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J Clin Invest. 2019 May 14;129(7):2745-2759. doi: 10.1172/JCI124738.

Targeting VLA4 integrin and CXCR2 mobilizes serially repopulating hematopoietic stem cells.

Author information

1
Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
2
Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany.
3
Oakland University William Beaumont School of Medicine, Rochester, Michigan, USA.
4
German Red Cross Blood Service and Institute for Transfusion Medicine and Immunohematology of the Goethe University, Frankfurt, Germany.
5
Genome Technology Access Center, Washington University, St. Louis, Missouri, USA.
6
Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri, USA.
7
Center for World Health and Medicine, Saint Louis University, St. Louis, Missouri, USA.
8
Magenta Therapeutics, Cambridge, Massachusetts, USA.
9
University of Washington, Department of Medicine/Hematology, Seattle, Washington, USA.

Abstract

Mobilized peripheral blood has become the primary source of hematopoietic stem and progenitor cells (HSPCs) for stem cell transplantation, with a five-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 co-administered 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 provided by the VLA4 inhibitor and CXCR2 agonist combination in mice compared to currently approved HSPC mobilization methods, it represents an exciting potential strategy for clinical development in the future.

KEYWORDS:

Bone marrow transplantation; Hematopoietic stem cells; Stem cells; Transplantation

PMID:
31085833
PMCID:
PMC6597242
[Available on 2019-10-01]
DOI:
10.1172/JCI124738
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