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Abstract

Hematopoietic stem cell (HSC) transplantation can be a potential cure for hematological malignancies and some nonhematologic diseases. Hematopoietic stem and progenitor cells (HSPCs) collected from peripheral blood after mobilization are the primary source to provide HSC transplantation. In most of the cases, mobilization by the cytokine granulocyte colony-stimulating factor with chemotherapy, and in some settings, with the CXC chemokine receptor type 4 antagonist plerixafor, can achieve high yield of hematopoietic progenitor cells (HPCs). However, adequate mobilization is not always successful in a significant portion of donors. Research is going on to find new agents or strategies to increase HSC mobilization. Here, we briefly review the history of HSC transplantation, current mobilization regimens, some of the novel agents that are under investigation for clinical practice, and our recent findings from animal studies regarding Notch and ligand interaction as potential targets for HSPC mobilization.

Keywords

hematopoietic stem cell transplantation mobilization G-CSF plerixafor Notch2 blockade

Introduction

E. Donnall Thomas was a pioneer in applying experience from animal bone marrow (BM) transplantation on leukemic patients. In 1959, he and his colleagues reported 3-month remission in a patient with total body irradiation followed by infusion of identical twin’s marrow¹. Though Thomas’ finding was exciting, it was limited to isologous marrow infusion. In 1960, however, allogeneic transplantation was accomplished after human leukocyte antigen (HLA), the major histocompatibility complex, was discovered. An immunodeficient patient received marrow transplantation from an HLA-matched sibling without rejecting the allograft². A decade later, after Thomas’ success, he and his colleagues cured some patients with end-stage acute leukemia by using a combination of chemotherapy, that is, cyclophosphamide (CY), with total body irradiation, followed by BM infusion from HLA-identical siblings³. Furthermore, the ability of donor lymphocyte to eliminate the tumor cells that have survived after ablative therapy was found to contribute to the reduction in the incidence of leukemic relapse after allograft transplantation. However, these lymphocytes may also contribute to a phenomenon called graft-versus-host disease⁴.

At the same time, other animal experiments discovered that nonleukemic blood cells egress from BM to peripheral blood system giving rise to mature blood cells and compensating damaged BM to maintain hematopoietic homeostasis^5,6. These hematopoietic cells act as substitute sources to BM progenitor cells. However, Lewis and colleagues in 1968 suggested that due to the low frequency of the repopulating peripheral blood leukocytes (estimated to be 1/100th that of marrow), grafting would not be accomplished using these cells for transplantation⁷. Fortuitously, around the same time, a continuous flow centrifuge (apheresis) machine was developed to improve harvesting enough peripheral repopulating units for transplantation in patients with chronic myelocytic leukemia^8,9. Nevertheless, several subsequent attempts to transfuse peripheral white blood cells among identical twins did not give a plausible engraftment result^8,10. Putatively, the reason for the failure was due to the insufficient number of hematopoietic stem and progenitor cells (HSPCs) present in the peripheral blood compared to those in the BM.

Cryopreservation technique was developed in the 1970s and was found effective in preserving the hematopoietic stem cells (HSCs) from the peripheral blood¹¹. Years later, using cryopreserved cells obtained from multiple rounds of apheresis before the transplantation resulted in successful hematopoietic engraftment^12

–16. Despite many successes of cryopreserved HSPC infusion, harvesting a sufficient number of peripheral blood stem cells (PBSCs) for multiple rounds over a long time of collection was not feasible. However, the subsequent introduction of the course of CY and adriamycin chemotherapy resulted in ∼20-fold increase of PBSC yield, suggesting that chemotherapy could enhance PBSCs mobilization^17,18.

In this review, we will first address the current HSPC-mobilizing agents, including chemotherapy, granulocyte colony-stimulating factor (G-CSF), and plerixafor, and other reagents that are still being investigated at various stages but not yet applied clinically. We will then discuss our recent animal research findings demonstrating the enhanced potential of HSPC egress and mobilization by blocking Notch or Notch ligands.

G-CSF and Chemotherapy

The clinically approved growth factor G-CSF has been widely used to mobilize both HSC and hematopoietic progenitor cell (HPC) for transplantation. G-CSF is a cytokine that promotes granulocyte proliferation and differentiation and enhances mobilization through direct or indirect protease activation. After G-CSF administration, neutrophil releases neutrophil elastase, cathepsin, and matrix metalloproteinase-9 (MMP-9), and the cell surface protease dipeptidyl peptidase 4 (DPP-4, cluster of differentiation (CD) 26) cleaves the adhesion molecules on HSPCs. These molecules, including stromal cell-derived factor 1 (SDF-1)/CXC chemokine receptor type 4 (CXCR4), stem cell factor (SCF; also called c-kit), and vascular cell adhesion molecule-1 (VCAM-1)/ very late antigen-4 (VLA-4), are responsible for HSCs retention in the BM^19

–23. In addition, G-CSF indirectly inhibits osteoblast (OB) activity and reduces SDF-1 (also called CXCL12) expression that enhances HSPC mobilization²⁴. Administration of G-CSF benefits both autologous and allogeneic mobilization, increases engraftment rate, and reduces hospitalization length and cost^25

–28. The minimum target dose (≥2 × 10⁶ CD34⁺ cells per kg weight) could be successfully achieved by 5–10 μg/kg of G-CSF per day for 5–7 days with one or more days of apheresis. However, a study led by Mayo Clinic demonstrated less than optimum mobilization in two groups of patients: non-Hodgkin lymphoma (71%) and multiple myeloma (30%)²⁹. In autologous stem cell transplantation, chemotherapy is commonly used along with G-CSF to reduce the tumor burden, to enhance mobilization as well as to decrease the apheresis sessions and transfusion volumes. In myeloma patients, an intermediate dose of CY effectively mobilized HSPC³⁰. On the other hand, in lymphoma patients, combination chemotherapies include G-CSF with CY, etoposide, dexamethasone, high-dose cytarabine, cisplatin (DHAP), and other chemotherapy regimens^31

–35 are often required for effective mobilization. Therefore, new agents with improved ability to increase stem cell yield and to reduce the number of apheresis sessions are required, particularly for those heavily pretreated patients.

Plerixafor

Plerixafor, or Mozobil (AMD3100), is the antagonist of CXCR4. AMD3100 prevents CXCR4 on HSCs from interacting with SDF-1 on BM stroma^36
–38. BM OB, mesenchymal stem cells, and CXCL12-abundant reticular cells secrete SDF-1 to maintain HSC retention³⁹, and disrupting this interaction between CXCR4 and SDF-1 leads to the mobilization of HSPCs to the periphery. AMD3100 administration not only blocks CXCR4, but also induces activation of MMP-9 and serine protease urokinase-type plasminogen activator^40,41. Currently, plerixafor is clinically approved to use alone or in combination with G-CSF to mobilize HSPC in heavily pretreated lymphoma and myeloma patients^42

–47. Although plerixafor is successful in increasing optimal CD34⁺ yield, decreasing mobilization failure, and reducing the number of apheresis sessions, its universal use is limited by its expensive cost^48

–53.

Other Mobilizing Agents

Studies in mice have shown that two main axes are targeted directly or indirectly by most mobilizing agents, CXCR4 and the integrin VLA-4 signaling, or both⁵⁴. Integrins are a family of proteins implicated in HSPC mobilization. Integrin adhesion receptors such as VLA-4 found on HSCs tether with VCAM-1 within the BM stroma^55
–57. Indeed administration of anti-VLA-4 led to the mobilization of HSPC to the peripheral blood^58,59.

While some agents, like G-CSF, target both pathways directly or indirectly, some only affect one adhesion molecule. An example of an approach that affects both CXCR4 and VLA-4 signaling is parathyroid hormone, which increases the secretion of G-CSF. In turn, this results in an increase in peripheral circulating HSC by 1.5- to 9.8-folds in mice⁶⁰, and in a phase I clinical trial study, it induced adequate mobilization in 40%–47% of patients who have failed prior mobilization for autologous stem cell transplantation⁶¹. Sphingosine-1-phosphate (S1P), an agent mainly targeting the CXCR4 signaling, is a bioactive lipid mediator mainly found in red blood cells and acts as a ligand to G-protein-coupled S1P receptors. A high concentration of plasma S1P creates a gradient and egresses HSPC^62

–65. Furthermore, during mobilization, HSPC egress is further mediated by the S1P gradient increase in peripheral blood as a result of erythrocyte lysis by the complement cascade and the membrane attack complex activation^66,67. An alternative adhesion molecule target exists for proteasome inhibitors, such as bortezomib, which affects angiopoietin levels. Bortezomib successfully stimulated HSC mobilization in 85% of multiple myeloma patients receiving a bortezomib-based induction regimen⁶⁸. Other agents or approaches that are currently undergoing investigation include cytokines, chemokines, chemokine receptor antagonists, bacterial toxins, proteases, inhibitors of adhesive cell interactions, ephrinA3 receptor antagonists, polymeric sugar molecules, prostaglandin inhibitors, blockade of heparan sulfate, Nlrp3 inflammasome activation, and stabilization of hypoxia-inducible factor-1α, among others⁵⁴. Table 1 summarizes various agents that have been used in mice and their target adhesion molecules.

Table 1.

Mobilizing Agents (Not Including G-CSF and Plerixafor) and Their Target Adhesion Molecules.

General class	Agent	Target adhesion molecule (direct or indirect)
Cytokines and chemokine	Stem cell factor^69 –71	CXCR4 and VLA-4
	FLT3 ligand^72,73	CXCR4 and VLA-4
	Thrombopoietin⁷⁴	Mpl
	Angiopoietin^75,76	Angiopoietin
	Vascular endothelial growth factor^76,77	VEGFR2
	IL-1⁷⁸, IL-3⁷⁹, IL-6⁸⁰, IL-7⁸¹, IL-12⁸², IL-17⁸³, and IL-33⁸⁴	Various
	CXCL12 and analogs⁸⁵	CXCR4
	Gro-α⁸⁶	CXCR2
	Gro-β^86,87	CXCR2
	Gro-γ⁸⁶	CXCR2
	IL-8^88,89	Unknown
Chemokine receptor antagonists	Inhibitors of the small Rho GTPase Rac1 inhibitors^90,91	CXCR4
Bioactive lipids	Sphingosine-1 phosphate⁹²	CXCR4
Bioactive lipids	Ceramide-1 phosphate⁹²	Unknown
Bacterial toxins⁹³	Lipopolysaccharide⁹⁴	CXCR4
Bacterial toxins⁹³	Pertussis toxin⁹⁵	CXCR4
Proteases	Trypsin⁹⁶	CXCR4
	Matrix metalloprotease 9⁹⁷	CXCR4
	CD26⁹⁸	CXCL12
	Cathepsin G⁹⁹	CXCR4
	Neutrophil elastase⁹⁹	CXCR4
Inhibitors of adhesive cell interactions⁵⁹	VLA-4^100,101	VLA-4
	VLA-4/VLA-9 inhibitors¹⁰²	VLA-4
	VCAM-1¹⁰³	VLA-4
	CD44 blockers¹⁰⁴	CD44v10
Polymeric sugar molecules	Dextran¹⁰⁵	Likely CXCR4
	Fucoidan¹⁰⁶	CXCL12 (SDF-1)
	Betafectin PGG-glucan¹⁰⁷	Unknown
	Glycosaminoglycan mimetics¹⁰⁸	CXCL12 (SDF-1)
Others	Defibrotide¹⁰⁹	Endothelial adhesion molecules
	Prostaglandin inhibitors¹¹⁰	Osteopontin
	Proteasome inhibitors (Bortezomib)¹¹¹	CXCL12, angiopoietin, etc.
	Parathyroid hormone⁶⁰	CXCR4 and VLA-4
	Blockade of heparan sulfate¹¹²	VLA-4
	Stabilization of hypoxia-inducible factor-1α¹¹³	CXCR4
	Ephrin A3 receptor antagonists¹¹⁴	VLA-4
	Activation of Nlrp3 inflammasome¹¹⁵	Nlrp3
	Notch2 blockade¹¹⁶	Notch2 and CXCR4

CD: cluster of differentiation; CXCR: CXC chemokine receptor type; CXCL12: C-X-C motif chemokine 12; FLT3: fms like tyrosine kinase 3; G-CSF: granulocyte colony-stimulating factor; IL: interleukin; PGG-glucan: Poly-[1-6]--D-glucopyranosyl-[1-3]--D-glucopyranose glucan; SDF-1: stromal cell-derived factor; VCAM-1: vascular cell adhesion molecule; VEGFR2: vascular endothelial growth factor receptor 2; VLA: very late antigen.

Systemic Factors

Several factors affect HPSC mobilization on the systemic level. These include cortisol level, the time of day, stress, exercise, trauma, infection and inflammation, elements in coagulation and complement cascades, and signals from the sympathetic and central nervous systems⁵⁴. These factors may contribute to the overall stem cell collection during apheresis procedures.

Notch2 and Notch Ligand Blockade

Notch signaling plays a critical role in multiple pathways that control cell fate determination, such as embryogenesis, neurogenesis^117

–120, angiogenesis¹²¹, cardiogenesis¹²², and hematopoiesis¹²³. In hematopoiesis, this signaling not only regulates lymphopoiesis but also regulates myelopoiesis^124,125. Notch pathway alterations play critical roles in several cancer types and particularly in hematologic malignancies. Therefore, it is a desirable target in these neoplasms. However, inhibiting a downstream enzyme, the gamma-secretase, in this pathway, has not been successful due to side effects from global inhibition of wild-type Notch proteins. On the other hand, targeting specific Notch proteins, for example, Notch1 or Notch2, may still be promising¹²⁶. An essential feature of Notch is its adhesive nature, which was first described by cell aggregation assays in Drosophila ^127,128. However, the precise role and the biological significance of Notch receptors and ligands as adhesion and signaling molecules in HSC biology, particularly in the context of HSC cell therapy, have not been well defined. Here we will report our recent findings suggesting that Notch2 and its interaction with Notch ligand may serve as potential effective HSPC-mobilizing targets.

In mammals, the canonical Notch signaling pathway is initiated by binding interactions between the extracellular domain of a Notch family member (Notch1–4) on a receiving cell and a Notch ligand of the Jagged (Jagged 1 and 2) or Delta-like (DLL1, 3, and 4) families on a sending cell¹²⁹. It is generally accepted that ligand binding initiates ligand endocytosis and successive proteolytic cleavages, which culminate in the release of the intracellular domain of Notch and the formation of a large transcriptional activation complex leading to the activation of downstream targets of Notch signaling^130,131. Despite in vitro evidence that activation of Notch stimulates HSC self-renewal^132

–135, the in vivo function of Notch in HSC is still debatable. Conditional deletion of Notch receptors, ligands, or Notch canonical targets does not appear to affect HSC steady-state homeostasis^136,137. In contrast, Notch2 was found responsible for the rate of generation of repopulating stem cells during stress hematopoiesis and the early phase of hematopoietic recovery¹³⁸. Also, Jagged1 expressed by BM endothelial cells regulates homeostasis and regenerative hematopoiesis, while DLL4 expressed by osteocalcin-expressing bone cells is responsible for generating early thymus progenitors^139,140.

We and others found that Notch2 is the primary Notch receptor expressed on HSCs and nonlymphoid committed progenitors. In comparison, Notch1 expression level is low on HSC cells but high on lymphoid progenitors^141,142. Notch transactivation is the result of the engagement of Notch receptors with Notch ligands. This process is dependent on posttranslational modification of Notch receptors with O-glucose and O-fucose, added to serine in the consensus C¹-X-S-X-(P/A)-C² or to serine or threonine residue in the consensus sequence C²-X-X-X-X-(S/T)-C³ ^143
–145, by protein O-glucosyltransferase 1 (Poglut) or protein O-fucosyltransferase 1 (Pofut1), respectively, on the epidermal growth factor (EGF) modules of Notch extracellular domain^146

–149. O-Fucose, but not O-glucose, enhances Notch affinity for Jagged or Delta-like ligands and regulates Notch signaling transactivation^{147,150
–152}. This notion is supported by crystal structural determinations showing that O-fucose attached to the Thr residue of Notch1 EGF-like repeat acts as a surrogate amino acid to make functional contact with a specific domain on DLL4 (contact Notch1 EGF12) and Jagged1 (contact Notch1 EGF8 and 12), and thus directly affects Notch ligand binding^153,154. Elongation of O-fucose to a disaccharide (GlcNAc-fucose) on EGF12 by any of three Fringe enzymes (N-acetyl-glucosaminyltransferase)-Lunic fringe (Lfng), Manic fringe (Mfng), or Radical fringe (Rfng) further increases Notch1 binding affinity to Jagged1 and DLL1 and affects Notch activity in slightly different ways^{145,155

–158}.

To understand the role of Notch O-fucose glycan modification in its adhesive interaction with Notch ligand in the marrow HSC compartment, we studied mice with Pofut1 deletion, and thus O-fucose deficiency^125,141,159. These mice developed increased HSC cycling and increased HSPC egress from the marrow manifested as neutrophilia along with an increase in circulating myeloid progenitors. The altered homeostasis of O-fucose-deficient HSC is accompanied by the more distal locations of Lin^–c-kit⁺Sca-1⁺ (LSK) cells relative to the endosteum and the OBs when compared to control HSCs¹⁵⁹. The increased cell-autonomous HSC cycling and egress are primarily accounted for by a loss of binding of O-fucose-deficient HSC to Notch ligands^141,160. The loss of binding results in a decreased adhesion of Pofut1-deficient HSCs to marrow stromal cells. In the in vitro cell adhesion assay, wild type (WT) long-term HSCs (LT-HSC; CD48^–CD150⁺LSK), but not O-fucose-deficient LT-HSCs from Pofut1-null mice, showed 15%–25% increased adhesion to a stromal cell line from mouse bone marrow (OP9) cells expressing Notch ligand (Jagged1, DLL1, or DLL4) relative to parental OP9 cells¹⁶⁰. The recombinant ligand entirely blocked the Notch ligand-mediated adhesion. Further, co-culture with OP9-DLL1, OP9-DLL4, or primary calvarium OBs increased the quiescent cell fraction of WT LSKs in G₀ phase (from basal level 17% to 37%, 48%, and 67%, respectively), whereas Pofut1-null LSKs remained less quiescent on OP9-DLL1/DLL4 or primary calvarium OBs.

To examine the specific contribution of different Notch ligands and Notch receptors that support HSC quiescence and niche retention, we applied neutralizing antibodies targeting Notch ligand Jagged1 or DLL4. These antibodies block specific interaction of each ligand to Notch receptors^161,162. Both Jagged1 and DLL4 are expressed in BM endothelial cells and OBs/osteolineage cells^{133,140,163
–165}. In vivo, we found that circulating LSK and LK cells in the periphery of mice receiving anti-Jagged1 or anti-DLL4 increased 2.5- to 3.3-fold, respectively, compared to those receiving isotype control antibodies. White blood cells increased modestly, while platelet numbers did not change significantly in mice receiving anti-Jagged1 or anti-DLL4. There was an increase in circulating granulocytes and a decrease in T lymphocytes in mice receiving anti-DLL4 but not in mice receiving anti-Jagged1¹⁶⁰. HSPC frequencies did not change, except that common lymphoid progenitors (CLPs) decreased in anti-DLL4-treated mice, consistent with the role of DLL4 in promoting CLP development in other reports¹⁴⁰. We found that there was an increase in marrow HSPC proliferation following DLL4 but not after Jagged1 blockade. Further, mice receiving Jagged1- or DLL4-antibody followed by G-CSF (4 doses) and plerixafor treatment showed a further ∼50% increase in LSK mobilization relative to control-treated mice¹⁶⁰.

More recently, we examined the effects of Notch receptor blockade. Unlike ligand neutralizing antibodies, Notch receptor-specific blocking antibodies do not interfere with receptor–ligand interaction, but instead block cleavage of Notch receptors and thus downstream signaling activation¹⁶¹. We found that in mice receiving Notch2-blocking antibodies, but not Notch1-blocking antibodies, spleen-residing LSKs and LKs increased three- to four-fold. When mice were given G-CSF and plerixafor following four doses of anti-Notch2 treatment, a 2.5-fold increase of white blood cells, a 3- and 3.3-fold increase of LSKs and LKs were seen in the periphery, and a 3.6- and 2-fold increase of spleen-residing LSKs and LKs were found in mice receiving anti-Notch2 compared to control-treated mice¹¹⁶. However, Notch2 blockade, combined with G-CSF or plerixafor, did not affect marrow HSPC homeostasis. We confirmed that increased HSPC egress following Notch2 blockade is a result of Notch2 signaling loss in the hematopoietic system, since Notch2 deletion in hematopoietic tissues caused increased cell-autonomous egress of HSPC to the PB and the spleen by reconstituted Notch2-deficient BM cells from Vav-Cre/Notch2^F/F mice in wild-type recipients. However, the HSPC homeostasis was not much affected in the marrow of Notch2-deficient mice.

Similar to the effect of anti-DLL4, the quiescent G₀ HSCs were decreased in mice receiving Notch2 antibodies or in the marrow of Notch2-deficient mice¹¹⁶. We show that transient Notch2 blockade or Notch2 loss in mice leads to decreased HSPC CXCR4 expression but increased cell cycling with CXCR4 transcription being directly regulated by the Notch transcriptional protein RBPJ. Surprisingly, we found that Notch2 blockade enhances HSPC homing and hematopoietic recovery. We observed that a 1.9-fold more of Notch2-blocked progenitors homed to the BM compared to their corresponding controls. We studied the hematopoietic reconstitution at various time points after the transplantation of cells from mice that received either control antibody, Notch1 or Notch2 blocking antibodies. Peripheral blood analysis revealed a better recovery of platelets at 4 and 8 weeks and a higher hemoglobin level until 10 weeks in recipient mice receiving Notch2-blocked cells than in mice receiving control-treated cells or Notch1-blocked cells. Analysis of BM 3 months after transplantation showed that the megakaryoerythroid progenitors and the common myeloid progenitors, derived from Notch2- but not Notch1-blocked donors, increased by ∼92% and 75%. At the same time, alteration to the HSC homeostasis did not occur.

In summary, either blocking Notch ligand adhesion through neutralizing Jagged1 or DLL4 or blocking Notch2 signaling induces HSPC egress and mobilization without significantly affecting HSC homeostasis (Fig. 1). In addition, transient Notch2 blockade results in higher engraftment and better myeloid reconstitution. The underlying mechanism is being investigated.

Figure 1.

Blocking of Notch2-ligand adhesion through neutralizing and blocking antibodies induces HSPC egress and mobilization. DLL4: Delta-like 4; HSPC: hematopoietic stem and progenitor cell.

Conclusion

Hematopoietic cell transplant (HCT) is a potentially curative therapy for blood and nonhematologic disorders. A successful outcome is dependent on the infusion of an adequate number of functionally active mobilized HSPCs. Until recently, G-CSF, either alone or in combination with chemotherapy, failed to mobilize an optimal CD34⁺ cell dose (5 × 10⁶/kg) in up to 40% of patients¹⁶⁶. Plerixafor, in combination with G-CSF, increased total CD34⁺ cells mobilized and often is used for HPC mobilization in myeloma and non-Hodgkin lymphoma patients¹⁶⁷. Unfortunately, this approach does not always lead to adequate HSPC collection in patients with prior extensive cytotoxic therapy. In some instances, multiple HCT procedures may require higher numbers of HSPCs^168
–170. Newer mobilizing regimens, either alone or in combination with G-CSF and plerixafor, have shown improved collection efficacy in preclinical models and could facilitate the collection of sufficient cells for multiple transplants and significantly decrease procedure-related risks, such as thrombocytopenia and infection associated with large volume or multiple collections^171
–173.

Footnotes

Author Contributions

Conceptualization: MA, LZ; literature search and data analysis: MA, HT, LZ; writing—original draft: MA, LZ; writing—review and editing: HT, LZ.

Ethical Approval

Our institution does not require ethical approval for reporting review articles.

Statement of Human and Animal Rights

This article does not contain any studies with human or animal subjects.

Statement of Informed Consent

There are no human subjects in this article and informed consent is not applicable.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported in part by research funding from NCI CA222064 and NIH HL103827 (to LZ), and by the Department of Pathology Case Western Reserve University faculty startup fund to LZ.

ORCID iD

Lan Zhou

References

Thomas

Lochte

Jr Cannon

Sahler

Ferrebee

. Supralethal whole body irradiation and isologous marrow transplantation in man. J Clin Invest. 1959;38(10 Pt 1-2):1709–1716.

Gatti

Meuwissen

Allen

Hong

Good

. Immunological reconstitution of sex-linked lymphopenic immunological deficiency. Lancet. 1968;2(7583):1366–1369.

Thomas

Buckner

Banaji

Clift

Fefer

Flournoy

Goodell

Hickman

Lerner

Neiman

Sale

, et al. One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood. 1977;49(4):511–533.

Weiden

Flournoy

Thomas

Prentice

Fefer

Buckner

Storb

. Antileukemic effect of graft-versus-host disease in human recipients of allogeneic-marrow grafts. N Engl J Med. 1979;300(19):1068–1073.

Bond

Fliedner

Cronkite

Rubini

Brecher

Schork

. Proliferative potentials of bone marrow and blood cells studied by in vitro uptake of H3-thymidine. Acta Haematol. 1959;21(1):1–15.

Bond

Cronkite

Fliedner

Schork

. Deoxyribonucleic acid synthesizing cells in peripheral blood of normal human beings. Science. 1958;128(3317):202–203.

Lewis

Passovoy

Freeman

Trobaugh

Jr . The repopulating potential and differentiation capacity of hematopoietic stem cells from the blood and bone marrow of normal mice. J Cell Physiol. 1968;71(2):121–132.

Hershko

Gale

Cline

. Cure of aplastic anaemia in paroxysmal nocturnal haemoglobinuria by marrow transfusion from identical twin: failure of peripheral-leucocyte transfusion to correct marrow aplasia. Lancet. 1979;1(8123):945–947.

Buckner

Graw

Jr Eisel

Henderson

Perry

. Leukapheresis by continuous flow centrifugation (CFC) in patients with chronic myelocytic leukemia (CML). Blood. 1969;33(2):353–369.

10.

Abrams

Glaubiger

Appelbaum

Deisseroth

. Result of attempted hematopoietic reconstitution using isologous, peripheral blood mononuclear cells: a case report. Blood. 1980;56(3):516–520.

11.

Fliedner

Korbling

Calvo

Bruch

Herbst

. Cryopreservation of blood mononuclear leukocytes and stem cells suspended in a large fluid volume. a preclinical model for a blood stem cell bank. Blut. 1977;35(3):195–202.

12.

Bell

Figes

Oscier

Hamblin

. Peripheral blood stem cell autografts in the treatment of lymphoid malignancies: initial experience in three patients. Br J Haematol. 1987;66(1):63–68.

13.

Dyson

Branford

Russell

Haylock

Kimber

Juttner

. Peripheral blood stem cells collected in very early remission produce rapid and sustained autologous haemopoietic reconstitution in acute non-lymphoblastic leukaemia. Bone Marrow Transplant. 1987;2(1):103–108.

14.

Reiffers

Bernard

David

Vezon

Sarrat

Marit

Moulinier

Broustet

. Successful autologous transplantation with peripheral blood hemopoietic cells in a patient with acute leukemia. Exp Hematol. 1986;14(4):312–315.

15.

Kessinger

Armitage

Landmark

Weisenburger

. Reconstitution of human hematopoietic function with autologous cryopreserved circulating stem cells. Exp Hematol. 1986;14(3):192–196.

16.

Korbling

Dorken

Pezzutto

Hunstein

Fliedner

. Autologous transplantation of blood-derived hemopoietic stem cells after myeloablative therapy in a patient with Burkitt’s lymphoma. Blood. 1986;67(2):529–532.

17.

Greenberg

Bax

Mara

Schrier

. Alterations of granulopoiesis following chemotherapy. Blood. 1974;44(3):375–383.

18.

Bull

DeVita

Carbone

. In vitro granulocyte production in patients with Hodgkin’s disease and lymphocytic, histiocytic, and mixed lymphomas. Blood. 1975;45(6):833–842.

19.

Levesque

Takamatsu

Nilsson

Haylock

Simmons

. Vascular cell adhesion molecule-1 (CD106) is cleaved by neutrophil proteases in the bone marrow following hematopoietic progenitor cell mobilization by granulocyte colony-stimulating factor. Blood. 2001;98(5):1289–1297.

20.

Levesque

Hendy

Takamatsu

Simmons

Bendall

. Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. J Clin Invest. 2003;111(2):187–196.

21.

Petit

Szyper-Kravitz

Nagler

Lahav

Peled

Habler

Ponomaryov

Taichman

Arenzana-Seisdedos

Fujii

Sandbank

, et al. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat Immunol. 2002;3(7):687–694.

22.

Levesque

Hendy

Takamatsu

Williams

Winkler

Simmons

. Mobilization by either cyclophosphamide or granulocyte colony-stimulating factor transforms the bone marrow into a highly proteolytic environment. Exp Hematol. 2002;30(5):440–449.

23.

Levesque

Hendy

Winkler

Takamatsu

Simmons

. Granulocyte colony-stimulating factor induces the release in the bone marrow of proteases that cleave c-KIT receptor (CD117) from the surface of hematopoietic progenitor cells. Exp Hematol. 2003;31(2):109–117.

24.

Semerad

Christopher

Liu

Short

Simmons

Winkler

Levesque

Chappel

Ross

Link

. G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the bone marrow. Blood. 2005;106(9):3020–3027.

25.

Tamura

Hattori

Nomura

Oheda

Kubota

Imazeki

Ono

Ueyama

Nagata

Shirafuji

, et al. Induction of neutrophilic granulocytosis in mice by administration of purified human native granulocyte colony-stimulating factor (G-CSF). Biochem Biophys Res Commun. 1987;142(2):454–460.

26.

Kennedy

Davis

Passos-Coelho

Noga

Huelskamp

Ohly

Davidson

. Administration of human recombinant granulocyte colony-stimulating factor (filgrastim) accelerates granulocyte recovery following high-dose chemotherapy and autologous marrow transplantation with 4-hydroperoxycyclophosphamide-purged marrow in women with metastatic breast cancer. Cancer Res. 1993;53(22):5424–5428.

27.

McQuaker

Hunter

Pacey

Haynes

Iqbal

Russell

. Low-dose filgrastim significantly enhances neutrophil recovery following autologous peripheral-blood stem-cell transplantation in patients with lymphoproliferative disorders: evidence for clinical and economic benefit. J Clin Oncol. 1997;15(2):451–457.

28.

Jansen

Thompson

Hanks

Greenspan

Thompson

Dugan

Akard

. Hematopoietic growth factor after autologous peripheral blood transplantation: comparison of G-CSF and GM-CSF. Bone Marrow Transplant. 1999;23(12):1251–1256.

29.

Gertz

Wolf

Micallef

Gastineau

. Clinical impact and resource utilization after stem cell mobilization failure in patients with multiple myeloma and lymphoma. Bone Marrow Transplant. 2010;45(9):1396–1403.

30.

Hiwase

Bollard

Hiwase

Bailey

Muirhead

Schwarer

. Intermediate-dose CY and G-CSF more efficiently mobilize adequate numbers of PBSC for tandem autologous PBSC transplantation compared with low-dose CY in patients with multiple myeloma. Cytotherapy. 2007;9(6):539–547.

31.

Pavone

Gaudio

Guarini

Perrone

Zonno

Curci

Liso

. Mobilization of peripheral blood stem cells with high-dose cyclophosphamide or the DHAP regimen plus G-CSF in non-Hodgkin’s lymphoma. Bone Marrow Transplant. 2002;29(4):285–290.

32.

Lee

Kim

Kang

Lee

Kim

Park

Chi

Huh

, et al. ESHAP plus G-CSF as an effective peripheral blood progenitor cell mobilization regimen in pretreated non-Hodgkin’s lymphoma: comparison with high-dose cyclophosphamide plus G-CSF. Bone Marrow Transplant. 2005;35(5):449–454.

33.

Watts

Ings

Leverett

MacMillan

Devereux

Goldstone

Linch

. ESHAP and G-CSF is a superior blood stem cell mobilizing regimen compared to cyclophosphamide 1.5 g m(-2) and G-CSF for pre-treated lymphoma patients: a matched pairs analysis of 78 patients. Br J Cancer. 2000;82(2):278–282.

34.

Mollee

Pereira

Nagy

Song

Saragosa

Keating

Crump

. Cyclophosphamide, etoposide and G-CSF to mobilize peripheral blood stem cells for autologous stem cell transplantation in patients with lymphoma. Bone Marrow Transplant. 2002;30(5):273–278.

35.

Pocali

De Simone

Annunziata

Palmieri

D’Amico

Copia

Viola

Mele

Schiavone

Ferrara

. Ifosfamide, epirubicin and etoposide (IEV) regimen as salvage and mobilization therapy for refractory or early relapsing patients with aggressive non-Hodgkin’s lymphoma. Leuk Lymphoma. 2004;45(8):1605–1609.

36.

De Clercq

. Antiviral drug discovery: ten more compounds, and ten more stories (part B). Med Res Rev. 2009;29(4):571–610.

37.

Nie

Han

Zou

. CXCR4 is required for the quiescence of primitive hematopoietic cells. J Exp Med. 2008;205(4):777–783.

38.

Tzeng

Kang

Chen

Cheng

Lai

. Loss of Cxcl12/Sdf-1 in adult mice decreases the quiescent state of hematopoietic stem/progenitor cells and alters the pattern of hematopoietic regeneration after myelosuppression. Blood. 2011;117(2):429–439.

39.

Nombela-Arrieta

Ritz

Silberstein

. The elusive nature and function of mesenchymal stem cells. Nat Rev Mol Cell Biol. 2011;12(2):126–131.

40.

Dar

Schajnovitz

Lapid

Kalinkovich

Itkin

Ludin

Kao

Battista

Tesio

Kollet

Cohen

, et al. Rapid mobilization of hematopoietic progenitors by AMD3100 and catecholamines is mediated by CXCR4-dependent SDF-1 release from bone marrow stromal cells. Leukemia. 2011;25(8):1286–1296.

41.

Janowska-Wieczorek

Marquez

Dobrowsky

Ratajczak

Cabuhat

. Differential MMP and TIMP production by human marrow and peripheral blood CD34(+) cells in response to chemokines. Exp Hematol. 2000;28(11):1274–1285.

42.

Clark

Bell

Clark

Braithwaite

Vithanarachchi

McGinnity

Callaghan

Francis

Salim

. Plerixafor is superior to conventional chemotherapy for first-line stem cell mobilisation, and is effective even in heavily pretreated patients. Blood Cancer J. 2014;4(10):e255.

43.

Broxmeyer

Orschell

Clapp

Hangoc

Cooper

Plett

Liles

Graham-Evans

Campbell

Calandra

, et al. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med. 2005;201(8):1307–1318.

44.

Broxmeyer

Hangoc

Cooper

Campbell

Ito

Mantel

. AMD3100 and CD26 modulate mobilization, engraftment, and survival of hematopoietic stem and progenitor cells mediated by the SDF-1/CXCL12-CXCR4 axis. Ann N Y Acad Sci. 2007Jun;1106:1–19.

45.

Devine

Vij

Rettig

Todt

McGlauchlen

Fisher

Devine

Link

Calandra

Bridger

Westervelt

, 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(4):990–998.

46.

Liles

Broxmeyer

Rodger

Wood

Hubel

Cooper

Hangoc

Bridger

Henson

Calandra

Dale

. Mobilization of hematopoietic progenitor cells in healthy volunteers by AMD3100, a CXCR4 antagonist. Blood. 2003;102(8):2728–2730.

47.

Liles

Rodger

Broxmeyer

Dehner

Badel

Calandra

Christensen

Wood

Price

Dale

. Augmented mobilization and collection of CD34+ hematopoietic cells from normal human volunteers stimulated with granulocyte-colony-stimulating factor by single-dose administration of AMD3100, a CXCR4 antagonist. Transfusion. 2005;45(3):295–300.

48.

Vishnu

Roy

Paulsen

Zubair

. Efficacy and cost-benefit analysis of risk-adaptive use of plerixafor for autologous hematopoietic progenitor cell mobilization. Transfusion. 2012;52(1):55–62.

49.

Hamilton

Vaughn

Graiser

Renfroe

Lechowicz

Langston

Prichard

Anderson

Gleason

Lonial

, et al. Effectiveness and cost analysis of “just-in-time” salvage plerixafor administration in autologous transplant patients with poor stem cell mobilization kinetics. Transfusion. 2011;51(10):2175–2182.

50.

Costa

Alexander

Hogan

Schaub

Fouts

Stuart

. Development and validation of a decision-making algorithm to guide the use of plerixafor for autologous hematopoietic stem cell mobilization. Bone Marrow Transplant. 2011;46(1):64–69.

51.

Maziarz

Nademanee

Micallef

Stiff

Calandra

Angell

Dipersio

Bolwell

. Plerixafor plus granulocyte colony-stimulating factor improves the mobilization of hematopoietic stem cells in patients with non-Hodgkin lymphoma and low circulating peripheral blood CD34+ cells. Biol Blood Marrow Transplant. 2013;19(4):670–675.

52.

Smith

Popat

Ciurea

Nieto

Anderlini

Rondon

Alousi

Qazilbash

Kebriaei

Khouri

de Lima

, et al. Just-in-time rescue plerixafor in combination with chemotherapy and granulocyte-colony stimulating factor for peripheral blood progenitor cell mobilization. Am J Hematol. 2013;88(9):754–757.

53.

Farina

Spina

Guidetti

Longoni

Ravagnani

Dodero

Montefusco

Carlo-Stella

Corradini

. Peripheral blood CD34+ cell monitoring after cyclophosphamide and granulocyte-colony-stimulating factor: an algorithm for the pre-emptive use of plerixafor. Leuk Lymphoma. 2014;55(2):331–336.

54.

Karpova

Rettig

DiPersio

. Mobilized peripheral blood: an updated perspective. F1000Res. 2019;8:F1000.

55.

Hynes

. Integrins: versatility, modulation, and signaling in cell adhesion. Cell. 1992;69(1):11–25. Faculty Rev-2125.

56.

Springer

. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994;76(2):301–314.

57.

Elices

Osborn

Takada

Crouse

Luhowskyj

Hemler

Lobb

. VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site. Cell. 1990;60(4):577–584.

58.

Papayannopoulou

Nakamoto

. Peripheralization of hemopoietic progenitors in primates treated with anti-VLA4 integrin. Proc Natl Acad Sci U S A. 1993;90(20):9374–9378.

59.

Vermeulen

Le Pesteur

Gagnerault

Mary

Sainteny

Lepault

. Role of adhesion molecules in the homing and mobilization of murine hematopoietic stem and progenitor cells. Blood. 1998;92(3):894–900.

60.

Brunner

Zaruba

Huber

David

Vallaster

Assmann

Mueller-Hoecker

Franz

. Parathyroid hormone effectively induces mobilization of progenitor cells without depletion of bone marrow. Exp Hematol. 2008;36(9):1157–1166.

61.

Ballen

Shpall

Avigan

Yeap

Fisher

McDermott

Dey

Attar

McAfee

Konopleva

Antin

, et al. Phase I trial of parathyroid hormone to facilitate stem cell mobilization. Biol Blood Marrow Transplant. 2007;13(7):838–843.

62.

Hanel

Andreani

Graler

. Erythrocytes store and release sphingosine 1-phosphate in blood. Faseb j. 2007;21(4):1202–1209.

63.

Ohkawa

Nakamura

Okubo

Hosogaya

Ozaki

Tozuka

Osima

Yokota

Ikeda

Yatomi

. Plasma sphingosine-1-phosphate measurement in healthy subjects: close correlation with red blood cell parameters. Ann Clin Biochem. 2008;45(Pt 4):356–363.

64.

Schwab

Pereira

Matloubian

Huang

Cyster

. Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science. 2005;309(5741):1735–1739.

65.

Massberg

Schaerli

Knezevic-Maramica

Kollnberger

Tubo

Moseman

Huff

Junt

Wagers

Mazo

von Andrian

. Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues. Cell. 2007;131(5):994–1008.

66.

Ratajczak

Lee

Wysoczynski

Wan

Marlicz

Laughlin

Kucia

Janowska-Wieczorek

Ratajczak

. Novel insight into stem cell mobilization-plasma sphingosine-1-phosphate is a major chemoattractant that directs the egress of hematopoietic stem progenitor cells from the bone marrow and its level in peripheral blood increases during mobilization due to activation of complement cascade/membrane attack complex. Leukemia. 2010;24(5):976–985.

67.

Lee

Wysoczynski

Liu

Zuba-Surma

Kucia

Ratajczak

. Impaired mobilization of hematopoietic stem/progenitor cells in C5-deficient mice supports the pivotal involvement of innate immunity in this process and reveals novel promobilization effects of granulocytes. Leukemia. 2009;23(11):2052–2062.

68.

Niesvizky

Mark

Ward

Jayabalan

Pearse

Manco

Stern

Christos

Mathews

Shore

Zafar

, et al. Overcoming the response plateau in multiple myeloma: a novel bortezomib-based strategy for secondary induction and high-yield CD34+ stem cell mobilization. Clin Cancer Res. 2013;19(6):1534–1546.

69.

Morstyn

Brown

Gordon

Crawford

Demetri

Rich

McGuire

Foote

McNiece

. Stem cell factor is a potent synergistic factor in hematopoiesis. Oncology. 1994;51(2):205–214.

70.

Nakamura

Tajima

Ishiga

Yamazaki

Oshimura

Shiota

Murawaki

. Soluble c-kit receptor mobilizes hematopoietic stem cells to peripheral blood in mice. Exp Hematol. 2004;32(4):390–396.

71.

Luens

Travis

Chen

Hill

Scollay

Murray

. Thrombopoietin, kit ligand, and flk2/flt3 ligand together induce increased numbers of primitive hematopoietic progenitors from human CD34+ Thy-1+ Lin− cells with preserved ability to engraft SCID-hu bone. Blood. 1998;91(4):1206–1215.

72.

Chu

Vasu

Deng

Yuan

Zhang

Fan

Hofmeister

Marsh

. FLT3 L and plerixafor combination increases hematopoietic stem cell mobilization and leads to improved transplantation outcome. Biol Blood Marrow Transplant. 2014;20(3):309–313.

73.

Urdziková

Likavčanová-Mašínová

Vaněček

Růžička

Šedý

Syková

Jendelová

. Flt3 ligand synergizes with granulocyte–colony-stimulating factor in bone marrow mobilization to improve functional outcome after spinal cord injury in the rat. Cytotherapy. 2011;13(9):1090–1104.

74.

Murray

Luens

Estrada

Bruno

Hoffman

Cohen

Ashby

Vadhan-Raj

. Thrombopoietin mobilizes CD34+ cell subsets into peripheral blood and expands multilineage progenitors in bone marrow of cancer patients with normal hematopoiesis. Exp Hematol. 1998;26(3):207–216.

75.

Hattori

Heissig

Tashiro

Honjo

Tateno

Shieh

J-H

Hackett

Quitoriano

Crystal

Rafii

. Plasma elevation of stromal cell–derived factor-1 induces mobilization of mature and immature hematopoietic progenitor and stem cells. Blood. 2001;97(11):3354–3360.

76.

Hattori

Dias

Heissig

Hackett

Lyden

Tateno

Hicklin

Zhu

Witte

Crystal

Moore

, et al. Vascular endothelial growth factor and angiopoietin-1 stimulate postnatal hematopoiesis by recruitment of vasculogenic and hematopoietic stem cells. J Exp Med. 2001;193(9):1005–1014.

77.

Moore

Hattori

Heissig

SHIEH

Dias

Crystal

Rafii

. Mobilization of endothelial and hematopoietic stem and progenitor cells by adenovector-mediated elevation of serum levels of SDF-1, VEGF, and angiopoietin-1. Ann N Y Acad Sci. 2001;938(1):36–47.

78.

Pruijt

van Kooyk

Figdor

Lindley

Willemze

Fibbe

. Anti–LFA-1 blocking antibodies prevent mobilization of hematopoietic progenitor cells induced by interleukin-8. Blood. 1998;91(11):4099–4105.

79.

Down

Awwad

Kurilla-Mahon

Moran

Ericsson

Oldmixon

Lachance

Watts

Treter

Nash

Gojo

, et al. Increases in autologous hematopoietic progenitors in the blood of baboons following irradiation and treatment with porcine stem cell factor and interleukin-3. Transplant Proc. 2000;32(5):1045–1046.

80.

Pettengell

Luft

De Wynter

Coutinho

Young

Fitzsimmons

Scarffe

Testa

. Effects of interleukin-6 on mobilization of primitive haemopoietic cells into the circulation. Br J Haematol. 1995;89(2):237–242.

81.

Grzegorzewski

Komschlies

Jacobsen

Ruscetti

Keller

Wiltrout

. Mobilization of long-term reconstituting hematopoietic stem cells in mice by recombinant human interleukin 7. J Exp Med. 1995;181(1):369–374.

82.

Jackson

Yan

Brunda

Kelsey

Talmadge

. Interleukin-12 enhances peripheral hematopoiesis in vivo . Blood. 1995;85(9):2371–2376.

83.

Schwarzenberger

Huang

Oliver

Byrne

La Russa

Zhang

Kolls

. IL-17 mobilizes peripheral blood stem cells with short-and long-term repopulating ability in mice. J Immunol. 2001;167(4):2081–2086.

84.

Alt

Yuan

Stankovich

Calaoagan

Schopies

Shen

Schneider

Zhu

. Long-acting IL-33 mobilizes high-quality hematopoietic stem and progenitor cells more efficiently than granulocyte colony-stimulating factor or AMD3100. Biol Blood Marrow Transplant. 2019;25(8):1475–1485.

85.

Pelus

Bian

Fukuda

Wong

Merzouk

Salari

. The CXCR4 agonist peptide, CTCE-0021, rapidly mobilizes polymorphonuclear neutrophils and hematopoietic progenitor cells into peripheral blood and synergizes with granulocyte colony-stimulating factor. Exp Hematol. 2005;33(3):295–307.

86.

Karpova

Rettig

Ritchey

Cancilla

Christ

Gehrs

Chendamarai

Evbuomwan

Holt

Zhang

Abou-Ezzi

, et al. Targeting VLA4 integrin and CXCR2 mobilizes serially repopulating hematopoietic stem cells. J Clin Invest. 2019;129(7):2745–2759.

87.

Fukuda

Bian

King

Pelus

. The chemokine GRObeta mobilizes early hematopoietic stem cells characterized by enhanced homing and engraftment. Blood. 2007;110(3):860–869.

88.

Pruijt

Fibbe

Laterveer

Pieters

Lindley

Paemen

Masure

Willemze

Opdenakker

. Prevention of interleukin-8-induced mobilization of hematopoietic progenitor cells in rhesus monkeys by inhibitory antibodies against the metalloproteinase gelatinase B (MMP-9). Proc Natl Acad Sci U S A. 1999;96(19):10863–10868.

89.

Laterveer

Lindley

Heemskerk

Camps

Pauwels

Willemze

Fibbe

. Rapid mobilization of hematopoietic progenitor cells in rhesus monkeys by a single intravenous injection of interleukin-8. Blood. 1996;87(2):781–788.

90.

Cancelas

Lee

Prabhakar

Stringer

Zheng

Williams

. Rac GTPases differentially integrate signals regulating hematopoietic stem cell localization. Nat Med. 2005;11(8):886–891.

91.

Ghiaur

Lee

Bailey

Cancelas

Zheng

Williams

. Inhibition of RhoA GTPase activity enhances hematopoietic stem and progenitor cell proliferation and engraftment. Blood. 2006;108(6):2087–2094.

92.

Ratajczak

Suszynska

Borkowska

Ratajczak

Schneider

. The role of sphingosine-1 phosphate and ceramide-1 phosphate in trafficking of normal stem cells and cancer cells. Expert Opin Ther Targets. 2014;18(1):95–107.

93.

Velders

van Os

Hagoort

Verzaal

Guiot

Lindley

Willemze

Opdenakker

Fibbe

. Reduced stem cell mobilization in mice receiving antibiotic modulation of the intestinal flora: involvement of endotoxins as cofactors in mobilization. Blood. 2004;103(1):340–346.

94.

Molendijk

van Oudenaren

van Dijk

Daha

Benner

. Complement split product C5a mediates the lipopolysaccharide-induced mobilization of CFU-s and haemopoietic progenitor cells, but not the mobilization induced by proteolytic enzymes. Cell Proliferation. 1986;19(4):407–417.

95.

Schneider

Weiss

Miller

. Pertussis toxin signals through the TCR to initiate cross-desensitization of the chemokine receptor CXCR4. J Immunol. 2009;182(9):5730–5739.

96.

Fehér

Gidáli

. Mobilizable stem cells: characteristics and replacement of the pool after exhaustion. Exp Hematol. 1982;10(8):661–667.

97.

Hoggatt

Singh

Tate

Chou

B-K

Datari

Fukuda

Liu

Kharchenko

Schajnovitz

Baryawno

. Rapid mobilization reveals a highly engraftable hematopoietic stem cell. Cell. 2018;172(1-2):191–204. e10.

98.

Christopherson

2nd Cooper

Broxmeyer

. Cell surface peptidase CD26/DPPIV mediates G-CSF mobilization of mouse progenitor cells. Blood. 2003;101(12):4680–4686.

99.

Lévesque

J-P

Hendy

Takamatsu

Simmons

Bendall

. Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. J Clin Invest. 2003;111(2):187–196.

100.

Bonig

Watts

Chang

Kiem

Papayannopoulou

. Concurrent blockade of α4-integrin and CXCR4 in hematopoietic stem/progenitor cell mobilization. Stem Cells. 2009;27(4):836–837.

101.

Ramirez

Rettig

Deych

Holt

Ritchey

DiPersio

. BIO5192, a small molecule inhibitor of VLA-4, mobilizes hematopoietic stem and progenitor cells. Blood. 2009;114(7):1340–1343.

102.

Cao

Zhang

Grassinger

Williams

Heazlewood

Churches

James

Papayannopoulou

Nilsson

. Therapeutic targeting and rapid mobilization of endosteal HSC using a small molecule integrin antagonist. Nat Commun. 2016;7:11007.

103.

Kikuta

Shimazaki

Ashihara

Sudo

Hirai

Sumikuma

Yamagata

Inaba

Fujita

Kina

. Mobilization of hematopoietic primitive and committed progenitor cells into blood in mice by anti-vascular adhesion molecule-1 antibody alone or in combination with granulocyte colony-stimulating factor. Exp Hematol. 2000;28(3):311–317.

104.

Zöller

. CD44v10 in hematopoiesis and stem cell mobilization. Leuk Lymphoma. 2000;38(5-6):463–480.

105.

Sweeney

Priestley

Nakamoto

Collins

Beaudet

Papayannopoulou

. Mobilization of stem/progenitor cells by sulfated polysaccharides does not require selectin presence. Proc Natl Acad Sci U S A. 2000;97(12):6544–6549.

106.

Sweeney

Lortat-Jacob

Priestley

Nakamoto

Papayannopoulou

. Sulfated polysaccharides increase plasma levels of SDF-1 in monkeys and mice: involvement in mobilization of stem/progenitor cells. Blood. 2002;99(1):44–51.

107.

Patchen

Liang

Vaudrain

Martin

Melican

Zhong

Stewart

Quesenberry

. Mobilization of Peripheral Blood Progenitor Cells by Betafectin® PGG-Glucan Alone and in Combination with Granulocyte Colony-Stimulating Factor. Stem Cells. 1998;16(3):208–217.

108.

Albanese

Caruelle

Frescaline

Delbé

Petit-Cocault

Huet

Charnaux

Uzan

Papy-Garcia

Courty

. Glycosaminoglycan mimetics–induced mobilization of hematopoietic progenitors and stem cells into mouse peripheral blood: structure/function insights. Exp Hematol. 2009;37(9):1072–1083.

109.

Carlo-Stella

Di Nicola

Magni

Longoni

Milanesi

Stucchi

Cleris

Formelli

Gianni

. Defibrotide in combination with granulocyte colony-stimulating factor significantly enhances the mobilization of primitive and committed peripheral blood progenitor cells in mice. Cancer Res. 2002;62(21):6152–6157.

110.

Hoggatt

Mohammad

Singh

Hoggatt

Chitteti

Speth

Poteat

Stilger

Ferraro

. Differential stem-and progenitor-cell trafficking by prostaglandin E 2. Nature. 2013;495(7441):365–369.

111.

Niesvizky

Mark

Ward

Jayabalan

Pearse

Manco

Stern

Christos

Mathews

Shore

. Overcoming the response plateau in multiple myeloma: a novel bortezomib-based strategy for secondary induction and high-yield CD34+ stem cell mobilization. Clin Cancer Res. 2013;19(6):1534–1546.

112.

Saez

Ferraro

Yusuf

Cook

Pardo-Saganta

Sykes

Palchaudhuri

Schajnovitz

Lotinun

Lymperi

, et al. Inhibiting stromal cell heparan sulfate synthesis improves stem cell mobilization and enables engraftment without cytotoxic conditioning. Blood. 2014;124(19):2937–2947.

113.

Forristal

Nowlan

Jacobsen

Barbier

Walkinshaw

Walkley

Winkler

Levesque

. HIF-1alpha is required for hematopoietic stem cell mobilization and 4-prolyl hydroxylase inhibitors enhance mobilization by stabilizing HIF-1alpha. Leukemia. 2015;29(6):1366–1378.

114.

Ting

Day

Spanevello

Boyd

. Activation of ephrin A proteins influences hematopoietic stem cell adhesion and trafficking patterns. Exp Hematol. 2010;38(11):1087–1098.

115.

Lenkiewicz

Adamiak

Thapa

Bujko

Pedziwiatr

Abdel-Latif

Kucia

Ratajczak

. The Nlrp3 inflammasome orchestrates mobilization of bone marrow-residing stem cells into peripheral blood. Stem Cell Rev Rep.2019;15(3):391–403.

116.

Wang

Myers

Wang

Xin

Albakri

Xin

Huang

Xin

Siebel

, et al. Notch2 blockade enhances hematopoietic stem cell mobilization and homing. Haematologica. 2017;102(10):1785–1795.

117.

Gaiano

Fishell

. The role of notch in promoting glial and neural stem cell fates. Annu Rev Neurosci. 2002;25:471–490.

118.

Bolos

Grego-Bessa

de la Pompa

. Notch signaling in development and cancer. Endocr Rev. 2007;28(3):339–363.

119.

Aguirre

Rubio

Gallo

. Notch and EGFR pathway interaction regulates neural stem cell number and self-renewal. Nature. 2010;467(7313):323–327.

120.

Hitoshi

Alexson

Tropepe

Donoviel

Elia

Nye

Conlon

Mak

Bernstein

van der Kooy

. Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells. Genes Dev. 2002;16(7):846–858.

121.

Liu

Shirakawa

Soma

Oka

Dotto

Fairman

Velazquez

Herlyn

. Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Mol Cell Biol. 2003;23(1):14–25.

122.

Grego-Bessa

Luna-Zurita

del Monte

Bolos

Melgar

Arandilla

Garratt

Zang

Mukouyama

Chen

Shou

, et al. Notch signaling is essential for ventricular chamber development. Dev Cell. 2007;12(3):415–429.

123.

Nobta

Tsukazaki

Shibata

Xin

Moriishi

Sakano

Shindo

Yamaguchi

. Critical regulation of bone morphogenetic protein-induced osteoblastic differentiation by Delta1/Jagged1-activated Notch1 signaling. J Biol Chem. 2005;280(16):15842–15848.

124.

Wang

Zimmerman

Huang

Myers

Wang

Moreton

Nthale

Awadallah

Beck

Xin

, et al. Aberrant Notch Signaling in the Bone Marrow Microenvironment of Acute Lymphoid Leukemia Suppresses Osteoblast-Mediated Support of Hematopoietic Niche Function. Cancer Res. 2016;76(6):1641–1652.

125.

Zhou

Yan

Petryniak

Man

Shim

Chervin

Lowe

. Notch-dependent control of myelopoiesis is regulated by fucosylation. Blood. 2008;112(2):308–319.

126.

Sorrentino

Cuneo

Roti

. Therapeutic targeting of notch signaling pathway in hematological malignancies. Mediterr J Hematol Infect Dis. 2019;11(1):e2019037.

127.

Fehon

Kooh

Rebay

Regan

Muskavitch

Artavanis-Tsakonas

. Molecular interactions between the protein products of the neurogenic loci Notch and Delta, two EGF-homologous genes in Drosophila. Cell. 1990;61(3):523–534.

128.

Rebay

Fleming

Fehon

Cherbas

Artavanis-Tsakonas

. Specific EGF repeats of Notch mediate interactions with Delta and Serrate: implications for Notch as a multifunctional receptor. Cell. 1991;67(4):687–699.

129.

Dumortier

Wilson

MacDonald

Radtke

. Paradigms of notch signaling in mammals. Int J Hematol. 2005;82(4):277–284.

130.

De Strooper

Annaert

Cupers

Saftig

Craessaerts

Mumm

Schroeter

Schrijvers

Wolfe

Ray

Goate

, et al. A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain. Nature. 1999;398(6727):518–522.

131.

Jeffries

Robbins

Capobianco

. Characterization of a high-molecular-weight Notch complex in the nucleus of Notch(ic)-transformed RKE cells and in a human T-cell leukemia cell line. Mol Cell Biol. 2002;22(11):3927–3941.

132.

Duncan

Rattis

DiMascio

Congdon

Pazianos

Zhao

Yoon

Cook

Willert

Gaiano

Reya

. Integration of Notch and Wnt signaling in hematopoietic stem cell maintenance. Nat Immunol. 2005;6(3):314–322.

133.

Karanu

Murdoch

Gallacher

Koremoto

Sakano

Bhatia

. The notch ligand jagged-1 represents a novel growth factor of human hematopoietic stem cells. J Exp Med. 2000;192(9):1365–1372.

134.

Stier

Cheng

Dombkowski

Carlesso

Scadden

. Notch1 activation increases hematopoietic stem cell self-renewal in vivo and favors lymphoid over myeloid lineage outcome. Blood. 2002;99(7):2369–2378.

135.

Varnum-Finney

Brashem-Stein

Nourigat

Flowers

Bakkour

Pear

Bernstein

. Pluripotent, cytokine-dependent, hematopoietic stem cells are immortalized by constitutive Notch1 signaling. Nat Med. 2000;6(11):1278–1281.

136.

Maillard

Koch

Dumortier

Shestova

Sai

Pross

Aster

Bhandoola

Radtke

Pear

. Canonical notch signaling is dispensable for the maintenance of adult hematopoietic stem cells. Cell Stem Cell. 2008;2(4):356–366.

137.

Mancini

Mantei

Dumortier

Suter

MacDonald

Radtke

. Jagged1-dependent Notch signaling is dispensable for hematopoietic stem cell self-renewal and differentiation. Blood. 2005;105(6):2340–2342.

138.

Varnum-Finney

Halasz

Sun

Gridley

Radtke

Bernstein

. Notch2 governs the rate of generation of mouse long- and short-term repopulating stem cells. J Clin Invest. 2011;121(3):1207–1216.

139.

Poulos

Guo

Kofler

Pinho

Gutkin

Tikhonova

Aifantis

Frenette

Kitajewski

Rafii

Butler

. Endothelial Jagged-1 is necessary for homeostatic and regenerative hematopoiesis. Cell Rep. 2013;4(5):1022–1034.

140.

Saez

Cook

Lotinun

Pardo-Saganta

Wang

Lymperi

Ferraro

Raaijmakers

Zhou

, et al. Specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow. J Exp Med. 2015;212(5):759–774.

141.

Yao

Huang

Wang

Yan

Wei

Xin

Gerson

Stanley

Lowe

Zhou

. Protein O-fucosyltransferase 1 (Pofut1) regulates lymphoid and myeloid homeostasis through modulation of Notch receptor ligand interactions. Blood. 2011;117(21):5652–5662.

142.

Lobry

Gao

Tikhonova

Loizou

Manent

van Handel

Ibrahim

Greve

Mikkola

Artavanis-Tsakonas

, et al. In vivo mapping of notch pathway activity in normal and stress hematopoiesis. Cell Stem Cell. 2013;13(2):190–204.

143.

Moloney

Shair

Xia

Locke

Matta

Haltiwanger

. Mammalian Notch1 is modified with two unusual forms of O-linked glycosylation found on epidermal growth factor-like modules. J Biol Chem. 2000;275(13):9604–9611.

144.

Rana

Nita-Lazar

Takeuchi

Kakuda

Luther

Haltiwanger

. O-glucose trisaccharide is present at high but variable stoichiometry at multiple sites on mouse Notch1. J Biol Chem. 2011;286(36):31623–31637.

145.

Shao

Moloney

Haltiwanger

. Fringe modifies O-fucose on mouse Notch1 at epidermal growth factor-like repeats within the ligand-binding site and the Abruptex region. J Biol Chem. 2003;278(10):7775–7782.

146.

Acar

Jafar-Nejad

Takeuchi

Rajan

Ibrani

Rana

Pan

Haltiwanger

Bellen

. Rumi is a CAP10 domain glycosyltransferase that modifies Notch and is required for Notch signaling. Cell. 2008;132(2):247–258.

147.

Okajima

Irvine

. Regulation of notch signaling by o-linked fucose. Cell. 2002;111(6):893–904.

148.

Wang

Shao

Shi

Harris

Spellman

Stanley

Haltiwanger

. Modification of epidermal growth factor-like repeats with O-fucose. molecular cloning and expression of a novel GDP-fucose protein O-fucosyltransferase. J Biol Chem. 2001;276(43):40338–40345.

149.

Luo

Haltiwanger

. O-fucosylation of notch occurs in the endoplasmic reticulum. J Biol Chem. 2005;280(12):11289–11294.

150.

Okajima

Irvine

. Modulation of notch-ligand binding by protein O-fucosyltransferase 1 and fringe. J Biol Chem. 2003;278(43):42340–42345.

151.

Shi

Stanley

. Protein O-fucosyltransferase 1 is an essential component of Notch signaling pathways. Proc Natl Acad Sci U S A. 2003;100(9):5234–5239.

152.

Okamura

Saga

. Pofut1 is required for the proper localization of the Notch receptor during mouse development. Mech Dev. 2008;125(8):663–673.

153.

Luca

Kim

Kakuda

Roein-Peikar

Haltiwanger

Zhu

Garcia

. Notch-Jagged complex structure implicates a catch bond in tuning ligand sensitivity. Science. 2017;355(6331):1320–1324.

154.

Luca

Jude

Pierce

Nachury

Fischer

Garcia

. Structural biology. structural basis for Notch1 engagement of Delta-like 4. Science. 2015;347(6224):847–853.

155.

Chen

Moloney

Stanley

. Fringe modulation of Jagged1-induced Notch signaling requires the action of beta 4galactosyltransferase-1. Proc Natl Acad Sci U S A. 2001;98(24):13716–13721.

156.

Taylor

Takeuchi

Sheppard

Chillakuri

Lea

Haltiwanger

Handford

. Fringe-mediated extension of O-linked fucose in the ligand-binding region of Notch1 increases binding to mammalian Notch ligands. Proc Natl Acad Sci U S A. 2014;111(20):7290–7295.

157.

Rampal

Moloney

Georgiou

Luther

Nita-Lazar

Haltiwanger

. Lunatic fringe, manic fringe, and radical fringe recognize similar specificity determinants in O-fucosylated epidermal growth factor-like repeats. J Biol Chem. 2005;280(51):42454–42463.

158.

Shimizu

Chiba

Saito

Kumano

Takahashi

Hirai

. Manic fringe and lunatic fringe modify different sites of the Notch2 extracellular region, resulting in different signaling modulation. J Biol Chem. 2001;276(28):25753–25758.

159.

Myers

Huang

Wei

Yan

Huang

Zhou

. Fucose-deficient hematopoietic stem cells have decreased self-renewal and aberrant marrow niche occupancy. Transfusion. 2010;50(12):2660–2669.

160.

Wang

Zimmerman

Wang

Myers

Huang

Shim

Huang

Xin

, et al. Notch Receptor-Ligand Engagement Maintains Hematopoietic Stem Cell Quiescence and Niche Retention. Stem Cells. 2015;33(7):2280–2293.

161.

Cain-Hom

Choy

Hagenbeek

de Leon

Chen

Finkle

Venook

Ridgway

Schahin-Reed

, et al. Therapeutic antibody targeting of individual Notch receptors. Nature. 2010;464(7291):1052–1057.

162.

Tran

Sandy

Carulli

Ebens

Chung

Shan

Radojcic

Friedman

Gridley

Shelton

Reddy

, et al. Blockade of individual Notch ligands and receptors controls graft-versus-host disease. J Clin Invest. 2013;123(4):1590–1604.

163.

Calvi

Adams

Weibrecht

Weber

Olson

Knight

Martin

Schipani

Divieti

Bringhurst

Milner

, et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature. 2003;425(6960):841–846.

164.

Weber

Forsythe

Christianson

Frisch

Gigliotti

Jordan

Milner

Guzman

Calvi

. Parathyroid hormone stimulates expression of the Notch ligand Jagged1 in osteoblastic cells. Bone. 2006;39(3):485–493.

165.

Guezguez

Campbell

Boyd

Karanu

Casado

Di Cresce

Collins

Shapovalova

Xenocostas

Bhatia

. Regional localization within the bone marrow influences the functional capacity of human HSCs. Cell Stem Cell. 2013;13(2):175–189.

166.

Pusic

Jiang

Landua

Rettig

Cashen

Westervelt

Vij

Abboud

Stockerl-Goldstein

Sempek

, et al. Impact of mobilization and remobilization strategies on achieving sufficient stem cell yields for autologous transplantation. Biol Blood Marrow Transplant. 2008;14(9):1045–1056.

167.

Mohty

Hubel

Kroger

Aljurf

Apperley

Basak

Bazarbachi

Douglas

Gabriel

Garderet

Geraldes

, et al. Autologous haematopoietic stem cell mobilisation in multiple myeloma and lymphoma patients: a position statement from the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 2014;49(7):865–872.

168.

Moskowitz

Glassman

Wuest

Maslak

Reich

Gucciardo

Coady-Lyons

Zelenetz

Nimer

. Factors affecting mobilization of peripheral blood progenitor cells in patients with lymphoma. Clin Cancer Res. 1998;4(2):311–316.

169.

Moreb

Salmasinia

Hsu

Hou

Cline

Rosenau

. Long-term outcome after autologous stem cell transplantation with adequate peripheral blood stem cell mobilization using plerixafor and G-CSF in poor mobilizer lymphoma and myeloma patients. Adv Hematol. 2011;2011:517561.

170.

Keating

. Plerixafor: a review of its use in stem-cell mobilization in patients with lymphoma or multiple myeloma. Drugs. 2011;71(12):1623–1647.

171.

Cecyn

Seber

Ginani

Goncalves

Caram

Oguro

Oliveira

Carvalho

Bordin

. Large-volume leukapheresis for peripheral blood progenitor cell collection in low body weight pediatric patients: a single center experience. Transfus Apher Sci. 2005;32(3):269–274.

172.

Bojanic

Dubravcic

Batinic

Cepulic

Mazic

Hren

Nemet

Labar

. Large volume leukapheresis: efficacy and safety of processing patient’s total blood volume six times. Transfus Apher Sci. 2011;44(2):139–147.

173.

Michon

Moghrabi

Winikoff

Barrette

Bernstein

Champagne

David

Duval

Hume

Robitaille

Belisle

, et al. Complications of apheresis in children. Transfusion. 2007;47(10):1837–1842.

A Review of Advances in Hematopoietic Stem Cell Mobilization and the Potential Role of Notch2 Blockade

Abstract

Keywords

Introduction

G-CSF and Chemotherapy

Plerixafor

Other Mobilizing Agents

Systemic Factors

Notch2 and Notch Ligand Blockade

Conclusion

Footnotes

Author Contributions

Ethical Approval

Statement of Human and Animal Rights

Statement of Informed Consent

Declaration of Conflicting Interests

Funding

ORCID iD

References