Context- and cell-dependent effects of Delta-like 4 targeting in the bone marrow microenvironment.

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...

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Autores principales:	Leonor Remédio, Tânia Carvalho, Francisco Caiado, Ana Bastos-Carvalho, Diana Martins, António Duarte, Hideo Yagita, Sergio Dias
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2d1894edb95f4f318936a2e8688ead60
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spelling	oai:doaj.org-article:2d1894edb95f4f318936a2e8688ead602021-11-18T08:04:09ZContext- and cell-dependent effects of Delta-like 4 targeting in the bone marrow microenvironment.1932-620310.1371/journal.pone.0052450https://doaj.org/article/2d1894edb95f4f318936a2e8688ead602012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23285048/?tool=EBIhttps://doaj.org/toc/1932-6203Delta-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.Leonor RemédioTânia CarvalhoFrancisco CaiadoAna Bastos-CarvalhoDiana MartinsAntónio DuarteHideo YagitaSergio DiasPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 12, p e52450 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Leonor Remédio Tânia Carvalho Francisco Caiado Ana Bastos-Carvalho Diana Martins António Duarte Hideo Yagita Sergio Dias Context- and cell-dependent effects of Delta-like 4 targeting in the bone marrow microenvironment.
description	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.
format	article
author	Leonor Remédio Tânia Carvalho Francisco Caiado Ana Bastos-Carvalho Diana Martins António Duarte Hideo Yagita Sergio Dias
author_facet	Leonor Remédio Tânia Carvalho Francisco Caiado Ana Bastos-Carvalho Diana Martins António Duarte Hideo Yagita Sergio Dias
author_sort	Leonor Remédio
title	Context- and cell-dependent effects of Delta-like 4 targeting in the bone marrow microenvironment.
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.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/2d1894edb95f4f318936a2e8688ead60
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Context- and cell-dependent effects of Delta-like 4 targeting in the bone marrow microenvironment.

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