Robo4 Cooperates with CXCR4 to Specify Hematopoietic Stem Cell Localization to Bone Marrow Niches

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2011 Jan 8

PMID 21211783

Citations 74

Authors

Stephanie Smith-Berdan

Andrew Nguyen

Deena Hassanein

Matthew Zimmer

Fernando Ugarte

Jesus Ciriza

Dean Li

Marcos E Garcia-Ojeda

Lindsay Hinck

E Camilla Forsberg

Affiliations

Soon will be listed here.

Abstract

Specific bone marrow (BM) niches are critical for hematopoietic stem cell (HSC) function during both normal hematopoiesis and in stem cell transplantation therapy. We demonstrate that the guidance molecule Robo4 functions to specifically anchor HSCs to BM niches. Robo4-deficient HSCs displayed poor localization to BM niches and drastically reduced long-term reconstitution capability while retaining multilineage potential. Cxcr4, a critical regulator of HSC location, is upregulated in Robo4(-/-) HSCs to compensate for Robo4 loss. Robo4 deletion led to altered HSC mobilization efficiency, revealing that inhibition of both Cxcr4- and Robo4-mediated niche interactions are necessary for efficient HSC mobilization. Surprisingly, we found that WT HSCs express very low levels of Cxcr4 and respond poorly to Cxcr4 manipulation relative to other hematopoietic cells. We conclude that Robo4 cooperates with Cxcr4 to endow HSCs with competitive access to limited stem cell niches, and we propose Robo4 as a therapeutic target in HSC transplantation therapy.

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