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