Jagged-1 Signaling in the Bone Marrow Microenvironment Promotes Endothelial Progenitor Cell Expansion and Commitment of CD133+ Human Cord Blood Cells for Postnatal Vasculogenesis.

Mika Ishige-Wada,Katsuto Hozumi,Sang-Mo Kwon,Hideki Iwaguro,Masamichi Eguchi,Noboru Fukuda,Hideo Mugishima,Takayuki Asahara,Taro Matsumoto,Haruchika Masuda,Gangjian Qin

doi:10.1371/journal.pone.0166660

Mika Ishige-Wada, Katsuto Hozumi + Show 9 more

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https://doi.org/10.1371/journal.pone.0166660

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Journal: PloS one	Publication Date: Nov 15, 2016
Citations: 14	License type: CC BY 4.0

Affiliation: Tokai University, Nihon University

Abstract

Notch signaling is involved in cell fate decisions during murine vascular development and hematopoiesis in the microenvironment of bone marrow. To investigate the close relationship between hematopoietic stem cells and human endothelial progenitor cells (EPCs) in the bone marrow niche, we examined the effects of Notch signals [Jagged-1 and Delta-like ligand (Dll)-1] on the proliferation and differentiation of human CD133+ cell-derived EPCs. We established stromal systems using HESS-5 murine bone marrow cells transfected with human Jagged-1 (hJagged-1) or human Dll-1 (hDll-1). CD133+ cord blood cells were co-cultured with the stromal cells for 7 days, and then their proliferation, differentiation, and EPC colony formation was evaluated. We found that hJagged-1 induced the proliferation and differentiation of CD133+ cord blood EPCs. In contrast, hDll-1 had little effect. CD133+ cells stimulated by hJagged-1 differentiated into CD31+/KDR+ cells, expressed vascular endothelial growth factor-A, and showed enhanced EPC colony formation compared with CD133+ cells stimulated by hDll-1. To evaluate the angiogenic properties of hJagged-1- and hDll-1-stimulated EPCs in vivo, we transplanted these cells into the ischemic hindlimbs of nude mice. Transplantation of EPCs stimulated by hJagged-1, but not hDll-1, increased regional blood flow and capillary density in ischemic hindlimb muscles. This is the first study to show that human Notch signaling influences EPC proliferation and differentiation in the bone marrow microenvironment. Human Jagged-1 induced the proliferation and differentiation of CD133+ cord blood progenitors compared with hDll-1. Thus, hJagged-1 signaling in the bone marrow niche may be used to expand EPCs for therapeutic angiogenesis.

Highlights

Notch signaling plays a crucial role in cell fate determination of a variety of cell types during development and postnatal tissue organization, including murine vascular development and angiogenesis [1, 2]
To investigate the close relationship between hematopoietic stem cells and human endothelial progenitor cells (EPCs) in the bone marrow niche, we examined the effects of Notch signals [Jagged-1 and Delta-like ligand (Dll)-1] on the proliferation and differentiation of human CD133+ cell-derived EPCs
CD133+ cells stimulated by hJagged-1 differentiated into CD31+/kinase-insert domain containing receptor (KDR)+ cells, expressed vascular endothelial growth factor-A, and showed enhanced EPC colony formation compared with CD133+ cells stimulated by human Dll-1 (hDll-1)

Summary

Introduction

Notch signaling plays a crucial role in cell fate determination of a variety of cell types during development and postnatal tissue organization, including murine vascular development and angiogenesis [1, 2]. Mutations of Notch receptors and ligands in mice cause abnormal organization of vascular and hematopoietic systems with severe hemorrhaging, which is embryonic lethal in the Notch signaling null mouse [3]. Primitive human CD34+ bone marrow cells express all Notch receptors [6]. Primary cells and cultured stromal cells derived from the aorta-gonad-mesonephros, fetal liver, bone marrow, and osteoblasts express Jagged-1, Dll-1, and Dll-4 [7,8,9]. These ligands expressed on stromal cells might interact with their respective Notch receptors on primitive hematopoietic cells in hematopoietic stem cell niches

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