Influence of a dual-injection regimen,plerixafor and CXCR4 on in utero hematopoietic stem cell transplantation and engraftment with use of the sheep model |
| |
| Institution: | 1. Department of Agriculture, Nutrition, and Veterinary Science, University of Nevada-Reno, Reno, Nevada, USA;2. Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, USA;3. Carbone Cancer Center, University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA;1. Division of Vascular Medicine, Department of Cardiovascular Medicine, University of Muenster, Muenster, Germany;2. Institute for Transfusion Medicine, University of Duisburg-Essen, Essen, Germany;3. Department of Angiology, University of Duisburg-Essen, Essen, Germany;4. Center of Angiology and Interventional Vascular Medicine, Agaplesion Bethesda Hospital Wuppertal, Germany;5. Department of Angiology, HELIOS Klinik Krefeld, Germany;1. Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada;;2. Department of Medicine, Hematology and Oncology, University of Frankfurt, Frankfurt/Main, Germany;;3. German Cancer Consortium (DKTK), Heidelberg, Germany;;4. German Cancer Research Center (DKFZ), Heidelberg, Germany;;5. Molecular Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada;;6. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada;;7. Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany;;8. Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany;;9. Canada’s Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada;;10. Department of Medicine, University of British Columbia, Vancouver, BC, Canada;;11. Simon Fraser University, Burnaby, BC, Canada;;12. Department of Microbiology and Immunology and Vancouver, BC, Canada;;13. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; and;14. Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada;1. Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA;2. Office of Biostatistics Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA;3. DNA Sequencing and Genomics Core, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA;4. Molecular and Clinical Hematology Branch, National Heart, Lung and Blood Institute/National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA;5. Department of Microbiology, Immunology and Molecular Genetics, David Geffen Schools of Medicine, Los Angeles, California, USA;6. Department of Medicine, University of Wisconsin-Madison, School of Medicine and Public Health, Madison, Wisconsin, USA;1. Division of Vascular Surgery, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, Pa;2. McGowan Institute for Regenerative Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pa;3. Mellon College of Science, Carnegie Mellon University, Pittsburgh, Pa;4. Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pa;5. University of Pittsburgh Cancer Institute, Pittsburgh, Pa |
| |
| Abstract: | Background aimsInadequate engraftment of hematopoietic stem cells (HSCs) after in utero HSC transplantation (IUHSCT) remains a major obstacle for the prenatal correction of numerous hereditary disorders. HSCs express CXCR4 receptors that allow homing and engraftment in response to stromal-derived factor 1 (SDF-1) ligand present in the bone marrow stromal niche. Plerixafor, a mobilization drug, works through the interruption of the CXCR4-SDF-1 axis.MethodsWe used the fetal sheep large-animal model to test our hypotheses that (i) by administering plerixafor in utero before performing IUHSCT to release fetal HSCs and thus vacating recipient HSC niches, (ii) by using human mesenchymal stromal/stem cells (MSCs) to immunomodulate and humanize the fetal BM niches and (iii) by increasing the CXCR4+ fraction of CD34+ HSCs, we could improve engraftment. Human cord blood-derived CD34+ cells and human bone marrow-derived MSCs were used for these studies.ResultsWhen MSCs were transplanted 1 week before CD34+ cells with plerixafor treatment, we observed 2.80% donor hematopoietic engraftment. Combination of this regimen with additional CD34+ cells at the time of MSC infusion increased engraftment levels to 8.77%. Next, increasing the fraction of CXCR4+ cells in the CD34+ population albeit transplanting at a late gestation age was not beneficial. Our results show engraftment of both lymphoid and myeloid lineages.ConclusionsPrior MSC and HSC cotransplantation followed by manipulation of the CXCR4–SDF-1 axis in IUHSCT provides an innovative conceptual approach for conferring competitive advantage to donor HSCs. Our novel approach could provide a clinically relevant approach for enhancing engraftment early in the fetus. |
| |
| Keywords: | hematopoietic stem cell transplantation in utero transplantation CXCR4 SDF-1 plerixafor sheep model |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
