Rapid Mobilization Reveals a Highly Engraftable Hematopoietic Stem Cell

doi:10.1016/j.cell.2017.11.003

. 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

Jonathan Hoggatt¹, Pratibha Singh², Tiffany A Tate³, Bin-Kuan Chou⁴, Shruti R Datari⁴, Seiji Fukuda², Liqiong Liu², Peter V Kharchenko⁵, Amir Schajnovitz⁶, Ninib Baryawno⁶, Francois E Mercier⁶, Joseph Boyer⁷, Jason Gardner⁸, Dwight M Morrow⁸, David T Scadden⁹, Louis M Pelus¹⁰

Affiliations

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.

PMID: 29224778
PMCID: PMC5812290
DOI: 10.1016/j.cell.2017.11.003

Rapid Mobilization Reveals a Highly Engraftable Hematopoietic Stem Cell

Jonathan Hoggatt et al. Cell. 2018.

. 2018 Jan 11;172(1-2):191-204.e10.

doi: 10.1016/j.cell.2017.11.003. Epub 2017 Dec 7.

Authors

Affiliations

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.

PMID: 29224778
PMCID: PMC5812290
DOI: 10.1016/j.cell.2017.11.003

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.

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Figures

**Figure 1. Peripheral blood CD34+ cells in a single blind, placebo controlled tolerability study**
(A) CD34+ cells in PB following IV infusion of GROβ (N=12 subjects). Each subject received a matched placebo administration in a prior session at least 4 weeks prior to GROβ administration (grey bar; mean±SEM). P=0.001 by ANOVA. (B) Individual maximal CD34+ cell counts after placebo or GROβ infusion. P=0.0014 by Students t-test.

**Figure 2. Timing and kinetics of single and combination mobilization in mice by GROβ and AMD3100**
(A) Mean±SEM CFU-GM/ml blood mobilized at: 15 min post GROβ; 60 min post AMD3100; or 60 min post injection of AMD3100, with GROβ injected 15 min before blood harvest (45 min post AMD3100). * P<0.001 compared to control; ^† P<0.001 compared to AMD3100; ns = not significant, ANOVA. (B) Mean ± SEM CFU-GM/ml blood at 15 min post GROβ; 15 and 60 min post AMD3100; and at 15, 30, 60 and 120 min post administration of GROβ+AMD3100. # P<0.05 compared to control; * P<0.001 compared to control; ^† P<0.001 compared to AMD3100; ^§ P<0.001 compared to GROβ; ns = not significant, ANOVA. (C) Mean ± SEM CFU-GM/ml blood at 15 min post GROβ, 60 min post AMD3100; and 15 min post GROβ+AMD3100, compared to mice treated with G-CSF *bid*, for 4 days. ^# P<0.05 compared to control; * P<0.001 compared to control; ^† P<0.001 compared to AMD3100; ^§ P<0.001 compared to GROβ; ns = not significant vs. GROβ or G-CSF, ANOVA.

**Figure 3. Combination treatment with GROβ+AMD3100 increases MMP-9 release**
(A) Representative zymogram and combined relative intensities of gelatinolytic activity in plasma from Balb/c mice collected at 60 min post AMD3100; 15 min post GROβ; and 15 min post GROβ+AMD3100. Mean ± SEM from n = 8–12 mice from 2–3 experiments. * P<0.001 compared to control; ANOVA. (B) MMP-9 and (C) TIMP-1 ELISA of mouse plasma collected at 60 min post AMD3100; 15 min post GROβ; and 15 min post combination. (D) The molar ratio of proMMP-9/TIMP-1. Data are expressed as Mean±SEM of 4–6 Balb/c mice/group, in 1–2 experiments. * P<0.001 vs. control or AMD3100; ^† P<0.001 vs. GROβ or AMD3100; ns = not significant; ANOVA. (E) Molar ratio of proMMP-9/TIMP-1 and (F) CFU-GM in blood assessed at various time points after administration of AMD3100 and GROβ alone or in combination. Mean±SEM from n=4 Balb/c mice/group/time point. * P<0.01 vs. GROβ or AMD3100; ANOVA. (G) Spearman’s rank correlation between CFU-GM mobilized to blood and proMMP-9/TIMP-1 molar ratio after (left) GROβ or (right) GROβ+AMD3100 treatment. Each symbol represents a single mouse.

**Figure 4. Crosstalk between CXCR4 and CXCR2 receptors on neutrophils enables MMP-9 release and hematopoietic mobilization**
(A) Potential interaction of CXCR4 and CXCR2 signaling in neutrophils leading to MMP-9 release and hematopoietic mobilization. (B–F) Mice were treated with GROβ, AMD3100 or combined administration as indicated. Blood was collected at 15 min post injection and CFU-GM determined. (B) Control IgG vs. anti-GR1 antibody treatment. Mean±SEM from n=6 mice/group/2expts. (C) Wild-type and conditional CXCR4 knockout mice. Mean±SEM from n=8 mice/group/2expts. (D) CXCR2 wild-type and knockout mice. Mean±SEM from n=8 mice/group/2expts. (E) MMP-9 wild-type and knockout mice. Mean±SEM from n=8 mice/group/2expts. (F) Control IgG or anti-MMP-9 antibody to block MMP-9 activity. Data are Mean±SEM from n=4 mice/group. In each graph, * P< 0.05, ^† P<0.01, ^‡ P<0.001 for GROβ or GROβ+AMD3100 compared to the same groups in control or wild-type mice; ANOVA.

**Figure 5. CXCR4 and CXCR2 signaling in human neutrophils**
(A) Calcium mobilization in human neutrophils stimulated with SDF-1, GROβ (left), or AMD3100 prior to stimulation by SDF-1 and GROβ (right). One of 6 expts. using 4 different donors. (B) Gelatinolytic activity in supernates of human peripheral blood neutrophils stimulated with PTX and/or Mastoparan prior to addition of mobilizing agents. Results are representative of 3 independent expts. using 3 different donors. (C) Pro-MMP-9 and TIMP-1 in supernates described in (B) were determined by ELISA and molar ratio of MMP-9/TIMP-1 calculated. Mean±SEM of ELISA measurements of triplicate samples from each of 3 donors. * P<0.001 vs. PBS; ^† P<0.001 vs. GROβ, ANOVA. (D) Gelatinolytic activity in supernates from neutrophils stimulated with GROβ, CTX or incubated with CTX for 15 min prior to stimulation with GROβ. Results are representative of 3 independent experiments using 3 different donors. (E) Pro-MMP-9 and TIMP-1 in supernates described in (D) were determined by ELISA. Mean±SEM of triplicate samples from each of 3 donors. * P<0.001 vs. PBS; ^† P<0.001 vs. GROβ; ANOVA. (F–K) Human PB neutrophils were incubated with the indicated intracellular signaling inhibitors for 15 min followed by stimulation with vehicle, GROβ or AMD3100 alone or in combination for 30 min. Cell free supernates were collected and MMP-9 and TIMP-1 determined by ELISA. Data represent Mean±SEM of quadruplicate cultures for each group. Each experiment was performed using freshly isolated neutrophils from a single donor, with 3 independent donors. * P< 0.05, ^† P<0.01, ^‡ P<0.001 vs. control. In each graph, GROβ+AMD3100 was compared to GROβ alone at each concentration of inhibitor and P values shown over brackets; ANOVA.

**Figure 6. Strain differences in MMP-9 activity alter mobilization response**
(A) Fold change in CFU-GM/ml blood at 15 min post GROβ; 60 min post AMD3100; and 15 min post GROβ+AMD3100, compared to PBS, in C57Bl/6, BDF1 and DBA/2 mice. Mean±SEM of N=4 mice/group; ANOVA. (B) Representative zymogram of gelatinolytic activity in plasma isolated from mice collected at 15 min post vehicle (V) or GROβ (G); 60 min post AMD3100 (A) and 15 min post GROβ+AMD3100. (C) CFU-GM/ml blood mobilized over control. Mean ± SEM of N=4 mice/group. * P<0.05, ^† P<0.01; ANOVA. (D) CFU-GM/ml blood in BDF1 chimeric mice transplanted with C57Bl/6, BDF1 or DBA/2 bone marrow and treated with GROβ or AMD3100 alone and in combination at 2 months post-transplant. Mean±SEM of N=4 mice/group. * P<0.05, ^† P<0.01; ANOVA. (E) Nucleotide sequence and amino acid differences in the hemoxpexin domain of the MMP-9 gene from C57Bl/6 and DBA/2 mice. (F) Recovery of C57Bl/6 or DBA/2 MMP-9 from TIMP-1 sepharose beads after elution with acetic acid. MMP-9 was measured by ELISA. Mean±SEM of quadruplicate samples/group assayed in duplicate from one of three identical experiments. Statistical analysis by Student’s T-test. (G) Study design for transplant and transduction study in panels (H) and (I). (H) CFU-GM/ml blood mobilized over control in MMP-9 knockout mice and wild-type C57Bl/6 and DBA/2 mice. Mean±SEM of N=4 mice/group. * P<0.05, ^† P<0.01, ^‡ P<0.001 compared to PBS or GROβ; ANOVA. (I) CFU-GM/ml blood mobilized over control in MMP-9 knockout mice transplanted with 2000 LSK cells transduced with DBA or C57 MMP-9 transgenes or a scrambled sequence. Mean±SEM of N=5 mice/group. * P<0.05, ^† P<0.01, ^‡ P<0.001 compared to PBS or GROβ; ANOVA. (J) Representative intra-vital snapshots of mouse calvaria vasculature immediately following injection of rhodamine dextran (left panels) and then 2 min later (right panels) in mice previously treated with vehicle control (top panels) or GROβ+AMD3100 (bottom panels) 5 min prior to rhodamine dextran administration (see supplemental videos 1 and 2). (K) Representative intensity of rhodamine dextran signal outside of calvaria bone marrow vessels in mice treated with GROβ, AMD3100, GROβ+AMD3100, or mice treated with anti-MMP-9 antibody prior to administration of GROβ+AMD3100. Representative data from 2–5 mice/treatment group.

**Figure 7. GROβ+AMD3100 mobilizes a hematopoietic graft with enhanced engrafting capacity**
(A) Neutrophil and (B) platelet recovery in mice transplanted with PBMC from mice mobilized by G-CSF or GROβ+AMD3100. Mean±SEM of N=5 mice/group/time point, n=10 mice total/group. (C) PB chimerism at 24 weeks post-transplantation in BoyJ mice transplanted competitively with G-CSF or GROβ+AMD3100 mobilized PBMC from C57Bl/6 mice with congenic Boy/J whole bone marrow competitors. Mean±SEM of N=11 mice/group/2expts. Statistical analysis by Student’s T-test. (D) Secondary transplantation chimerism at 24 weeks in BoyJ mice transplanted with whole bone marrow from primary recipients described in (C) taken at 24 weeks post primary transplant. Mean±SEM of N=4 primary recipient mice/group each transplanted into duplicate secondary recipients (N=8 recipients/group), with each secondary recipient assayed individually. Statistical analysis by Student’s T-test. (E) Representative LSK and SLAM-LSK frequency analysis of lineage negative PBMC from mice mobilized by G-CSF or GROβ+AMD3100. (F) Percentage of LSK and (G) SLAM-LSK cells in peripheral blood of mobilized mice. Mean±SEM of N=13 mice from 3 independent experiments, each mouse assayed individually. Statistical analysis by Student’s T-test. (H) PB chimerism at 16, 24 or 36 weeks in BoyJ mice transplanted with 195 (Exp 1), 50 (Exp 2) or 100 (Exp 3) FACS sorted SLAM-LSK cells from PB of C57Bl/6 mice mobilized by G-CSF or GROβ+AMD3100. PB SLAM-LSK cells from GROβ+AMD3100 treated donors resulted in a 2-fold increase in competitiveness (P<0.0004). (I) Tri-lineage reconstitution in mice from (H) Exp 2; N=8 and (J) in mice from Exp 3; N=6 mice. Mean±SEM, each assayed individually. (K) SLAM LSK cells were sorted from GROβ+AMD3100 or G-CSF treated mice as performed in panel (H), and total RNA was isolated. GSEA was conducted based on the log2 fold expression ratio between GROβ+AMD3100 and G-CSF stem cells. Gene sets were taken based on data from (Ivanova et al., 2002) selecting 300 most up-regulated based on comparison of FLSca+ and BMR^h°^l°^w samples. Statistical significance was determined based on one million randomizations.

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References

1. Broxmeyer HE, Orschell CM, Clapp DW, Hangoc G, Cooper S, Plett PA, Liles WC, Li X, Graham-Evans B, Campbell TB, et al. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med. 2005;201:1307–1318. - PMC - PubMed
1. Cha H, Kopetzki E, Huber R, Lanzendorfer M, Brandstetter H. Structural basis of the adaptive molecular recognition by MMP9. J Mol Biol. 2002;320:1065–1079. - PubMed
1. Cotignola J, Reva B, Mitra N, Ishill N, Chuai S, Patel A, Shah S, Vanderbeek G, Coit D, Busam K, et al. Matrix Metalloproteinase-9 (MMP-9) polymorphisms in patients with cutaneous malignant melanoma. BMC Med Genet. 2007;8:10. - PMC - PubMed
1. D’Souza A, Lee S, Zhu X, Pasquini M. Current Use and Trends in Hematopoietic Cell Transplantation in the United States. Biol Blood Marrow Transplant 2017 - PMC - PubMed
1. Devine SM, Vij R, Rettig M, Todt L, McGlauchlen K, Fisher N, Devine H, Link DC, Calandra G, Bridger G, et al. Rapid mobilization of functional donor hematopoietic cells without G-CSF using AMD3100, an antagonist of the CXCR4/SDF-1 interaction. Blood. 2008;112:990–998. - PubMed

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[1] Broxmeyer HE, Orschell CM, Clapp DW, Hangoc G, Cooper S, Plett PA, Liles WC, Li X, Graham-Evans B, Campbell TB, et al. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med. 2005;201:1307–1318. - PMC - PubMed

[2] Broxmeyer HE, Orschell CM, Clapp DW, Hangoc G, Cooper S, Plett PA, Liles WC, Li X, Graham-Evans B, Campbell TB, et al. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med. 2005;201:1307–1318. - PMC - PubMed

[3] Cha H, Kopetzki E, Huber R, Lanzendorfer M, Brandstetter H. Structural basis of the adaptive molecular recognition by MMP9. J Mol Biol. 2002;320:1065–1079. - PubMed

[4] Cha H, Kopetzki E, Huber R, Lanzendorfer M, Brandstetter H. Structural basis of the adaptive molecular recognition by MMP9. J Mol Biol. 2002;320:1065–1079. - PubMed

[5] Cotignola J, Reva B, Mitra N, Ishill N, Chuai S, Patel A, Shah S, Vanderbeek G, Coit D, Busam K, et al. Matrix Metalloproteinase-9 (MMP-9) polymorphisms in patients with cutaneous malignant melanoma. BMC Med Genet. 2007;8:10. - PMC - PubMed

[6] Cotignola J, Reva B, Mitra N, Ishill N, Chuai S, Patel A, Shah S, Vanderbeek G, Coit D, Busam K, et al. Matrix Metalloproteinase-9 (MMP-9) polymorphisms in patients with cutaneous malignant melanoma. BMC Med Genet. 2007;8:10. - PMC - PubMed

[7] D’Souza A, Lee S, Zhu X, Pasquini M. Current Use and Trends in Hematopoietic Cell Transplantation in the United States. Biol Blood Marrow Transplant 2017 - PMC - PubMed

[8] D’Souza A, Lee S, Zhu X, Pasquini M. Current Use and Trends in Hematopoietic Cell Transplantation in the United States. Biol Blood Marrow Transplant 2017 - PMC - PubMed

[9] Devine SM, Vij R, Rettig M, Todt L, McGlauchlen K, Fisher N, Devine H, Link DC, Calandra G, Bridger G, et al. Rapid mobilization of functional donor hematopoietic cells without G-CSF using AMD3100, an antagonist of the CXCR4/SDF-1 interaction. Blood. 2008;112:990–998. - PubMed

[10] Devine SM, Vij R, Rettig M, Todt L, McGlauchlen K, Fisher N, Devine H, Link DC, Calandra G, Bridger G, et al. Rapid mobilization of functional donor hematopoietic cells without G-CSF using AMD3100, an antagonist of the CXCR4/SDF-1 interaction. Blood. 2008;112:990–998. - PubMed

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Rapid Mobilization Reveals a Highly Engraftable Hematopoietic Stem Cell

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Rapid Mobilization Reveals a Highly Engraftable Hematopoietic Stem Cell

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