Context- and Cell-Dependent Effects of Delta-Like 4 Targeting in the Bone Marrow Microenvironment

Detalhes bibliográficos
Autor(a) principal: Remédio, Leonor
Data de Publicação: 2012
Outros Autores: Carvalho, Tânia, Caiado, Francisco, Bastos-Carvalho, Ana, Martins, Diana, Duarte, António, Yagita, Hideo, Dias, Sergio
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
Texto Completo: https://doi.org/10.1371/journal.pone.0052450
Resumo: This work was supported by FCT PTDC/SAU-ORG/113617/2009 (www.fct.pt). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors would like to thank other members of the Angiogenesis Lab for their input and suggestions. The Program for Advanced Medical Education is sponsored by Fundacao Calouste Gulbenkian, Fundacao Champalimaud, Ministerio da Saude and Fundacao para a Ciencia e Tecnologia, Portugal.
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spelling Context- and Cell-Dependent Effects of Delta-Like 4 Targeting in the Bone Marrow MicroenvironmentHEMATOPOIETIC STEM-CELL; SINUSOIDAL ENDOTHELIAL-CELLSINHIBITS TUMOR-GROWTHNOTCH LIGANDIN-VIVOPROGENITOR CELLSVASCULAR NICHESELF-RENEWALINDUCED MOBILIZATIONLINEAGE COMMITMENTAgricultural and Biological Sciences(all)Biochemistry, Genetics and Molecular Biology(all)Medicine(all)This work was supported by FCT PTDC/SAU-ORG/113617/2009 (www.fct.pt). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors would like to thank other members of the Angiogenesis Lab for their input and suggestions. The Program for Advanced Medical Education is sponsored by Fundacao Calouste Gulbenkian, Fundacao Champalimaud, Ministerio da Saude and Fundacao para a Ciencia e Tecnologia, Portugal.Delta-like 4 (Dll4) is a ligand of the Notch pathway family which has been widely studied in the context of tumor angiogenesis, its blockade shown to result in non-productive angiogenesis and halted tumor growth. As Dll4 inhibitors enter the clinic, there is an emerging need to understand their side effects, namely the systemic consequences of Dll4:Notch blockade in tissues other than tumors. The present study focused on the effects of systemic anti-Dll4 targeting in the bone marrow (BM) microenvironment. Here we show that Dll4 blockade with monoclonal antibodies perturbs the BM vascular niche of sub-lethally irradiated mice, resulting in increased CD31+, VE-Cadherin+ and c-kit+ vessel density, and also increased megakaryocytes, whereas CD105+, VEGFR3+, SMA+ and lectin+ vessel density remained unaltered. We investigated also the expression of angiocrine genes upon Dll4 treatment in vivo, and demonstrate that IGFbp2, IGFbp3, Angpt2, Dll4, DHH and VEGF-A are upregulated, while FGF1 and CSF2 are reduced. In vitro treatment of endothelial cells with anti-Dll4 reduced Akt phosphorylation while maintaining similar levels of Erk 1/2 phosphorylation. Besides its effects in the BM vascular niche, anti-Dll4 treatment perturbed hematopoiesis, as evidenced by increased myeloid (CD11b+), decreased B (B220+) and T (CD3+) lymphoid BM content of treated mice, with a corresponding increase in myeloid circulating cells. Moreover, anti-Dll4 treatment also increased the number of CFU-M and -G colonies in methylcellulose assays, independently of Notch1. Finally, anti-Dll4 treatment of donor BM improved the hematopoietic recovery of lethally irradiated recipients in a transplant setting. Together, our data reveals the hematopoietic (BM) effects of systemic anti-Dll4 treatment result from qualitative vascular changes and also direct hematopoietic cell modulation, which may be favorable in a transplant setting.Centro de Estudos de Doenças Crónicas (CEDOC)NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)RUNRemédio, LeonorCarvalho, TâniaCaiado, FranciscoBastos-Carvalho, AnaMartins, DianaDuarte, AntónioYagita, HideoDias, Sergio2017-08-02T22:05:24Z2012-12-202012-12-20T00:00:00Zinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/articleapplication/pdfhttps://doi.org/10.1371/journal.pone.0052450eng1932-6203PURE: 2988185http://www.scopus.com/inward/record.url?scp=84871412471&partnerID=8YFLogxKhttps://doi.org/10.1371/journal.pone.0052450info:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-03-11T04:10:03Zoai:run.unl.pt:10362/22432Portal AgregadorONGhttps://www.rcaap.pt/oai/openaireopendoar:71602024-03-20T03:27:17.849182Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse
dc.title.none.fl_str_mv Context- and Cell-Dependent Effects of Delta-Like 4 Targeting in the Bone Marrow Microenvironment
title Context- and Cell-Dependent Effects of Delta-Like 4 Targeting in the Bone Marrow Microenvironment
spellingShingle Context- and Cell-Dependent Effects of Delta-Like 4 Targeting in the Bone Marrow Microenvironment
Remédio, Leonor
HEMATOPOIETIC STEM-CELL
; SINUSOIDAL ENDOTHELIAL-CELLS
INHIBITS TUMOR-GROWTH
NOTCH LIGAND
IN-VIVO
PROGENITOR CELLS
VASCULAR NICHE
SELF-RENEWAL
INDUCED MOBILIZATION
LINEAGE COMMITMENT
Agricultural and Biological Sciences(all)
Biochemistry, Genetics and Molecular Biology(all)
Medicine(all)
title_short Context- and Cell-Dependent Effects of Delta-Like 4 Targeting in the Bone Marrow Microenvironment
title_full Context- and Cell-Dependent Effects of Delta-Like 4 Targeting in the Bone Marrow Microenvironment
title_fullStr Context- and Cell-Dependent Effects of Delta-Like 4 Targeting in the Bone Marrow Microenvironment
title_full_unstemmed Context- and Cell-Dependent Effects of Delta-Like 4 Targeting in the Bone Marrow Microenvironment
title_sort Context- and Cell-Dependent Effects of Delta-Like 4 Targeting in the Bone Marrow Microenvironment
author Remédio, Leonor
author_facet Remédio, Leonor
Carvalho, Tânia
Caiado, Francisco
Bastos-Carvalho, Ana
Martins, Diana
Duarte, António
Yagita, Hideo
Dias, Sergio
author_role author
author2 Carvalho, Tânia
Caiado, Francisco
Bastos-Carvalho, Ana
Martins, Diana
Duarte, António
Yagita, Hideo
Dias, Sergio
author2_role author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Centro de Estudos de Doenças Crónicas (CEDOC)
NOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
RUN
dc.contributor.author.fl_str_mv Remédio, Leonor
Carvalho, Tânia
Caiado, Francisco
Bastos-Carvalho, Ana
Martins, Diana
Duarte, António
Yagita, Hideo
Dias, Sergio
dc.subject.por.fl_str_mv HEMATOPOIETIC STEM-CELL
; SINUSOIDAL ENDOTHELIAL-CELLS
INHIBITS TUMOR-GROWTH
NOTCH LIGAND
IN-VIVO
PROGENITOR CELLS
VASCULAR NICHE
SELF-RENEWAL
INDUCED MOBILIZATION
LINEAGE COMMITMENT
Agricultural and Biological Sciences(all)
Biochemistry, Genetics and Molecular Biology(all)
Medicine(all)
topic HEMATOPOIETIC STEM-CELL
; SINUSOIDAL ENDOTHELIAL-CELLS
INHIBITS TUMOR-GROWTH
NOTCH LIGAND
IN-VIVO
PROGENITOR CELLS
VASCULAR NICHE
SELF-RENEWAL
INDUCED MOBILIZATION
LINEAGE COMMITMENT
Agricultural and Biological Sciences(all)
Biochemistry, Genetics and Molecular Biology(all)
Medicine(all)
description This work was supported by FCT PTDC/SAU-ORG/113617/2009 (www.fct.pt). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors would like to thank other members of the Angiogenesis Lab for their input and suggestions. The Program for Advanced Medical Education is sponsored by Fundacao Calouste Gulbenkian, Fundacao Champalimaud, Ministerio da Saude and Fundacao para a Ciencia e Tecnologia, Portugal.
publishDate 2012
dc.date.none.fl_str_mv 2012-12-20
2012-12-20T00:00:00Z
2017-08-02T22:05:24Z
dc.type.status.fl_str_mv info:eu-repo/semantics/publishedVersion
dc.type.driver.fl_str_mv info:eu-repo/semantics/article
format article
status_str publishedVersion
dc.identifier.uri.fl_str_mv https://doi.org/10.1371/journal.pone.0052450
url https://doi.org/10.1371/journal.pone.0052450
dc.language.iso.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv 1932-6203
PURE: 2988185
http://www.scopus.com/inward/record.url?scp=84871412471&partnerID=8YFLogxK
https://doi.org/10.1371/journal.pone.0052450
dc.rights.driver.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron:RCAAP
instname_str Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
instacron_str RCAAP
institution RCAAP
reponame_str Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
collection Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
repository.name.fl_str_mv Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação
repository.mail.fl_str_mv
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