Targeting VLA4 integrin and CXCR2 mobilizes serially repopulating hematopoietic stem cells
| Autor: | Leah Gehrs, Dwight M. Morrow, David W. Griggs, Stephanie Christ, Andreas Trumpp, Richard F. Heier, Eliza Wiercinska, Halvard Bonig, Moses O. Evbuomwan, Darja Karpova, Peter G. Ruminski, Julie Ritchey, Michael P. Rettig, Feng Gao, Daniel Cancilla, Ezhilarasi Chendamarai, Michael J. Prinsen, Hamza Celik, Grazia Abou-Ezzi, Daniel C. Link, John F. DiPersio, Marvin J. Meyers, Wei Yang, Stacy D. Arnett, Jingzhu Zhang, Matthew Holt, Linda Eissenberg |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
CXCR4 Inhibitor medicine.medical_treatment Hematopoietic stem cell transplantation Integrin alpha4beta1 Biology Receptors Interleukin-8B Mice 03 medical and health sciences 0302 clinical medicine Bone Marrow medicine Animals Progenitor cell Mice Knockout Mice Inbred BALB C Plerixafor Hematopoietic Stem Cell Transplantation General Medicine Allografts Hematopoietic Stem Cells Hematopoietic Stem Cell Mobilization Granulocyte colony-stimulating factor Transplantation Haematopoiesis 030104 developmental biology 030220 oncology & carcinogenesis Cancer research Stem cell Research Article Granulocytes medicine.drug |
| Zdroj: | Journal of Clinical Investigation. 129:2745-2759 |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci124738 |
| Popis: | Mobilized peripheral blood has become the primary source of hematopoietic stem and progenitor cells (HSPCs) for stem cell transplantation, with a 5-day course of granulocyte colony-stimulating factor (G-CSF) as the most common regimen used for HSPC mobilization. The CXCR4 inhibitor plerixafor is a more rapid mobilizer, yet not potent enough when used as a single agent, thus emphasizing the need for faster acting agents with more predictable mobilization responses and fewer side effects. We sought to improve hematopoietic stem cell transplantation by developing a new mobilization strategy in mice through combined targeting of the chemokine receptor CXCR2 and the very late antigen 4 (VLA4) integrin. Rapid and synergistic mobilization of HSPCs along with an enhanced recruitment of true HSCs was achieved when a CXCR2 agonist was coadministered in conjunction with a VLA4 inhibitor. Mechanistic studies revealed involvement of CXCR2 expressed on BM stroma in addition to stimulation of the receptor on granulocytes in the regulation of HSPC localization and egress. Given the rapid kinetics and potency of HSPC mobilization achieved by the VLA4 inhibitor and CXCR2 agonist combination in mice compared with currently approved HSPC mobilization methods, the combination represents an exciting potential strategy for clinical development in the future. |
| Databáze: | OpenAIRE |
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