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Cell. 2018 Jan 11;172(1-2):191-204.e10. doi: 10.1016/j.cell.2017.11.003. Epub 2017 Dec 7.

Rapid Mobilization Reveals a Highly Engraftable Hematopoietic Stem Cell.

Author information

1
Harvard Medical School, Cancer Center and Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA 02129, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: hoggatt.jonathan@mgh.harvard.edu.
2
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
3
Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
4
Harvard Medical School, Cancer Center and Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA 02129, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
5
Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Biomedical Informatics, Harvard Medical School, Boston, MA 02115, USA.
6
Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
7
Department of Statistical Sciences, GlaxoSmithKline, Collegeville, PA 19426, USA; GlaxoSmithKline, Collegeville, PA 19426, USA.
8
GlaxoSmithKline, Collegeville, PA 19426, USA.
9
Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. Electronic address: david_scadden@harvard.edu.
10
Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: lpelus@iupui.edu.

Abstract

Hematopoietic stem cell transplantation is a potential curative therapy for malignant and nonmalignant diseases. Improving the efficiency of stem cell collection and the quality of the cells acquired can broaden the donor pool and improve patient outcomes. We developed a rapid stem cell mobilization regimen utilizing a unique CXCR2 agonist, GROβ, and the CXCR4 antagonist AMD3100. A single injection of both agents resulted in stem cell mobilization peaking within 15 min that was equivalent in magnitude to a standard multi-day regimen of granulocyte colony-stimulating factor (G-CSF). Mechanistic studies determined that rapid mobilization results from synergistic signaling on neutrophils, resulting in enhanced MMP-9 release, and unexpectedly revealed genetic polymorphisms in MMP-9 that alter activity. This mobilization regimen results in preferential trafficking of stem cells that demonstrate a higher engraftment efficiency than those mobilized by G-CSF. Our studies suggest a potential new strategy for the rapid collection of an improved hematopoietic graft.

KEYWORDS:

AMD3100; CXCR2; CXCR4; MMP-9; bone marrow transplantation; granulocyte colony-stimulating factor; hematopoiesis; hematopoietic stem cell mobilization; neutrophils; stem cell trafficking

PMID:
29224778
PMCID:
PMC5812290
[Available on 2019-01-11]
DOI:
10.1016/j.cell.2017.11.003

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