Endothelial Cells Are Essential for the Self-renewal and Repopulation of Notch-dependent Hematopoietic Stem Cells

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2010 Mar 9

PMID 20207228

Citations 360

Authors

Jason M Butler

Daniel J Nolan

Eva L Vertes

Barbara Varnum-Finney

Hideki Kobayashi

Andrea T Hooper

Marco Seandel

Koji Shido

Ian A White

Mariko Kobayashi

Larry Witte

Chad May

Carrie Shawber

Yuki Kimura

Jan Kitajewski

Zev Rosenwaks

Irwin D Bernstein

Shahin Rafii

Affiliations

Soon will be listed here.

Abstract

Bone marrow endothelial cells (ECs) are essential for reconstitution of hematopoiesis, but their role in self-renewal of long-term hematopoietic stem cells (LT-HSCs) is unknown. We have developed angiogenic models to demonstrate that EC-derived angiocrine growth factors support in vitro self-renewal and in vivo repopulation of authentic LT-HSCs. In serum/cytokine-free cocultures, ECs, through direct cellular contact, stimulated incremental expansion of repopulating CD34(-)Flt3(-)cKit(+)Lineage(-)Sca1(+) LT-HSCs, which retained their self-renewal ability, as determined by single-cell and serial transplantation assays. Angiocrine expression of Notch ligands by ECs promoted proliferation and prevented exhaustion of LT-HSCs derived from wild-type, but not Notch1/Notch2-deficient, mice. In transgenic notch-reporter (TNR.Gfp) mice, regenerating TNR.Gfp(+) LT-HSCs were detected in cellular contact with sinusoidal ECs. Interference with angiocrine, but not perfusion, function of SECs impaired repopulation of TNR.Gfp(+) LT-HSCs. ECs establish an instructive vascular niche for clinical-scale expansion of LT-HSCs and a cellular platform to identify stem cell-active trophogens.

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