handle.net/10230/53527
dc.language.iso eng
dc.publisher Company of Biologists
dc.relation.ispartof Development. 2022 Apr 15;149(8):dev200361
dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/669622
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/RTI2018-101071-B-I00
dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/SAF2017-82613-R
dc.rights © 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.
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri https://creativecommons.org/licenses/by/4.0
dc.subject.keyword Immune system
dc.subject.keyword Mouse
dc.subject.keyword NK receptor ligands
dc.subject.keyword Natural killer cells
dc.subject.keyword Organoids
dc.subject.keyword Plasticity
dc.subject.keyword Pluripotency
dc.subject.keyword Reprogramming
dc.title Natural killer cells act as an extrinsic barrier for in vivo reprogramming
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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