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

Leonor Remédio, Tânia Carvalho, Francisco Caiado, Ana Bastos-Carvalho, Diana Martins, António Duarte, Hideo Yagita, Sergio Dias

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5 Citations (Scopus)
6 Downloads (Pure)

Abstract

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.

Original languageEnglish
Article numbere52450
Pages (from-to)Online
JournalPlosOne
Volume7
Issue number12
DOIs
Publication statusPublished - 20 Dec 2012

Keywords

  • HEMATOPOIETIC STEM-CELL
  • ; SINUSOIDAL ENDOTHELIAL-CELLS
  • INHIBITS TUMOR-GROWTH
  • NOTCH LIGAND
  • IN-VIVO
  • PROGENITOR CELLS
  • VASCULAR NICHE
  • SELF-RENEWAL
  • INDUCED MOBILIZATION
  • LINEAGE COMMITMENT

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