Selective Enhancement of Donor Hematopoietic Cell Engraftment by the CXCR4 Antagonist AMD3100 in a Mouse Transplantation Model Yubin Kang 1 , Benny J. Chen2, Divino DeOliveira2, Jeffrey Mito2, Nelson J. Chao2* 1 Divisions of Hematology, Oncology and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America, 2 Division of Cellular Therapy/Adult Bone Marrow Transplantation, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America Abstract The interaction between stromal cell-derived factor-1 (SDF-1) with CXCR4 chemokine receptors plays an important role in hematopoiesis following hematopoietic stem cell transplantation. We examined the efficacy of post transplant administration of a specific CXCR4 antagonist (AMD3100) in improving animal survival and in enhancing donor hematopoietic cell engraftment using a congeneic mouse transplantation model. AMD3100 was administered subcutaneously at 5 mg/kg body weight 3 times a week beginning at day +2 post-transplant. Post-transplant administration of AMD3100 significantly improves animal survival. AMD3100 reduces pro-inflammatory cytokine/chemokine production. Furthermore, post transplant administration of AMD3100 selectively enhances donor cell engraftment and promotes recovery of all donor cell lineages (myeloid cells, T and B lymphocytes, erythrocytes and platelets). This enhancement results from a combined effect of increased marrow niche availability and greater cell division induced by AMD3100. Our studies shed new lights into the biological roles of SDF-1/CXCR4 interaction in hematopoietic stem cell engraftment following transplantation and in transplant-related mortality. Our results indicate that AMD3100 provides a novel approach for enhancing hematological recovery following transplantation, and will likely benefit patients undergoing transplantation. Citation: Kang Y, Chen BJ, DeOliveira D, Mito J, Chao NJ (2010) Selective Enhancement of Donor Hematopoietic Cell Engraftment by the CXCR4 Antagonist AMD3100 in a Mouse Transplantation Model. PLoS ONE 5(6): e11316. doi:10.1371/journal.pone.0011316 Editor: Annarosa Leri, Harvard Medical School, United States of America Received November 20, 2009; Accepted May 27, 2010; Published June 28, 2010 Copyright: 2010 Kang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The study was supported by National Institutes of Health (NIH) grant 1U19 AI067798-01 (PI: NJC) and a research grant from Genzyme Corp (PI: NJC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The study was supported in part by a research grant from Genzyme Corp. There are no competing interests relating to employment, consultancy, or patents. The research support does not alter the authors’ adherence to all the PLoS ONE policies. * E-mail: chao0002@mc.duke.edu Introduction Hematopoietic cell transplantation (HCT) provides a potentially curative treatment approach for a variety of diseases[1]. However, HCT is associated with high incidence of morbidity and mortality. Reducing transplant-related mortality and facilitating donor cell engraftment are very important goals in HCT. Recombinant granulocyte colony stimulating factor (G-CSF) is commonly used to accelerate neutrophil recovery following HCT[2]; its effects are limited to myeloid cells[3]. Hematopoietic stem cell (HSC) niche is a specific site in the marrow cavity where HSCs reside and undergo self-renewal, proliferation and differentiation[4]. HSC niche consists of supporting cells such as osteoblasts and other stromal cells that provide a microenvironment for HSCs, as well as molecules produced by these cells. At least two types of HSC niches have been identified in the bone marrow: osteoblastic/endosteal niche and vascular endothelial niche[5,6]. The osteoblastic/endosteal niche is thought to be the primary site for very primitive, quiescent HSCs; while the vascular endothelial niche is the predominant site for activated HSCs that are on their way to be released into circulation. The detailed structure and the roles of these 2 niches in hematopoiesis remain to be elucidated[7]. Following HCT, donor HSCs home to the marrow niches (mainly osteoblastic niche), engraft, proliferate, and eventually reconstitute the whole hematological and immunological reper- toire of the recipient. HSC engraftment is limited by the availability of niches during and after transplant when HSCs still survive. Increasing the number of ‘‘unoccupied’’ marrow niches enhances transplant efficiency[8,9,10]. The proliferative status of HSCs also affects their ‘‘transplantability’’ and engraftment. Some studies suggest that dividing HSCs are more efficient than resting HSCs in engraft[11] and in vivo proliferation of HSCs is crucial to hematological recovery following transplantation[12,13], while others found that prolif- erating HSCs displayed engraftment defect when transiting S/ G2/M phase[14,15]. An array of chemokines, growth factors, cell-surface and adhesion molecules are required to function in concert for HSCs to home to the niches and to engraft following HCT. In particular, the interaction of stromal cell-derived factor-1 (SDF-1, CXCL-12) in the marrow matrix with the CXCR4 chemokine receptor on HSCs plays a critical role in all aspects of donor cell reconstitution including HSC homing[16,17,18], engraftment[9] and proliferation[14,19,20]. SDF-1 is secreted by endothelial cells, osteoblasts and other stromal cells, and is present in marrow PLoS ONE | www.plosone.org 1 June 2010 | Volume 5 | Issue 6 | e11316