Glycosaminoglycan mimetics–induced mobilization of hematopoietic progenitors and stem cells into mouse peripheral blood: Structure/function insights∗
Received 12 September 2008; received in revised form 18 May 2009; accepted 9 June 2009. published online 18 June 2009.
Objective
Glycosaminoglycans (GAG) are major components of bone marrow extracellular matrix because they have the property to interact with cells and growth factors in hematopoietic niches. In this study, we investigated the effect of two different chemically defined GAG mimetics on mobilization of hematopoietic stem and progenitor cells (HSPCs) in mice peripheral blood.
Materials and Methods
Mobilization was achieved by intraperitoneal injection of GAG mimetics. Mobilized cells were characterized phenotypically by reverse transcription polymerase chain reaction and fluorescence-activated cell sorting analysis and functionally by colony-forming cell, cobblestone area−forming cell and long-term culture-initiating cell assays in vitro. Radioprotection assays were performed to confirm the functionality of primitive hematopoietic cells in vivo. Involvement of stromal-derived factor−1 (SDF-1) and matrix metalloproteinase-9 (MMP-9) were investigated.
Results
GAG mimetics treatment induces hyperleukocytosis and mobilization of HSPC. They synergize with the effects of granulocyte colony-stimulating factor or AMD3100 on hematopoietic progenitors mobilization. Reconstitution of lethally irradiated recipient mice with peripheral blood mononuclear cells from GAG mimetic-treated donor mice improves engraftment and survival. BiAcore studies indicate that the mimetics interact directly with SDF-1. In addition, GAG mimetics-induced mobilization is associated with increased levels of pro- and active MMP-9 from bone marrow cells and increased level of SDF-1 in peripheral blood. Finally, mobilization is partially inhibited by co-injection with anti−SDF-1 antibody.
Conclusion
This study demonstrates that GAG mimetics induce efficient mobilization of HSPCs, associated with an activation of pro−MMP-9 and a modification in the SDF-1 concentration gradient between bone marrow and peripheral blood. We suggest that structural features of GAGs can modify the nature of mobilized cells.
aCNRS UMR 7149, Laboratoire CRRET, “Croissance Cellulaire, Réparation et Régénération Tissulaire”, Créteil, France
bUniversité Paris 12, Val de Marne, Faculté des Sciences, Créteil, France
cINSERM U972, Hôpital Paul Brousse, Villejuif, France
dINSERM UMR U698, Université Paris 13, Bobigny, France
Offprints request to: Patricia Albanese, Ph.D., CNRS/UMR-7149, Laboratoire CRRET, 61 avenue du Général de Gaulle, 94010 Créteil cedex, France
∗ Dedicated to the memory of Jean-Pierre Caruelle.
ABSTRACT