Generation of dyskeratosis congenita-like hematopoietic stem cells through the stable inhibition of DKC1

© The Author(s).

Detalhes bibliográficos
Autores: Carrascoso-Rubio, C., Zittersteijn, H. A., Pintado-Berninches, Laura, Fernández-Varas, Beatriz, Lozano, M. L., Manguan-García, Cristina, Sastre, Leandro, Bueren-Calabuig, Juan A., Perona Abellón, Rosario, Guenechea, Guillermo
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Recursos:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/265080
Acesso em linha:http://hdl.handle.net/10261/265080
Access Level:acceso abierto
Palavra-chave:Dyskeratosis congenita
DKC1 gene
Bone marrow failure disorders
Hematopoietic stem cells
Short hairpin RNA
Lentiviral vectors
id ES_bfb8bf14e4616da4dbf5abbd43fd76f9
oai_identifier_str oai:digital.csic.es:10261/265080
network_acronym_str ES
network_name_str España
repository_id_str
spelling Generation of dyskeratosis congenita-like hematopoietic stem cells through the stable inhibition of DKC1Carrascoso-Rubio, C.Zittersteijn, H. A.Pintado-Berninches, LauraFernández-Varas, BeatrizLozano, M. L.Manguan-García, CristinaSastre, LeandroBueren-Calabuig, Juan A.Perona Abellón, RosarioGuenechea, GuillermoDyskeratosis congenitaDKC1 geneBone marrow failure disordersHematopoietic stem cellsShort hairpin RNALentiviral vectors© The Author(s).Dyskeratosis congenita (DC) is a rare telomere biology disorder, which results in different clinical manifestations, including severe bone marrow failure. To date, the only curative treatment for the bone marrow failure in DC patients is allogeneic hematopoietic stem cell transplantation. However, due to the toxicity associated to this treatment, improved therapies are recommended for DC patients. Here, we aimed at generating DC-like human hematopoietic stem cells in which the efficacy of innovative therapies could be investigated. Because X-linked DC is the most frequent form of the disease and is associated with an impaired expression of DKC1, we have generated DC-like hematopoietic stem cells based on the stable knock-down of DKC1 in human CD34+ cells with lentiviral vectors encoding for DKC1 short hairpin RNAs. At a molecular level, DKC1-interfered CD34+ cells showed a decreased expression of TERC, as well as a diminished telomerase activity and increased DNA damage, cell senescence, and apoptosis. Moreover, DKC1-interfered human CD34+ cells showed defective clonogenic ability and were incapable of repopulating the hematopoiesis of immunodeficient NSG mice. The development of DC-like hematopoietic stem cells will facilitate the understanding of the molecular and cellular basis of this inherited bone marrow failure syndrome and will serve as a platform to evaluate the efficacy of new hematopoietic therapies for DC.This work was supported by grants from the “Ministerio de Economía, Comercio y Competitividad and Fondo Europeo de Desarrollo Regional (FEDER)” (SAF2015-68073-R) and from the “Ministerio de Ciencia, Innovación y Universidades and Fondo Europeo de Desarrollo Regional (FEDER)” (RTI2018-097125-B-I00) and P17-01401 from “Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III (FIS-ISCIII)”. The authors also thank the Fundación Botín for promoting translational research at the Hematopoietic Innovative Therapies Division of the CIEMAT. CIBERER is an initiative of the “Instituto de Salud Carlos III” and “FEDER”. CCR was supported by an FPI grant from the Universidad Autónoma de Madrid (UAM).BioMed CentralMinisterio de Economía y Competitividad (España)Ministerio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Instituto de Salud Carlos IIIFundación BotínUniversidad Autónoma de MadridConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2022202220212022info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/265080reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO//SAF2015-68073-Rinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-097125-B-I00http://dx.doi.org/10.1186/s13287-021-02145-8Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2650802026-05-22T06:33:51Z
dc.title.none.fl_str_mv Generation of dyskeratosis congenita-like hematopoietic stem cells through the stable inhibition of DKC1
title Generation of dyskeratosis congenita-like hematopoietic stem cells through the stable inhibition of DKC1
spellingShingle Generation of dyskeratosis congenita-like hematopoietic stem cells through the stable inhibition of DKC1
Carrascoso-Rubio, C.
Dyskeratosis congenita
DKC1 gene
Bone marrow failure disorders
Hematopoietic stem cells
Short hairpin RNA
Lentiviral vectors
title_short Generation of dyskeratosis congenita-like hematopoietic stem cells through the stable inhibition of DKC1
title_full Generation of dyskeratosis congenita-like hematopoietic stem cells through the stable inhibition of DKC1
title_fullStr Generation of dyskeratosis congenita-like hematopoietic stem cells through the stable inhibition of DKC1
title_full_unstemmed Generation of dyskeratosis congenita-like hematopoietic stem cells through the stable inhibition of DKC1
title_sort Generation of dyskeratosis congenita-like hematopoietic stem cells through the stable inhibition of DKC1
dc.creator.none.fl_str_mv Carrascoso-Rubio, C.
Zittersteijn, H. A.
Pintado-Berninches, Laura
Fernández-Varas, Beatriz
Lozano, M. L.
Manguan-García, Cristina
Sastre, Leandro
Bueren-Calabuig, Juan A.
Perona Abellón, Rosario
Guenechea, Guillermo
author Carrascoso-Rubio, C.
author_facet Carrascoso-Rubio, C.
Zittersteijn, H. A.
Pintado-Berninches, Laura
Fernández-Varas, Beatriz
Lozano, M. L.
Manguan-García, Cristina
Sastre, Leandro
Bueren-Calabuig, Juan A.
Perona Abellón, Rosario
Guenechea, Guillermo
author_role author
author2 Zittersteijn, H. A.
Pintado-Berninches, Laura
Fernández-Varas, Beatriz
Lozano, M. L.
Manguan-García, Cristina
Sastre, Leandro
Bueren-Calabuig, Juan A.
Perona Abellón, Rosario
Guenechea, Guillermo
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
Instituto de Salud Carlos III
Fundación Botín
Universidad Autónoma de Madrid
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Dyskeratosis congenita
DKC1 gene
Bone marrow failure disorders
Hematopoietic stem cells
Short hairpin RNA
Lentiviral vectors
topic Dyskeratosis congenita
DKC1 gene
Bone marrow failure disorders
Hematopoietic stem cells
Short hairpin RNA
Lentiviral vectors
description © The Author(s).
publishDate 2021
dc.date.none.fl_str_mv 2021
2022
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/265080
url http://hdl.handle.net/10261/265080
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO//SAF2015-68073-R
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/RTI2018-097125-B-I00
http://dx.doi.org/10.1186/s13287-021-02145-8
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869418415869919233
score 15.81155

Registos relacionados