Skip to main content
Download PDF

Comparison of the efficacy of hematopoietic stem cell mobilization regimens: a systematic review and network meta-analysis of preclinical studies

Stem Cell Research & Therapy volume 12, Article number: 310 (2021) Cite this article

Abstract

Background

Mobilization failure may occur when the conventional hematopoietic stem cells (HSCs) mobilization agent granulocyte colony-stimulating factor (G-CSF) is used alone, new regimens were developed to improve mobilization efficacy. Multiple studies have been performed to investigate the efficacy of these regimens via animal models, but the results are inconsistent. We aim to compare the efficacy of different HSC mobilization regimens and identify new promising regimens with a network meta-analysis of preclinical studies.

Methods

We searched Medline and Embase databases for the eligible animal studies that compared the efficacy of different HSC mobilization regimens. Primary outcome is the number of total colony-forming cells (CFCs) in per milliliter of peripheral blood (/ml PB), and the secondary outcome is the number of Lin− Sca1+ Kit+ (LSK) cells/ml PB. Bayesian network meta-analyses were performed following the guidelines of the National Institute for Health and Care Excellence Decision Support Unit (NICE DSU) with WinBUGS version 1.4.3. G-CSF-based regimens were classified into the SD (standard dose, 200–250 μg/kg/day) group and the LD (low dose, 100–150 μg/kg/day) group based on doses, and were classified into the short-term (2–3 days) group and the long-term (4–5 days) group based on administration duration. Long-term SD G-CSF was chosen as the reference treatment. Results are presented as the mean differences (MD) with the associated 95% credibility interval (95% CrI) for each regimen.

Results

We included 95 eligible studies and reviewed the efficacy of 94 mobilization agents. Then 21 studies using the poor mobilizer mice model (C57BL/6 mice) to investigate the efficacy of different mobilization regimens were included for network meta-analysis. Network meta-analyses indicated that compared with long-term SD G-CSF alone, 14 regimens including long-term SD G-CSF + Me6, long-term SD G-CSF + AMD3100 + EP80031, long-term SD G-CSF + AMD3100 + FG-4497, long-term SD G-CSF + ML141, long-term SD G-CSF + desipramine, AMD3100 + meloxicam, long-term SD G-CSF + reboxetine, AMD3100 + VPC01091, long-term SD G-CSF + FG-4497, Me6, long-term SD G-CSF + EP80031, POL5551, long-term SD G-CSF + AMD3100, AMD1300 + EP80031 and long-term LD G-CSF + meloxicam significantly increased the collections of total CFCs. G-CSF + Me6 ranked first among these regimens in consideration of the number of harvested CFCs/ml PB (MD 2168.0, 95% CrI 2062.0−2272.0). In addition, 7 regimens including long-term SD G-CSF + AMD3100, AMD3100 + EP80031, long-term SD G-CSF + EP80031, short-term SD G-CSF + AMD3100 + IL-33, long-term SD G-CSF + ML141, short-term LD G-CSF + ARL67156, and long-term LD G-CSF + meloxicam significantly increased the collections of LSK cells compared with G-CSF alone. Long-term SD G-CSF + AMD3100 ranked first among these regimens in consideration of the number of harvested LSK cells/ml PB (MD 2577.0, 95% CrI 2422.0–2733.0).

Conclusions

Considering the number of CFC and LSK cells in PB as outcomes, G-CSF plus AMD3100, Me6, EP80031, ML141, FG-4497, IL-33, ARL67156, meloxicam, desipramine, and reboxetine are all promising mobilizing regimens for future investigation.

Background

Hematopoietic stem cell transplantation (HSCT) is a life-saving strategy for variety of severe disorders, including bone marrow failure after high-dose radiation and various hematological malignancies [1]. Peripheral blood stem cells (PBSCs) have been gradually replaced bone marrow (BM) as the predominant source of stem cell for transplantation in clinical practice [2, 3]. It has been demonstrated that PBSCs transplantation is associated with more convenient and safer harvest procedure, faster hematological recovery, lower risk of graft failure, and comparable disease-free survival (DFS) and overall survival (OS) in comparison with BM transplantation [4,5,6]. However, hematopoietic stem cells (HSCs) mainly reside in specialized BM niches during steady state; the number of HSCs circulating in peripheral blood (PB) is very low and not sufficient for harvest [6]. Administration of exogenous cytokines or chemokines could induce the egress of HSCs from BM into PB in a process termed mobilization. Successful mobilization allows for efficient collection of HSCs sufficient for transplantation, and increment in the dose of harvested HSCs could improve transplantation efficiency via promoting hematopoietic reconstitution, as well as reducing the need for supportive blood transfusion and the risks of infections [7, 8]. Therefore, efficient mobilization is the key to successful HSCT and sustained hematopoietic recovery.

Granulocyte colony-stimulating factor (G-CSF) is the most commonly used steady-state HSC mobilization agent in clinical practice. However, mobilization failure may occur when G-CSF is used alone [8]. In addition, mobilization using G-CSF alone requires multiple doses beginning at least 4 days before first apheresis and a median of 2–5 apheresis sessions to collect sufficient PBSCs, which increased the risk of adverse events [7]. The incidences of bone pain induced by G-CSF is higher than 80% at day 4, in addition, other G-CSF-related severe adverse events including myocardial infarctions, pulmonary embolism, and splenic rupture also have been reported [9,10,11]. To improve mobilization efficacy and attenuate toxicity, novel mobilization regimens are developed and investigated in a variety of animal studies before applied in clinical practice, but the results are inconsistent. This study aims to review and compare the efficacy of different HSC mobilization regimens and identify new promising regimens with a network meta-analysis of preclinical studies, which may be helpful for guiding future clinical trials.

Methods

Literature search and study selection

We searched Medline and Embase from inception to February 23, 2021, with the search term “stem cell mobilization” and a filter of “animals”. The titles and abstracts of retrieved citations were independently screened by two investigators (CXL and XL) for eligibility. Disagreements were resolved by full-text review and discussion with a third investigator (SNX). Preclinical studies that met the following criteria were included for review: (1) compared the efficacy of two or more different regimens in the mobilization of hematopoietic stem and progenitor cells (HSPCs) and (2) using any species of mice as experimental animals. As for network meta-analysis, the inclusion criteria were (1) using the poor mobilizer mice model-C57BL/6 mice as experimental animals [12] and (2) reporting data for at least one of the outcomes of mobilization efficacy, including the number of total colony-forming cells (CFCs) and Lin− Sca1+ Kit+ (LSK) cells per milliliter of peripheral blood (/ml PB). Since aged mice were reported to have better mobilization efficiency compared with young mice and no significant difference was reported among mice younger than 3 months, we excluded studies using mice older than 12 weeks in meta-analysis to reduce heterogeneity [13]. In addition, we only included studies that administrated G-CSF via subcutaneously injection. Furthermore, G-CSF-based regimens were classified into the SD (standard dose, 200–250 μg/kg/day) group and the LD (low dose, 100–150 μg/kg/day) group based on G-CSF doses and were classified into the short-term (2–3 days) group and the long-term (4–5 days) group based on administration duration of G-CSF. Studies with significant heterogeneity in dosage and injection route of G-CSF were excluded in meta-analysis.

Data extraction and quality assessment

Full text of all eligible studies was reviewed, and two investigators (CXL and XL) independently extracted data using predesigned data collection forms. Data was extracted on studies characteristics, animal’s characteristics, dosage of mobilization regimens, and efficacy outcomes. We chose the number of total CFCs per milliliter PB as primary outcome, and the number of LSK cells per milliliter PB as secondary outcome. The mean, standard deviation (SD) or standard error (SE) of each outcome are extracted directly from published text or from related graphs with Adobe Photoshop version CS3 via previously validated methods [14]. The methodological quality of included studies was assessed using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk of bias tool, which contains 10 items, including random sequence generation, similar baseline characteristics, allocation concealment, random housing, blinding of caregivers and investigators, random selection for outcome assessment, blinding of outcome assessor, adequate addressing of incomplete outcome data, free from selective outcome reporting, and free from other bias [15]. For each item, judgment of “yes”, “no”, and “unclear” respectively indicate low, high and unclear risk of bias.

Statistical analyses

We conducted network meta-analyses to compare the efficacy of multiple mobilization regimens simultaneously. Network plot for each outcome was obtained using Stata version 12.0. Bayesian network meta-analyses were performed with WinBUGS version 1.4.3 (MRC Biostatistics Unit, Cambridge, UK), employing the Markov Chain Monte Carlo (MCMC) approach and following the guidelines of the National Institute for Health and Care Excellence Decision Support Unit (NICE DSU) [16]. We used the WinBUGS code previously established by Dias et al., which could handle trials with multiple arms and rank treatments with additional code [16]. Three chains were run to yield 150,000 iterations, and the initial 5000 burn-ins were discarded. The convergence of models was assessed with trace plots and Brooks-Gelman-Rubin statistic. Model fit of fixed-effect model and random-effect model were compared with the Deviance Information Criterion (DIC), and model with lower DIC was adopted. Long-term SD G-CSF monotherapy was chosen as the common comparator. Estimates of treatment effects were reported as mean differences (MD) with the associated 95% credibility interval (95% CrI). The 95% CrI calculated in Bayesian meta-analysis can be interpreted like the 95% confidence intervals (95% CI) in traditional meta-analysis [17]. The probability of each regimen to be the best was calculated by ranking the relative effects of all treatments in each iteration and defined as the proportion of times a regimen ranked first. This work is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) extension statement for network meta-analyses [18].

Results

Characteristics of included trials

We identified 3826 records from database searches. After removing 835 duplicates, 2991 records were screened on title and abstract, and 2749 clearly irrelevant records were excluded. We retrieved the full text of the remaining 242 records for further assessment. We excluded 147 records for the reasons listed in the flow diagram (Fig. 1). Ultimately, 95 eligible studies were included for review [19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113]. The characteristics of the 95 included studies are summarized in Supplementary Table 1. The efficacy of 94 HSC mobilization agents were investigated, including cytokines, agents targeting the CXCR4 (C-X-C chemokine receptor type 4)/CXCL12 (SDF1, stromal cell-derived factor-1) axis, agents targeting the VLA-4(very late antigen-4)/VCAM-1 (vascular cell adhesion molecule-1) axis, chemotherapeutic agents, nonsteroidal anti-inflammatory drugs (NSAIDs), and other agents. Most of these agents not only can induce the mobilization of hematopoietic stem and progenitor cells (HSPCs) alone, but also can enhanced the mobilization mediated by G-CSF or AMD3100 synergistically or additively. The detailed information and mobilization efficacy of these agents are reviewed in Table 1. Compared with the conventional G-CSF, modified G-CSF including SD/0 (an engineered pegylated G-CSF), IMG-CSF (G-CSF immobilized on polyethylenoxide by nanotechnology), and PEGLip-G-CSF (pegylated liposome formulated G-CSF) exhibited enhanced mobilization efficacy. Among other cytokines, IL-33 showed superior mobilization potential than G-CSF and AMD3100, and tGROβ (a truncated form of chemokine GROβ) showed superior mobilization AMD3100. AMD3100-a CXCR4 antagonist was the most commonly used agents in combined regimens, which can significantly increase mobilization with a single dose when in combination with G-CSF. There are 7 new CXCR4 antagonist investigated and compared with AMD 3100, among which T-140, POL5551, and CX0714 showed significant superior mobilization AMD3100.

Fig. 1
figure 1

Flow chart of study selection. The PRISMA flow chart of study screening and selection

Full size image
Table 1 Detailed information and mobilization efficacy of all included novel agents
Full size table

After excluding studies using non-C57BL/6 mice model, studies including mice older than 12 weeks, studies that did not reported data about the number of total CFCs or LSK cell per milliliter PB, studies with significant heterogeneity in G-CSF dosage, and studies that were unrelated to the main network, 21 eligible studies were included in meta-analysis [51, 56, 72, 74, 77, 78, 81,82,83,84,85,86, 91, 94, 96, 104,105,106, 108, 109, 112]. All of the 21 included studies are controlled studies, and the most widely used controls are phosphate-buffered saline (PBS), saline, and G-CSF. There are 40 mobilization agents and 57 regimens investigated. The characteristics of these 21 studies are summarized in Table 2. The results of methodological quality evaluation are listed in Supplementary Table 2. Risk of bias regarding random allocation and blinding in all included studies are unclear since the lack of relevant information. The baseline characteristics including mice strain and gender are unified among groups in 10 studies, the other 11 studies did not report the animal gender and age. There are 2 studies that only reported representative data for mobilization outcomes; the other studies are all free from bias caused by incomplete outcome data, selective outcome reporting, and other reasons.

Table 2 Characteristics of the 21 studies included in meta-analysis
Full size table

Total CFCs

The number of total CFCs (also known as colony-forming units, CFUs) per milliliter of PB was reported as primary outcome in 17 studies and involved 43 mobilization regimens. The network graph of all comparisons in these 17 studies is shown in Fig. 2. The results of Bayesian network meta-analysis indicate that compared with long-term SD G-CSF alone, 14 mobilization regimens significantly increased the number of total CFCs/ml PB, including long-term SD G-CSF + Me6 (MD 2168.0, 95% CrI 2062.0–2272.0), long-term SD G-CSF + AMD3100 + EP80031 (MD 1144.0, 95% CrI 974.9–1311.0), long-term SD G-CSF + AMD3100 + FG-4497 (MD 903.9, 95% CrI 727.5, 1080.0), long-term SD G-CSF + ML141 (MD 720.9, 95% CrI 567.1–875.3), long-term SD G-CSF + desipramine (MD 594.7, 95% CrI 419.4–768.8), AMD3100 + meloxicam (MD 580.1, 95% CrI 446.2–713.8), long-term SD G-CSF + reboxetine (MD 576.0, 95% CrI 395.1–756.6), AMD3100 + VPC01091 (MD 558.7, 95% CrI 446.6–668.9), long-term SD G-CSF + FG-4497 (MD 515.3, 95% CrI 338.8–692.6), Me6 (MD 493.5, 95% CrI 397.1–590.6), long-term SD G-CSF + EP80031 (MD 484.7, 95% CrI 361.4–608.4), POL5551 (MD 429.8, 95% CrI 259.0–600.9), long-term SD G-CSF + AMD3100 (MD 424.6, 95% CrI 360.1–487.9), AMD1300 + EP80031 (MD 417.2, 95% CrI 306.1–530.7), and long-term LD G-CSF + meloxicam (MD 316.1, 95% CrI 126.2, 502.4) (Fig. 3). Long-term SD G-CSF + Me6 ranked first among these regimens in regard to the ability to mobilize CFCs. AMD1300 + desipramine, Cdc42 activity-specific inhibitor (CASIN) alone, AMD3100 alone, EP80031 alone, and meloxicam alone are inferior to long-term SD G-CSF. No significant differences are identified between the other regimens and long-term SD G-CSF.

Fig. 2.
figure 2

Network graph for total CFCs. The network graph of all comparisons in the 21 studies that have data about total colony-forming cells (CFCs) per milliliter of peripheral blood (/ml PB). Each node represents a mobilization regimen, while each line represents a direct comparison between regimens, with the thickness reflecting the number of available direct comparisons. All included regimens are described in the supplementary materials

Full size image
Fig. 3
figure 3

Forest plots for total CFCs. Forest plot of the Bayesian network meta-analysis results about the number of harvested total colony-forming cells (CFCs) per milliliter of peripheral blood (/ml PB). Estimate of treatment effect for each mobilization regimen was reported as mean differences (MD) with the associated 95% credibility interval (95% CrI). Granulocyte colony-stimulating factor monotherapy (G-CSF) is a common comparator. All included regimens are described in the supplementary materials

Full size image

LSK cells

The number of LSK cells/ml PB was reported as primary outcome in 11 studies, which have evaluated the efficacy of 34 mobilization regimens with mice models. The network graph of all comparisons in these 11 studies is shown in Fig. 4. The results of Bayesian network meta-analysis indicate that in comparison with long-term SD G-CSF alone, 7 mobilization regimens significantly increased the number of LSK cells collected from peripheral blood, including long-term SD G-CSF + AMD3100 (MD 2577.0, 95% CrI 2422.0–2733.0), AMD3100 + EP80031 (MD 1543.0, 95% CrI 1385.0–1705.0), long-term SD G-CSF + EP80031 (MD 1031.0, 95% CrI 851.7–1213.0), short-term SD G-CSF + AMD3100 + IL-33 (MD 766.3, 95% CrI 576.4–960.6), long-term SD G-CSF + ML141(MD 390.7, 95% CrI 193.2–585.9), short-term LD G-CSF + ARL67156 (MD 390.4, 95% CrI 207.4–574.4), and long-term LD G-CSF + meloxicam (MD 239.0, 95% CrI 55.9–426.5). The MD and 95% CrI of all included regimens are presented in forest plot in the order of median rank (Fig. 5). Long-term SD G-CSF + AMD3100 ranked first among these regimens considering this parameter since it is associated with most favorable MD and ranked first in all simulations. AMD3100 + LECT2, long-term LD G-CSF, short-term SD G-CSF, AMD3100 + IL-33, meloxicam alone, LECT2 alone, short-term LD G-CSF, and EP80031 alone are inferior to G-CSF in regard to the ability of mobilizing LSK cells into blood. No significant differences are identified between the other regimens and long-term SD G-CSF.

Fig. 4
figure 4

Network graph for LSK cells. The network graph of all comparisons in the 10 studies that have data about Lin− Sca1+ Kit+ (LSK) cells per milliliter of peripheral blood (/ml PB). Each node represents a mobilization regimen, while each line represents a direct comparison between regimens, with the thickness reflecting the number of available direct comparisons. All included regimens are described in the supplementary materials.

Full size image
Fig. 5
figure 5

Forest plots for LSK cells. Forest plot of the Bayesian network meta-analysis results about the number of harvested Lin− Sca1+ Kit+ (LSK) cells per milliliter of peripheral blood (/ml PB). Estimate of treatment effect for each mobilization regimen was reported as mean differences (MD) with the associated 95% credibility interval (95% CrI). Granulocyte colony-stimulating factor monotherapy (G-CSF) is a common comparator. All included regimens are described in the supplementary materials

Full size image

Long-term repopulating ability

Although the number of CFCs and LSK cells are the most commonly used outcomes to evaluate HSPC mobilization efficiency, enriched cell subsets such as CFCs and LSK cells do not measure long-term reconstituting HSCs, and additional markers such as fms-like tyrosine kinase-3 (Flt3) and signaling lymphocyte activation molecule (SLAM) CD150 were used to identify LSK subsets and assess the mobilization of self-renewing HSCs and long-term HSCs (LT-HSCs) [114]. The mobilization of different LSK subsets were examined in 12 studies, and the results are summarized in Supplementary Table 3. In brief, combination of desipramine, meloxicam, hypoxia-inducible transcription factor 1α (HIF-1α) prolyl hydroxylase domain enzyme (PHD) inhibitors (FG-4497, PHI-1, or PHI-2), the dual α9β1/α4β1 integrin antagonist BOP, Viagra, new CXCR4 antagonist HF51116, and colony-stimulating factor 1 Fc fusion protein (CSF1-Fc) significantly increased the mobilization of LSKF cells (Lin−Sca-1+c-kit+Flt3− cells), SLAM LSK cells (Lin−Sca-1+c-kit+ CD48−CD150+ cells), or LT-HSCs compared with G-CSF alone. The truncated form of chemokine GROβ (tGROβ) plus AMD3100, Cobalt protoporphyrin IX (CoPP), mobilized higher levels of SLAM LSK cells than G-CSF.

To further assess the mobilization of long-term repopulating HSCs, in vivo transplantation experiments were performed in 49 studies. The characteristics and results of these 49 studies are reviewed in Supplementary Table 4. In summary, lethally irradiated recipient mice received mobilized PB cells from donor mice with or without competitive cells, and the long-term repopulating ability are assessed by the survival of recipients and the long-term reconstitution donor-derived cells at different time point (usually in at months after transplantation). Furthermore, serial transplantation analysis was performed via transplanting BM cells from primary recipients to secondary or tertiary recipients to assess the long-term repopulating and self-renewing capacity of mobilized cells in 20 studies. Results indicate that the combination of new mobilization agents (including FLT-3L, MIP-1α, IL-8, PEG-rHuMGDF, SB-251353, s-kit, AMD3100, T-140, tGROβ, VTP195183, SCA, erlotinib, EP80031, meloxicam, UDP-G, Anti-VCAM-1 Ab, heparin, Me6, HF51116, and CSF1-Fc) significantly increased the mobilization of long-term repopulating HSCs compared with G-CSF alone. In addition, the combination of BOP, BIO5192, SEW2871, VPC01091, LGB321, or Viagra with AMD3100 enhanced the mobilization of long-term repopulating HSCs compared with AMD3100 alone. Moreover, cells mobilized by LECT2, POL5551, UDP-G, or CoPP alone showed superior long-term repopulating capacity than those mobilized by G-CSF, whereas cells mobilized by Me6, CasNa, or CASIN alone showed superior long-term repopulating capacity than those mobilized by AMD3100.

Discussion

This work reviewed the efficacy of 94 new HSC mobilization agents from 95 preclinical studies. In addition, we included 21 studies using the poor mobilizer model-C57BL/6 mice for network meta-analysis and compared the efficacy of 57 mobilization regimens. We identified several promising regimens with great HSC mobilization efficacy, including long-term SD G-CSF + Me6, long-term SD G-CSF + AMD3100 + EP80031, long-term SD G-CSF + AMD3100 + FG-4497, long-term SD G-CSF + ML141, long-term SD G-CSF + desipramine, AMD3100 + meloxicam, long-term SD G-CSF + reboxetine, AMD3100 + VPC01091, long-term SD G-CSF + FG-4497, Me6, POL5551, long-term SD G-CSF + AMD3100, long-term LD G-CSF + meloxicam, AMD3100 + EP80031, long-term SD G-CSF + EP80031, short-term SD G-CSF + AMD3100 + IL-33, and short-term LD G-CSF + ARL67156.

To our best of knowledge, this study is the first network meta-analysis that compared the efficacy of different HSC mobilization regimens with data from preclinical studies. We provide a comprehensive summary of new mobilization agents that have been investigated in mice models. The efficacy of these agents alone or in combination with other agents was indirectly compared via network meta-analysis. Moreover, we ranked all of the investigated regimens based on their ability to mobilize HSCs into blood stream. We identified several promising agents and regimens that have the most potent mobilizing capacity. The majority of mobilization regimens that show great improvements over G-CSF are combined regimens containing both G-CSF and new mobilization agents. Although these regimens would be unlikely to reduce severe adverse events, they provide a perspective that the incorporation of new agents could reduce the incidences of G-CSF-related adverse events through reducing the doses of G-CSF that required to mobilization sufficient HSCs since they can synergistically enhance the G-CSF-mediated mobilization. In addition, we identified several agents showed superior mobilization potential than G-CSF even when used alone, such as Me6 and POL5551. It is worth further investigation that whether these agents could reduce mobilization-related toxicity compared with G-CSF.

Among the new agents, EP80031, Me6, FG-4497, and ML141 significantly improved the efficiency of G-CSF-induced HSC mobilization. EP80031 is a synthetic octosaccharide mimicking the structure of heparan sulfate. A single dose of EP80031 (15mg/kg, intravenously injection) could lead to rapid and prominent mobilization of hematopoietic stem and progenitor cells (HSPCs), and the combination of EP80031 with G-CSF and AMD3100 resulted in 3-fold increase in the number of LSK cells and total CFCs [72]. In addition, HSCs mobilized with the regimen G-CSF + AMD3100 + EP80031 are associated with enhanced hematopoietic reconstitution [72]. Me6 is a small molecule that was screened from a group of chemicals by Zhang et al. and has been proved to have robust ability of mobilizing HSPCs [85]. The combination of Me6 and G-CSF (G-CSF + Me6) resulted in remarkable increase in the number of total CFUs, moreover, it is suggested that Me6-mobilized HSCs are associated with greater long-term repopulating capacity and more efficient engraftment [85]. FG-4497 is a prolyl hydroxylase inhibitor that could enhance HSC mobilization through stabilizing the hypoxia-inducible transcription factor-1α (HIF-1α) protein [106]. The addition of FG-4497 significantly increased the mobilization of HSPCs induced by G-CSF [86, 106]. In addition, FG-4497 exerts protective effects in ischemia-induced kidney injury and high-dose irradiation-induced BM failure [115]. ML141 is an inhibitor of cell division control protein 42 (Cdc42). The mobilization effect of ML141 is modest, but ML141 could synergistically enhance G-CSF-mediated mobilization of LSK cells and CFCs in mice model [81]. Taking our results of meta-analysis together into consideration, G-CSF + AMD3100 + EP80031, G-CSF + Me6, G-CSF + FG-4497, and G-CSF + ML141 are new promising mobilization regimens that could significantly increase the quantity of HSCs in PB without interfering their functions. However, the safety profiles of these new agents remain unclear. Further studies are required to determine the efficacy and safety of these potential regimens in human before applied in clinical practice.

In addition, we established the favorable efficacy of G-CSF and AMD3100 in HSC mobilization, which has been verified by clinical trials. AMD3100, also known as plerixafor, is an antagonist of the chemokine receptor CXCR4 that could rapidly induce the mobilization of stem cells through antagonizing the interaction of CXCR4 and stromal cell-derived factor-1α (SDF-1α) [116]. Multiple studies have demonstrated that AMD3100 alone mobilized lower numbers of HSCs compared with G-CSF, but the addition of AMD3100 dramatically increased the G-CSF-induced mobilization of HSCs both in mice models and non-human primates’ model [117, 118]. Our results from network meta-analyses indicated that G-CSF in combination of AMD3100 not only significantly increased the number of LSK cells, but also increased total CFCs. Despite we only pooled data from murine models, which are different from human in regard to physiological conditions, our conclusions are consistent with that obtained from clinical studies in human beings. A group of randomized controlled trials (RCTs) have demonstrated that G-CSF in combination of AMD3100 led to higher rates of successful mobilization and increased the total collection of HSCs without increasing the risk of severe adverse events in patients with non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM) [119,120,121]. Moreover, it is suggested that AMD3100-mobilized cell products are associated with greater capacity to repopulate the marrow and potential of protecting against graft-versus-host disease due to an enrichment of regulatory T cells (GVHD) [118, 122]. AMD3100 has been approved for HSC mobilization and subsequent autologous transplantation in patients with NHL and MM [123]. Therefore, before the efficacy and safety of new regimens in human were well established, G-CSF in combination with AMD3100 remains the most efficient and safe regimens in patients with high risk of mobilization failure. Although G-CSF plus AMD3100 significantly improved mobilization efficiency compared with G-CSF alone, two well-designed RCTs indicated that successful rate of achieving optimal target with G-CSF plus AMD3100 is only 59.3% in NHL patients and 75.7% in MM patients [119, 120]. Therefore, we speculate that almost 25–40% of patients with high risk of mobilization failure would still benefit from new mobilization regimens.

Nevertheless, there are some limitations in this study. Firstly, we integrated evidences from animal models. It is suggested that HSC mobilization is evolutionarily conserved from mice to humans, so mice models also represent a valuable experimental system for investigating the efficacy and mechanisms of mobilization regimens [67, 81]. Even so, animal model could not completely simulate the physiological condition of human; hence, the translation of our results integrated from preclinical studies to human should be in cautions. Future clinical trials are needed for validation these regimens in human. Secondly, our meta-analysis did not include safety outcomes. Most of the included studies did not provide information about toxicity, and the toxicity data collected from animal experiments are hard to be pooled with meta-analysis. Further studies are required to compare the safety of these new mobilization regimens. Thirdly, the results of meta-analysis may be confounded by the heterogeneity in mice gender since it was reported that male mice have better mobilization outcome compared with female mice [114]. It is impractical to perform subgroup analysis based on animal gender since most of the studies did not report the gender of mice and some studies included both male and female mice. However, since the network meta-analyses were performed with well-established methods and the most efficacious regimens are associated with robust MD values, we believe that the effects of these differences are minimal. Last but not least, there is a big gap between our results and translational medicine since the lack of data from human systems, but we think this study may contribute to the translation of basic research results into clinical investigations through providing comprehensive review of new promising mobilization regimens and related mechanisms.

Conclusions

In summary, this study identified several promising mobilization agents and regimens that significantly increased the mobilization of HSCs compared with the conventional agent G-CSF alone. We think that our results can provide important perspectives for future researches.

Availability of data and materials

All supporting data are included in the article and its additional files.

Abbreviations

ALT1188:

A small molecule CXCR4 antagonist

AMD3100:

A C-X-C chemokine receptor type 4 (CXCR4) antagonist

AMP:

Adenosine monophosphate

ATP:

Adenosine triphosphate

BOP:

A dual α9β1/α4β1 antagonist

BM:

Bone marrow

CFCs:

Colony-forming cells

CFUs:

Colony-forming units

CASIN:

Cell division control protein 42 (Cdc42) activity-specific inhibitor

CasNa:

Sodium caseinate

CY:

Cyclophosphamide

DFS:

Disease-free survival

CWHM-823:

Small molecule very late antigen 4 (VLA4) antagonist

CrI:

Credibility interval

DIC:

Deviance information criterion

EP80031:

Synthetic octo-saccharides, a heparan sulfate mimetic

FG-4497:

Hypoxia-inducible transcription factor prolyl hydroxylase domain enzymes inhibitor

FLT-3L:

fms-like tyrosine kinase-3 ligand

G-CSF:

Granulocyte colony-stimulating factor

HF51116:

A new CXCR4 antagonist

HSCs:

Hematopoietic stem cells

HSCT:

Hematopoietic stem cell transplantation

HSPCs:

Hematopoietic stem and progenitor cells

LD:

Low dose

LFA-1:

Leukocyte function antigen-1

LGB321:

Proviral integration site for Moloney murine leukemia virus (PIM) kinase inhibitor

LSK cells:

Lin−Sca1+ Kit+ cells;

LT-HSCS:

Long-term hematopoietic stem cells

MD:

Mean differences

Mac-1:

Macrophage antigen-1

Me6:

Me6TREN, Tris[2-(dimethylamino)ethyl]amine)

MIP-2:

Macrophage inflammatory protein-2

ML141:

Cell division control protein 42 (Cdc42) inhibitor

NA:

Not applicable

Neam-r9:

Nona-d-arginine-neamine conjugate

Neo-r9:

Nona-d-arginine-neomycin conjugate

NOX-A12:

A PEGylated mirror-image oligonucleotide that binds to CXCL12 and inhibits CXCL12 signaling

NSAIDs:

Nonsteroidal anti-inflammatory drugs

OS:

Overall survival

PB:

Peripheral blood

PBS:

Phosphate-buffered saline

PBSCs:

Peripheral blood stem cells

PEGLip-G-CSF:

Pegylated liposome formulated granulocyte colony-stimulating factor

POL5551:

A peptidic CXCR4 antagonist

RARα:

Retinoic acid receptor alpha

rhPlGF-1:

Recombinant human placental growth factor-1

r9:

N-α-acetyl-nona-D-arginine

SCA:

Sulfated colominic acid

SD:

Standard dose

SDF-1α:

Stromal cell-derived factor-1α

SLAM LSK cells:

Lin−Sca-1+c-kit+ CD48−CD150+ cells

SYRCLE:

SYstematic Review Centre for Laboratory animal Experimentation

S1PR1:

Sphingosine-1-phosphate receptor 1

S1PR3:

Sphingosine-1-phosphate receptor 3

THI:

Tetrahydroxybutylimidazole

T-140:

4F-benzoyl-TN14003, a short-modified peptide, a highly selective CXCR4 antagonist

uPAR:

Urokinase receptor

VCAM-1:

Vascular cell adhesion molecule-1

VLA-4:

Very late antigen-4

VPC01091:

A selective sphingosine-1-phosphate receptor 3 antagonist

References

  1. Chabannon C, Kuball J, Bondanza A, Dazzi F, Pedrazzoli P, Toubert A, et al. Hematopoietic stem cell transplantation in its 60s: A platform for cellular therapies. Sci Transl Med. 2018;10(436):eaap9630.

  2. Passweg JR, Baldomero H, Bader P, Bonini C, Cesaro S, Dreger P, et al. Hematopoietic SCT in Europe 2013: recent trends in the use of alternative donors showing more haploidentical donors but fewer cord blood transplants. Bone Marrow Transplant. 2015;50(4):476–82. https://doi.org/10.1038/bmt.2014.312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Shimosato Y, Tanoshima R, Tsujimoto SI, Takeuchi M, Shiba N, Kobayashi T, et al. Allogeneic bone marrow transplantation versus peripheral blood stem cell transplantation for hematologic malignancies in children: a systematic review and meta-analysis. Biol Blood Marrow Transplant. 2020;26(1):88–93.

    Article  CAS  Google Scholar 

  4. Yu X, Liu L, Xie Z, Dong C, Zhao L, Zhang J, et al. Bone marrow versus peripheral blood as a graft source for haploidentical donor transplantation in adults using post-transplant cyclophosphamide-a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2019;133:120–8. https://doi.org/10.1016/j.critrevonc.2018.05.017.

    Article  PubMed  Google Scholar 

  5. Amouzegar A, Dey BR, Spitzer TR. Peripheral blood or bone marrow stem cells? Practical considerations in hematopoietic stem cell transplantation. Transfusion medicine reviews. 2019;33(1):43–50. https://doi.org/10.1016/j.tmrv.2018.11.003.

    Article  PubMed  Google Scholar 

  6. Bonig H, Papayannopoulou T. Hematopoietic stem cell mobilization: updated conceptual renditions. Leukemia. 2013;27(1):24–31.

    Article  CAS  Google Scholar 

  7. Bensinger W, DiPersio JF, McCarty JM. Improving stem cell mobilization strategies: future directions. Bone Marrow Transplant. 2009;43(3):181–95. https://doi.org/10.1038/bmt.2008.410.

    Article  CAS  PubMed  Google Scholar 

  8. To LB, Levesque JP, Herbert KE. How I treat patients who mobilize hematopoietic stem cells poorly. Blood. 2011;118(17):4530–40. https://doi.org/10.1182/blood-2011-06-318220.

    Article  CAS  PubMed  Google Scholar 

  9. Pulsipher MA, Chitphakdithai P, Miller JP, Logan BR, King RJ, Rizzo JD, et al. Adverse events among 2408 unrelated donors of peripheral blood stem cells: results of a prospective trial from the National Marrow Donor Program. Blood. 2009;113(15):3604–11. https://doi.org/10.1182/blood-2008-08-175323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Halter J, Kodera Y, Ispizua AU, Greinix HT, Schmitz N, Favre G, et al. Severe events in donors after allogeneic hematopoietic stem cell donation. Haematologica. 2009;94(1):94–101. https://doi.org/10.3324/haematol.13668.

    Article  PubMed  Google Scholar 

  11. Cashen AF, Lazarus HM, Devine SM. Mobilizing stem cells from normal donors: is it possible to improve upon G-CSF? Bone Marrow Transplant. 2007;39(10):577–88. https://doi.org/10.1038/sj.bmt.1705616.

    Article  CAS  PubMed  Google Scholar 

  12. Roberts AW, Foote S, Alexander WS, Scott C, Robb L, Metcalf D. Genetic influences determining progenitor cell mobilization and leukocytosis induced by granulocyte colony-stimulating factor. Blood. 1997;89(8):2736–44. https://doi.org/10.1182/blood.V89.8.2736.

    Article  CAS  PubMed  Google Scholar 

  13. Xing Z, Ryan MA, Daria D, Nattamai KJ, Van Zant G, Wang L, et al. Increased hematopoietic stem cell mobilization in aged mice. Blood. 2006;108(7):2190–7.

    Article  CAS  Google Scholar 

  14. Gheibi S, Mahmoodzadeh A, Kashfi K. Data extraction from graphs using Adobe Photoshop: applications for meta-analyses. Int J Endocrinol Metab. 2019;17(4):e95216.

  15. Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE’s risk of bias tool for animal studies. BMC Med Res Method. 2014;14(1):43. https://doi.org/10.1186/1471-2288-14-43.

    Article  Google Scholar 

  16. Dias S, Welton NJ, Sutton AJ, Ades AE. NICE DSU Technical Support Document 2: a generalised linear modelling framework for pairwise and network meta-analysis of randomised controlled trials. 2011; last updated April 2014; available from http://www.nicedsu.org.uk. Accessed 19 May 2016.

  17. Skoetz N, Trelle S, Rancea M, Haverkamp H, Diehl V, Engert A, et al. Effect of initial treatment strategy on survival of patients with advanced-stage Hodgkin’s lymphoma: a systematic review and network meta-analysis. Lancet Oncol. 2013;14(10):943–52. https://doi.org/10.1016/S1470-2045(13)70341-3.

    Article  PubMed  Google Scholar 

  18. Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015;162(11):777–84. https://doi.org/10.7326/M14-2385.

    Article  PubMed  Google Scholar 

  19. Neben S, Marcus K, Mauch P. Mobilization of hematopoietic stem and progenitor cell subpopulations from the marrow to the blood of mice following cyclophosphamide and/or granulocyte colony-stimulating factor. Blood. 1993;81(7):1960–7. https://doi.org/10.1182/blood.V81.7.1960.1960.

    Article  CAS  PubMed  Google Scholar 

  20. Lord BI, Woolford LB, Wood LM, Czaplewski LG, McCourt M, Hunter MG, et al. Mobilization of early hematopoietic progenitor cells with BB-10010: a genetically engineered variant of human macrophage inflammatory protein-1 alpha. Blood. 1995;85(12):3412–5. https://doi.org/10.1182/blood.V85.12.3412.bloodjournal85123412.

    Article  CAS  PubMed  Google Scholar 

  21. Mauch P, Lamont C, Neben TY, Quinto C, Goldman SJ, Witsell A. Hematopoietic stem cells in the blood after stem cell factor and interleukin-11 administration: evidence for different mechanisms of mobilization. Blood. 1995;86(12):4674–80. https://doi.org/10.1182/blood.V86.12.4674.bloodjournal86124674.

    Article  CAS  PubMed  Google Scholar 

  22. Brasel K, McKenna HJ, Charrier K, Morrissey PJ, Williams DE, Lyman SD. Flt3 ligand synergizes with granulocyte-macrophage colony-stimulating factor or granulocyte colony-stimulating factor to mobilize hematopoietic progenitor cells into the peripheral blood of mice. Blood. 1997;90(9):3781–8. https://doi.org/10.1182/blood.V90.9.3781.

    Article  CAS  PubMed  Google Scholar 

  23. Sudo Y, Shimazaki C, Ashihara E, Kikuta T, Hirai H, Sumikuma T, et al. Synergistic effect of FLT-3 ligand on the granulocyte colony-stimulating factor-induced mobilization of hematopoietic stem cells and progenitor cells into blood in mice. Blood. 1997;89(9):3186–91. https://doi.org/10.1182/blood.V89.9.3186.

    Article  CAS  PubMed  Google Scholar 

  24. Wang J, Mukaida N, Zhang Y, Ito T, Nakao S, Matsushima K. Enhanced mobilization of hematopoietic progenitor cells by mouse MIP-2 and granulocyte colony-stimulating factor in mice. J Leukoc Biol. 1997;62(4):503–9. https://doi.org/10.1002/jlb.62.4.503.

    Article  CAS  PubMed  Google Scholar 

  25. Neipp M, Zorina T, Domenick MA, Exner BG, Ildstad ST. Effect of FLT3 ligand and granulocyte colony-stimulating factor on expansion and mobilization of facilitating cells and hematopoietic stem cells in mice: kinetics and repopulating potential. Blood. 1998;92(9):3177–88. https://doi.org/10.1182/blood.V92.9.3177.

    Article  CAS  PubMed  Google Scholar 

  26. Patchen ML, Liang J, Vaudrain T, Martin T, Melican D, Zhong S, et al. Mobilization of peripheral blood progenitor cells by Betafectin PGG-Glucan alone and in combination with granulocyte colony-stimulating factor. Stem Cells. 1998;16(3):208–17. https://doi.org/10.1002/stem.160208.

    Article  CAS  PubMed  Google Scholar 

  27. Torii Y, Nitta Y, Akahori H, Tawara T, Kuwaki T, Ogami K, et al. Mobilization of primitive haemopoietic progenitor cells and stem cells with long-term repopulating ability into peripheral blood in mice by pegylated recombinant human megakaryocyte growth and development factor. Br J Haematol. 1998;103(4):1172–80. https://doi.org/10.1046/j.1365-2141.1998.01113.x.

    Article  CAS  PubMed  Google Scholar 

  28. Zhang Y, Zhu J, Zhang Y. Effect of intravenous injection of interleukin-8 on mouse hematopoietic progenitor cell mobilization. Zhonghua Xue Ye Xue Za Zhi. 1998;19(12):642–5.

    CAS  PubMed  Google Scholar 

  29. Verma UN, van den Blink B, Pillai R, Chawla J, Mazumder A, Herscowitz HB, et al. Paclitaxel vs cyclophosphamide in peripheral blood stem cell mobilization: comparative studies in a murine model. Exp Hematol. 1999;27(3):553–60.

    Article  CAS  Google Scholar 

  30. de Haan G, Ausema A, Wilkens M, Molineux G, Dontje B. Efficient mobilization of haematopoietic progenitors after a single injection of pegylated recombinant human granulocyte colony-stimulating factor in mouse strains with distinct marrow-cell pool sizes. Br J Haematol. 2000;110(3):638–46. https://doi.org/10.1046/j.1365-2141.2000.02252.x.

    Article  PubMed  Google Scholar 

  31. Frenette PS, Weiss L. Sulfated glycans induce rapid hematopoietic progenitor cell mobilization: evidence for selectin-dependent and independent mechanisms. Blood. 2000;96(7):2460–8. https://doi.org/10.1182/blood.V96.7.2460.

    Article  CAS  PubMed  Google Scholar 

  32. Kikuta T, Shimazaki C, Ashihara E, Sudo Y, Hirai H, Sumikuma T, et al. 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):311–7.

    Article  CAS  Google Scholar 

  33. Robinson S, Mosley RL, Parajuli P, Pisarev V, Sublet J, Ulrich A, et al. Comparison of the hematopoietic activity of flt-3 ligand and granulocyte-macrophage colony-stimulating factor acting alone or in combination. J Hematother Stem Cell Res. 2000;9(5):711–20. https://doi.org/10.1089/15258160050196759.

    Article  CAS  PubMed  Google Scholar 

  34. Sweeney EA, Priestley GV, Nakamoto B, Collins RG, Beaudet AL, Papayannopoulou T. Mobilization of stem/progenitor cells by sulfated polysaccharides does not require selectin presence. Proc Natl Acad Sci U S A. 2000;97(12):6544–9. https://doi.org/10.1073/pnas.97.12.6544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Fleming WH, Mulcahy JM, McKearn JP, Streeter PR. Progenipoietin-1: a multifunctional agonist of the granulocyte colony-stimulating factor receptor and fetal liver tyrosine kinase-3 is a potent mobilizer of hematopoietic stem cells. Exp Hematol. 2001;29(8):943–51.

    Article  CAS  Google Scholar 

  36. Honda K, Takenaka K, Shinagawa K, Ishimaru F, Ikeda K, Niiya K, et al. Synergistic effects of pegylated recombinant human megakaryocyte growth and development factor and granulocyte colony-stimulating factor on mobilization of hematopoietic progenitor and stem cells with long-term repopulating ability into peripheral blood in mice. Bone Marrow Transplant. 2001;28(4):329–34. https://doi.org/10.1038/sj.bmt.1703140.

    Article  CAS  PubMed  Google Scholar 

  37. King AG, Horowitz D, Dillon SB, Levin R, Farese AM, MacVittie TJ, et al. Rapid mobilization of murine hematopoietic stem cells with enhanced engraftment properties and evaluation of hematopoietic progenitor cell mobilization in rhesus monkeys by a single injection of SB-251353, a specific truncated form of the human CXC chemokine GRObeta. Blood. 2001;97(6):1534–42.

    Article  CAS  Google Scholar 

  38. Carlo-Stella C, Di Nicola M, Magni M, Longoni P, Milanesi M, Stucchi C, et al. 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):6152–7.

    CAS  PubMed  Google Scholar 

  39. Sweeney EA, Lortat-Jacob H, Priestley GV, Nakamoto B, Papayannopoulou T. 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. https://doi.org/10.1182/blood.V99.1.44.

    Article  CAS  PubMed  Google Scholar 

  40. Velders GA, Pruijt JF, Verzaal P, van Os R, van Kooyk Y, Figdor CG, et al. Enhancement of G-CSF-induced stem cell mobilization by antibodies against the beta 2 integrins LFA-1 and Mac-1. Blood. 2002;100(1):327–33.

    Article  CAS  Google Scholar 

  41. Hofer M, Weiterová L, Vacek A, Znojil V, Pospísil M, Vácha J. Elevation of extracellular adenosine mobilizes haematopoietic progenitor cells and granulocytes into peripheral blood and enhances the mobilizing effects of granulocyte colony-stimulating factor. Eur J Haematol. 2003;71(3):204–10. https://doi.org/10.1034/j.1600-0609.2003.00120.x.

    Article  CAS  PubMed  Google Scholar 

  42. Meng FY, Jiang ZJ, Yi ZS, Xu D. Study of murine hematopoietic stem/progenitor cell mobilized by recombinant human interleukin 11 combination with granulocyte-colony stimulating factor. Zhonghua Xue Ye Xue Za Zhi. 2003;24(5):225–7.

    CAS  PubMed  Google Scholar 

  43. Ojeifo JO, Wu AG, Herscowitz HB, Meehan KR. Phenotypic and immunologic characteristics of docetaxel-mobilized peripheral blood stem cells in mice. J Hematother Stem Cell Res. 2003;12(2):189–97. https://doi.org/10.1089/152581603321628331.

    Article  CAS  PubMed  Google Scholar 

  44. Robinson SN, Chavez JM, Pisarev VM, Mosley RL, Rosenthal GJ, Blonder JM, et al. Delivery of Flt3 ligand (Flt3L) using a poloxamer-based formulation increases biological activity in mice. Bone Marrow Transplant. 2003;31(5):361–9. https://doi.org/10.1038/sj.bmt.1703816.

    Article  CAS  PubMed  Google Scholar 

  45. Liu CF, Du ZM, Zhagn YK. Effect of anti-CD49d monoclonal antibody on mobilization of CD34 positive cell into peripheral blood in mice. Zhongguo shi yan xue ye xue za zhi. 2004;12(1):59–62.

    CAS  PubMed  Google Scholar 

  46. Nakamura Y, Tajima F, Ishiga K, Yamazaki H, Oshimura M, Shiota G, et al. Soluble c-kit receptor mobilizes hematopoietic stem cells to peripheral blood in mice. Exp Hematol. 2004;32(4):390–6. https://doi.org/10.1016/j.exphem.2004.01.004.

    Article  CAS  PubMed  Google Scholar 

  47. Pelus LM, Bian H, King AG, Fukuda S. Neutrophil-derived MMP-9 mediates synergistic mobilization of hematopoietic stem and progenitor cells by the combination of G-CSF and the chemokines GRObeta/CXCL2 and GRObetaT/CXCL2delta4. Blood. 2004;103(1):110–9. https://doi.org/10.1182/blood-2003-04-1115.

    Article  CAS  PubMed  Google Scholar 

  48. Broxmeyer HE, Orschell CM, Clapp DW, Hangoc G, Cooper S, Plett PA, et al. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med. 2005;201(8):1307–18. https://doi.org/10.1084/jem.20041385.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Pelus LM, Bian H, Fukuda S, Wong D, Merzouk A, Salari H. 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. https://doi.org/10.1016/j.exphem.2004.11.008.

    Article  CAS  PubMed  Google Scholar 

  50. Selleri C, Montuori N, Ricci P, Visconte V, Baiano A, Carriero MV, et al. In vivo activity of the cleaved form of soluble urokinase receptor: a new hematopoietic stem/progenitor cell mobilizer. Cancer Res. 2006;66(22):10885–90. https://doi.org/10.1158/0008-5472.CAN-06-1311.

    Article  CAS  PubMed  Google Scholar 

  51. Abraham M, Biyder K, Begin M, Wald H, Weiss ID, Galun E, et al. Enhanced unique pattern of hematopoietic cell mobilization induced by the CXCR4 antagonist 4F-benzoyl-TN14003. Stem Cells. 2007;25(9):2158–66. https://doi.org/10.1634/stemcells.2007-0161.

    Article  CAS  PubMed  Google Scholar 

  52. Broxmeyer HE, Hangoc G, Cooper S, Campbell T, Ito S, Mantel C. AMD3100 and CD26 modulate mobilization, engraftment, and survival of hematopoietic stem and progenitor cells mediated by the SDF-1/CXCL12-CXCR4 axis. Ann New York Acad Sci. 2007;1106(1):1–19. https://doi.org/10.1196/annals.1392.013.

    Article  CAS  Google Scholar 

  53. Carlo-Stella C, Di Nicola M, Longoni P, Cleris L, Lavazza C, Milani R, et al. Placental growth factor-1 potentiates hematopoietic progenitor cell mobilization induced by granulocyte colony-stimulating factor in mice and nonhuman primates. Stem Cells. 2007;25(1):252–61. https://doi.org/10.1634/stemcells.2006-0020.

    Article  CAS  PubMed  Google Scholar 

  54. Fukuda S, Bian H, King AG, Pelus LM. The chemokine GROβ mobilizes early hematopoietic stem cells characterized by enhanced homing and engraftment. Blood. 2007;110(3):860–9. https://doi.org/10.1182/blood-2006-06-031401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Herbert KE, Walkley CR, Winkler IG, Hendy J, Olsen GH, Yuan YD, et al. Granulocyte colony-stimulating factor and an RARalpha specific agonist, VTP195183, synergize to enhance the mobilization of hematopoietic progenitor cells. Transplantation. 2007;83(4):375–84. https://doi.org/10.1097/01.tp.0000251376.75347.b4.

    Article  CAS  PubMed  Google Scholar 

  56. Kubonishi S, Kikuchi T, Yamaguchi S, Tamamura H, Fujii N, Watanabe T, et al. Rapid hematopoietic progenitor mobilization by sulfated colominic acid. Biochem Biophys Res Commun. 2007;355(4):970–5. https://doi.org/10.1016/j.bbrc.2007.02.069.

    Article  CAS  PubMed  Google Scholar 

  57. Brunner S, Zaruba MM, Huber B, David R, Vallaster M, Assmann G, et al. Parathyroid hormone effectively induces mobilization of progenitor cells without depletion of bone marrow. Exp Hematol. 2008;36(9):1157–66. https://doi.org/10.1016/j.exphem.2008.03.014.

    Article  CAS  PubMed  Google Scholar 

  58. Cramer DE, Wagner S, Li B, Liu J, Hansen R, Reca R, et al. Mobilization of hematopoietic progenitor cells by yeast-derived beta-glucan requires activation of matrix metalloproteinase-9. Stem Cells. 2008;26(5):1231–40. https://doi.org/10.1634/stemcells.2007-0712.

    Article  CAS  PubMed  Google Scholar 

  59. Tjwa M, Janssens S, Carmeliet P. Plasmin therapy enhances mobilization of HPCs after G-CSF. Blood. 2008;112(10):4048–50. https://doi.org/10.1182/blood-2008-07-166587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Albanese P, Caruelle D, Frescaline G, Delbé J, Petit-Cocault L, Huet E, et al. Glycosaminoglycan mimetics-induced mobilization of hematopoietic progenitors and stem cells into mouse peripheral blood: structure/function insights. Exp Hematol. 2009;37(9):1072–83. https://doi.org/10.1016/j.exphem.2009.06.005.

    Article  CAS  PubMed  Google Scholar 

  61. Bonig H, Chudziak D, Priestley G, Papayannopoulou T. Insights into the biology of mobilized hematopoietic stem/progenitor cells through innovative treatment schedules of the CXCR4 antagonist AMD3100. Exp Hematol. 2009;37(3):402–15.e1.

    Article  CAS  Google Scholar 

  62. Dygai AM, Vereshchagin EI, Zyuz'kov GN, Zhdanov VV, Madonov PG, Simanina EV, et al. Mobilization of progenitor cells into the blood by immobilized granulocytic colony-stimulating factor. Bull Exp Biol Med. 2009;147(4):499–502. https://doi.org/10.1007/s10517-009-0550-y.

    Article  CAS  PubMed  Google Scholar 

  63. Huang YH, Liu YC, Yen CF, Chen HC, Chen SJ, R. King CH, et al. Rapid mobilization of murine hematopoietic stem and progenitor cells with TG-0054, a novel CXCR4 antagonist. Blood. 2009;114(22):3542.

  64. Ramirez P, Rettig MP, Uy GL, Deych E, Holt MS, Ritchey JK, et al. BIO5192, a small molecule inhibitor of VLA-4, mobilizes hematopoietic stem and progenitor cells. Blood. 2009;114(7):1340–3. https://doi.org/10.1182/blood-2008-10-184721.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Yatuv R, Carmel-Goren L, Dayan I, Robinson M, Baru M. Binding of proteins to PEGylated liposomes and improvement of G-CSF efficacy in mobilization of hematopoietic stem cells. J Controlled Release. 2009;135(1):44–50. https://doi.org/10.1016/j.jconrel.2008.12.004.

    Article  CAS  Google Scholar 

  66. de Kruijf EJ, Hagoort H, Velders GA, Fibbe WE, van Pel M. Hematopoietic stem and progenitor cells are differentially mobilized depending on the duration of Flt3-ligand administration. Haematologica. 2010;95(7):1061–7. https://doi.org/10.3324/haematol.2009.016691.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ryan MA, Nattamai KJ, Xing E, Schleimer D, Daria D, Sengupta A, et al. Pharmacological inhibition of EGFR signaling enhances G-CSF-induced hematopoietic stem cell mobilization. Nat Med. 2010;16(10):1141–6. https://doi.org/10.1038/nm.2217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Tchernychev B, Ren Y, Sachdev P, Janz JM, Haggis L, O'Shea A, et al. Discovery of a CXCR4 agonist pepducin that mobilizes bone marrow hematopoietic cells. Proc Natl Acad Sci U S A. 2010;107(51):22255–9. https://doi.org/10.1073/pnas.1009633108.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Berchanski A, Kalinkovich A, Ludin A, Lapidot T, Lapidot A. Insights into the mechanism of enhanced mobilization of hematopoietic progenitor cells and release of CXCL12 by a combination of AMD3100 and aminoglycoside-polyarginine conjugates. FEBS J. 2011;278(21):4150–65. https://doi.org/10.1111/j.1742-4658.2011.08348.x.

    Article  CAS  PubMed  Google Scholar 

  70. Chigaev A, Wu Y, Williams DB, Smagley Y, Sklar LA. Discovery of very late antigen-4 (VLA-4, alpha4beta1 integrin) allosteric antagonists. J Biol Chem. 2011;286(7):5455–63. https://doi.org/10.1074/jbc.M110.162636.

    Article  CAS  PubMed  Google Scholar 

  71. Dar A, Schajnovitz A, Lapid K, Kalinkovich A, Itkin T, Ludin A, 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):1286–96. https://doi.org/10.1038/leu.2011.62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Di Giacomo F, Lewandowski D, Cabannes E, Nancy-Portebois V, Petitou M, Fichelson S, et al. Heparan sulfate mimetics can efficiently mobilize long-term hematopoietic stem cells. Haematologica. 2012;97(4):491–9.

    Article  Google Scholar 

  73. Juarez JG, Harun N, Thien M, Welschinger R, Baraz R, Pena AD, et al. Sphingosine-1-phosphate facilitates trafficking of hematopoietic stem cells and their mobilization by CXCR4 antagonists in mice. Blood. 2012;119(3):707–16. https://doi.org/10.1182/blood-2011-04-348904.

    Article  CAS  PubMed  Google Scholar 

  74. Lucas D, Bruns I, Battista M, Mendez-Ferrer S, Magnon C, Kunisaki Y, et al. Norepinephrine reuptake inhibition promotes mobilization in mice: potential impact to rescue low stem cell yields. Blood. 2012;119(17):3962–5. https://doi.org/10.1182/blood-2011-07-367102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Chen C, Cao J, Song X, Zeng L, Li Z, Li Y, et al. Adrenaline administration promotes the efficiency of granulocyte colony stimulating factor-mediated hematopoietic stem and progenitor cell mobilization in mice. Int J Hematol. 2013;97(1):50–7. https://doi.org/10.1007/s12185-012-1228-1.

    Article  CAS  PubMed  Google Scholar 

  76. Dygai AM, Zyuz'kov GN, Zhdanov VV, Udut EV, Miroshnichenko LA, Simanina EV, et al. Specific activity of electron-beam synthesis immobilized hyaluronidase on G-CSF induced mobilization of bone marrow progenitor cells. Stem Cell Rev Rep. 2013;9(2):140–7.

    Article  CAS  Google Scholar 

  77. Hoggatt J, Mohammad KS, Singh P, Hoggatt AF, Chitteti BR, Speth JM, et al. Differential stem- and progenitor-cell trafficking by prostaglandin E2. Nature. 2013;495(7441):365–9.

    Article  CAS  Google Scholar 

  78. Karpova D, Dauber K, Spohn G, Chudziak D, Wiercinska E, Schulz M, et al. The novel CXCR4 antagonist POL5551 mobilizes hematopoietic stem and progenitor cells with greater efficiency than Plerixafor. Leukemia. 2013;27(12):2322–31. https://doi.org/10.1038/leu.2013.266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kook S, Cho J, Lee SB, Lee BC. The nucleotide sugar UDP-glucose mobilizes long-term repopulating primitive hematopoietic cells. J Clin Investig. 2013;123(8):3420–35. https://doi.org/10.1172/JCI64060.

    Article  CAS  PubMed  Google Scholar 

  80. Vater A, Sahlmann J, Kröger N, Zöllner S, Lioznov M, Maasch C, et al. Hematopoietic stem and progenitor cell mobilization in mice and humans by a first-in-class mirror-image oligonucleotide inhibitor of CXCL12. Clin Pharmacol Ther. 2013;94(1):150–7. https://doi.org/10.1038/clpt.2013.58.

    Article  CAS  PubMed  Google Scholar 

  81. Chen C, Song X, Ma S, Wang X, Xu J, Zhang H, et al. Cdc42 inhibitor ML141 enhances G-CSF-induced hematopoietic stem and progenitor cell mobilization. Int J Hematol. 2014;101(1):5–12. https://doi.org/10.1007/s12185-014-1690-z.

    Article  CAS  PubMed  Google Scholar 

  82. Ghobadi A, Rettig MP, Cooper ML, Holt MS, Ritchey JK, Eissenberg L, et al. Bortezomib is a rapid mobilizer of hematopoietic stem cells in mice via modulation of the VCAM-1/VLA-4 axis. Blood. 2014;124(17):2752–4. https://doi.org/10.1182/blood-2014-08-595967.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. He S, Chu J, Vasu S, Deng Y, Yuan S, Zhang J, et al. FLT3L and plerixafor combination increases hematopoietic stem cell mobilization and leads to improved transplantation outcome. Biol Blood Marrow Transplant. 2014;20(3):309–13. https://doi.org/10.1016/j.bbmt.2013.11.024.

    Article  CAS  PubMed  Google Scholar 

  84. Saez B, Ferraro F, Yusuf RZ, Cook CM, Yu VW, Pardo-Saganta A, et al. Inhibiting stromal cell heparan sulfate synthesis improves stem cell mobilization and enables engraftment without cytotoxic conditioning. Blood. 2014;124(19):2937–47. https://doi.org/10.1182/blood-2014-08-593426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Zhang J, Ren X, Shi W, Wang S, Chen H, Zhang B, et al. Small molecule Me6TREN mobilizes hematopoietic stem/progenitor cells by activating MMP-9 expression and disrupting SDF-1/CXCR4 axis. Blood. 2014;123(3):428–41. https://doi.org/10.1182/blood-2013-04-498535.

    Article  CAS  PubMed  Google Scholar 

  86. Forristal CE, Nowlan B, Jacobsen RN, Barbier V, Walkinshaw G, Walkley CR, et al. HIF-1α is required for hematopoietic stem cell mobilization and 4-prolyl hydroxylase inhibitors enhance mobilization by stabilizing HIF-1α. Leukemia. 2015;29(6):1366–78. https://doi.org/10.1038/leu.2015.8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Santiago-Osorio E, Ledesma-Martínez E, Aguiñiga-Sánchez I, Poblano-Pérez I, Weiss-Steider B, Montesinos-Montesinos JJ, et al. Sodium caseinate (CasNa) induces mobilization of hematopoietic stem cells in a BALB/c mouse model. Med Sci Monit Basic Res. 2015;21:206–12. https://doi.org/10.12659/MSMBR.895442.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Wysoczynski M, Ratajczak J, Pedziwiatr D, Rokosh G, Bolli R, Ratajczak MZ. Identification of heme oxygenase 1 (HO-1) as a novel negative regulator of mobilization of hematopoietic stem/progenitor cells. Stem Cell Rev Rep. 2015;11(1):110–8.

    Article  CAS  Google Scholar 

  89. Xing S, Xiong GL, Shen X, Liu XL, Yang M, Dong B, et al. Mobilization effect of HS6101 on hematopoietic cells of mice. Zhongguo shi yan xue ye xue za zhi. 2015;23(5):1427–31. https://doi.org/10.7534/j.issn.1009-2137.2015.05.039.

    Article  CAS  PubMed  Google Scholar 

  90. Cao B, Zhang Z, Grassinger J, Williams B, Heazlewood CK, Churches QI, et al. Therapeutic targeting and rapid mobilization of endosteal HSC using a small molecule integrin antagonist. Nature Commun. 2016;7(1):11007. https://doi.org/10.1038/ncomms11007.

    Article  CAS  Google Scholar 

  91. Lu XJ, Chen Q, Rong YJ, Yang GJ, Li CH, Xu NY, et al. LECT2 drives haematopoietic stem cell expansion and mobilization via regulating the macrophages and osteolineage cells. Nature commun. 2016;7:12719.

    Article  CAS  Google Scholar 

  92. Yan BZ, Ma HM, Kong CQ, Liang Y, Zhu WY, Jiang ST. Combination effect of AMD3100 and dexamethasone on the mobilization of hematopoietic stem cells. Chinese J Tissue Eng Res. 2016;20(36):5351–7.

    Google Scholar 

  93. Adamiak M, Chelvarajan L, Lynch KR, Santos WL, Abdel-Latif A, Ratajczak MZ. Mobilization studies in mice deficient in sphingosine kinase 2 support a crucial role of the plasma level of sphingosine-1-phosphate in the egress of hematopoietic stem progenitor cells. Oncotarget. 2017;8(39):65588–600. https://doi.org/10.18632/oncotarget.19514.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Karpova D, Ritchey JK, Holt MS, Abou-Ezzi G, Monlish D, Batoon L, et al. Continuous blockade of CXCR4 results in dramatic mobilization and expansion of hematopoietic stem and progenitor cells. Blood. 2017;129(21):2939–49. https://doi.org/10.1182/blood-2016-10-746909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Nowlan B, Futrega K, Brunck ME, Walkinshaw G, Flippin LE, Doran MR, et al. HIF-1α-stabilizing agent FG-4497 rescues human CD34(+) cell mobilization in response to G-CSF in immunodeficient mice. Exp Hematol. 2017;52:50–5.e6.

    Article  CAS  Google Scholar 

  96. Ogle ME, Olingy CE, Awojoodu AO, Das A, Ortiz RA, Cheung HY, et al. Sphingosine-1-phosphate receptor-3 supports hematopoietic stem and progenitor cell residence within the bone marrow niche. Stem Cells. 2017;35(4):1040–52. https://doi.org/10.1002/stem.2556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Redpath AN, François M, Wong SP, Bonnet D, Rankin SM. Two distinct CXCR4 antagonists mobilize progenitor cells in mice by different mechanisms. Blood Adv. 2017;1(22):1934–43.

    Article  CAS  Google Scholar 

  98. Wang W, Yu S, Myers J, Wang Y, Xin WW, Albakri M, et al. Notch2 blockade enhances hematopoietic stem cell mobilization and homing. Haematologica. 2017;102(10):1785–95. https://doi.org/10.3324/haematol.2017.168674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Adamiak M, Bujko K, Cymer M, Plonka M, Glaser T, Kucia M, et al. Novel evidence that extracellular nucleotides and purinergic signaling induce innate immunity-mediated mobilization of hematopoietic stem/progenitor cells. Leukemia. 2018;32(9):1920–31. https://doi.org/10.1038/s41375-018-0122-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Ghobadi A, Rettig MP, Holt MS, Ritchey JK, Kennerly K, Chendamarai E, et al. Ixazomib, an oral proteasome inhibitor, induces rapid mobilization of hematopoietic progenitor cells in mice. Blood. 2018;131(23):2594–6.

    Article  CAS  Google Scholar 

  101. Hoggatt J, Singh P, Tate TA, Chou BK, Datari SR, Fukuda S, et al. Rapid mobilization reveals a highly engraftable hematopoietic stem cell. Cell. 2018;172(1-2):191–204.e10.

    Article  CAS  Google Scholar 

  102. Notario L, Alari-Pahissa E, Albentosa A, Leiva M, Sabio G, Lauzurica P. Anti-CD69 therapy induces rapid mobilization and high proliferation of HSPCs through S1P and mTOR. Leukemia. 2018;32(6):1445–57.

  103. Wu CH, Song JS, Kuan HH, Wu SH, Chou MC, Jan JJ, et al. Development of stem-cell-mobilizing agents targeting CXCR4 receptor for peripheral blood stem sell transplantation and beyond. J Med Chem. 2018;61(3):818–33.

    Article  CAS  Google Scholar 

  104. Adamiak M, Bujko K, Brzezniakiewicz-Janus K, Kucia M, Ratajczak J, Ratajczak MZ. The inhibition of CD39 and CD73 cell surface ectonucleotidases by small molecular inhibitors enhances the mobilization of bone marrow residing stem cells by decreasing the extracellular level of adenosine. Stem Cell Rev Rep. 2019;15(6):892–9.

  105. Alt C, Yuan S, Wu F, Stankovich B, Calaoagan J, Schopies S, et al. 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):1475–85.

    Article  CAS  Google Scholar 

  106. Bisht K, Brunck ME, Matsumoto T, McGirr C, Nowlan B, Fleming W, et al. HIF prolyl hydroxylase inhibitor FG-4497 enhances mouse hematopoietic stem cell mobilization via VEGFR2/KDR. Blood Adv. 2019;3(3):406–18.

  107. Karpova D, Rettig MP, Ritchey J, Cancilla D, Christ S, Gehrs L, et al. Targeting VLA4 integrin and CXCR2 mobilizes serially repopulating hematopoietic stem cells. J Clin Investig. 2019;129(7):2745–59. https://doi.org/10.1172/JCI124738.

    Article  PubMed  Google Scholar 

  108. Liu W, Du W. Rational identification of a Cdc42 inhibitor presents a new regimen for long-term hematopoietic stem cell mobilization. Diabetes. 2019;33(3):749–61.

    CAS  Google Scholar 

  109. Müller TA, Pennisi S, Zwick A, Decker S, Klein C, Rister B, et al. PIM1 inhibition effectively enhances plerixafor-induced HSC mobilization by counteracting CXCR4 upregulation and blocking CXCL12 secretion. Leukemia. 2019;33(5):1296–301.

  110. Smith-Berdan S, Bercasio A, Rajendiran S, Forsberg EC. Viagra enables efficient, single-day hematopoietic stem cell mobilization. Stem cell Rep. 2019;13(5):787–92.

    Article  CAS  Google Scholar 

  111. Szade A, Szade K, Nowak WN, Bukowska-Strakova K, Muchova L, Gońka M, et al. Cobalt protoporphyrin IX increases endogenous G-CSF and mobilizes HSC and granulocytes to the blood. EMBO Mol Med. 2019;11(12):e09571.

  112. Fang X, Fang X, Mao Y, Ciechanover A, Xu Y, An J, et al. A novel small molecule CXCR4 antagonist potently mobilizes hematopoietic stem cells in mice and monkeys. Stem Cell Res Ther. 2021;12(1):17.

  113. Kaur S, Sehgal A, Wu AC, Millard SM, Batoon L, Sandrock CJ, et al. Stable colony-stimulating factor 1 fusion protein treatment increases hematopoietic stem cell pool and enhances their mobilisation in mice. J Hematol Oncol. 2021;14(1):3.

  114. Pesek G, Cottler-Fox M. Hematopoietic stem cell mobilization: a clinical protocol. Methods Mol Biol. 2012;904:69–77. https://doi.org/10.1007/978-1-61779-943-3_5.

    Article  CAS  PubMed  Google Scholar 

  115. Forristal CE, Levesque JP. Targeting the hypoxia-sensing pathway in clinical hematology. Stem Cells Transl Med. 2014;3(2):135–40. https://doi.org/10.5966/sctm.2013-0134.

    Article  CAS  PubMed  Google Scholar 

  116. Bilgin YM, de Greef GE. Plerixafor for stem cell mobilization: the current status. Curr Opin Hematol. 2016;23(1):67–71. https://doi.org/10.1097/MOH.0000000000000200.

    Article  CAS  PubMed  Google Scholar 

  117. Donahue RE, Jin P, Bonifacino AC, Metzger ME, Ren J, Wang E, et al. Plerixafor (AMD3100) and granulocyte colony-stimulating factor (G-CSF) mobilize different CD34+ cell populations based on global gene and microRNA expression signatures. Blood. 2009;114(12):2530–41. https://doi.org/10.1182/blood-2009-04-214403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Kean LS, Sen S, Onabajo O, Singh K, Robertson J, Stempora L, et al. Significant mobilization of both conventional and regulatory T cells with AMD3100. Blood. 2011;118(25):6580–90. https://doi.org/10.1182/blood-2011-06-359331.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. DiPersio JF, Micallef IN, Stiff PJ, Bolwell BJ, Maziarz RT, Jacobsen E, et al. Phase III prospective randomized double-blind placebo-controlled trial of plerixafor plus granulocyte colony-stimulating factor compared with placebo plus granulocyte colony-stimulating factor for autologous stem-cell mobilization and transplantation for patients with non-Hodgkin's lymphoma. J Clin Oncol. 2009;27(28):4767–73. https://doi.org/10.1200/JCO.2008.20.7209.

    Article  CAS  PubMed  Google Scholar 

  120. DiPersio JF, Stadtmauer EA, Nademanee A, Micallef IN, Stiff PJ, Kaufman JL, et al. Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood. 2009;113(23):5720–6. https://doi.org/10.1182/blood-2008-08-174946.

    Article  CAS  PubMed  Google Scholar 

  121. Zhu J, Huang H, Chen H, Zhang X, Li Z, Wu D, et al. Plerixafor and granulocyte-colony-stimulating factor for mobilization of hematopoietic stem cells for autologous transplantation in Chinese patients with non-Hodgkin's lymphoma: a randomized Phase 3 study. Transfusion. 2018;58(1):81–7. https://doi.org/10.1111/trf.14426.

    Article  CAS  PubMed  Google Scholar 

  122. Giralt S, Costa L, Schriber J, Dipersio J, Maziarz R, McCarty J, et al. Optimizing autologous stem cell mobilization strategies to improve patient outcomes: consensus guidelines and recommendations. Biol Blood Marrow Transplant. 2014;20(3):295–308. https://doi.org/10.1016/j.bbmt.2013.10.013.

    Article  PubMed  Google Scholar 

  123. Duarte RF, Shaw BE, Marín P, Kottaridis P, Ortiz M, Morante C, et al. Plerixafor plus granulocyte CSF can mobilize hematopoietic stem cells from multiple myeloma and lymphoma patients failing previous mobilization attempts: EU compassionate use data. Bone Marrow Transplant. 2011;46(1):52–8. https://doi.org/10.1038/bmt.2010.54.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This work is supported by the Military Logistics Project (BWS13C018) and the National Natural Science Foundation of China (NSFC 81800172). The funding had no role in the study design, data collection, data analysis, data interpretation, or manuscript writing.

Author information

Author notes

  1. Chengxin Luo and Li Wang contributed equally to this work.

Authors and Affiliations

  1. Center for Hematology, Southwest Hospital, Third Military Medical University, #30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China

    Chengxin Luo, Guixian Wu, Xiangtao Huang, Yali Zhang, Yanni Ma, Mingling Xie, Yanni Sun, Yarui Huang, Zhen Huang, Hui Li, Yu Hou, Shuangnian Xu & Jieping Chen

  2. Key Laboratory of Cancer Immunotherapy of Chongqing, Chongqing, China

    Chengxin Luo, Guixian Wu, Xiangtao Huang, Yali Zhang, Yanni Ma, Mingling Xie, Yanni Sun, Yarui Huang, Zhen Huang, Hui Li, Yu Hou, Shuangnian Xu & Jieping Chen

  3. Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

    Li Wang

  4. Department of Health Statistics, Third Military Medical University, Chongqing, China

    Qiuyue Song

  5. Institute of Infectious Disease, Southwest Hospital, Third Military Medical University, #30 Gaotanyan Street, Shapingba District, Chongqing, 400038, China

    Xi Li

Authors
  1. Chengxin Luo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Li Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guixian Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiangtao Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yali Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yanni Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Mingling Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yanni Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yarui Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zhen Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Qiuyue Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hui Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yu Hou
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Xi Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Shuangnian Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Jieping Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SNX and JPC designed and supervised the study. CXL and XL performed database searching, study selection, data extraction, statistical analyses, and manuscript writing. LW and SNX contributed to data checking and manuscript revision. GXW, XTH, YLZ, YNM, MLX, YNS, YRH, ZH, QYS, HL, and YH helped with data extraction, data checking, and statistical analyses. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Xi Li, Shuangnian Xu or Jieping Chen.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file 1: Supplementary Table 1

. Characteristics of the 95 studies included for review.

Additional file 2: Supplementary Table 2

. Risk of bias assessment using the SYRCLE tool.

Additional file 3: Supplementary Table 3

. Results about the mobilization of different LSK subsets.

Additional file 4: Supplementary Table 4

. Characteristics and results of in vivo transplantation experiments.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Luo, C., Wang, L., Wu, G. et al. Comparison of the efficacy of hematopoietic stem cell mobilization regimens: a systematic review and network meta-analysis of preclinical studies. Stem Cell Res Ther 12, 310 (2021). https://doi.org/10.1186/s13287-021-02379-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13287-021-02379-6

Keywords

  • Hematopoietic stem cells
  • Mobilization
  • Animal studies
  • Network meta-analysis

Stem Cell Research & Therapy

ISSN: 1757-6512