Extracellular molecules in hematopoietic stem cell mobilisation

Bendall, Linda J.

doi:10.1007/s12185-016-2123-y

Cited by 15 publications

(11 citation statements)

References 120 publications

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“…2E-H The poor efficacy of human G-CSF to mobilize human HSPCs in NSG mice in our experiments is consistent with previous publications [9,10]. Poor human HSPC mobilization in humanized NSG or NOD/SCID mice has been linked to lack of immunoglobulins that promote the activation of complement proteins C3 and C5 in response to G-CSF [10][11][12] and the formation of the membrane attack complex that lyses blood erythrocytes, releasing the chemoattractant shingossine-1-phosphate into the blood [13,14]. In addition, irradiation of mice before transplantation could further account for poor HSPC mobilization [4,15].…”

Section: Resultssupporting

confidence: 87%

HIF-1α-stabilizing agent FG-4497 rescues human CD34+ cell mobilization in response to G-CSF in immunodeficient mice

Nowlan

Futrega

Brunck

et al. 2017

Experimental Hematology

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Granulocyte colony-stimulating factor (G-CSF) is used routinely in the clinical setting to mobilize hematopoietic stem progenitor cells (HSPCs) into the patient's blood for collection and subsequent transplantation. However, a significant proportion of patients who have previously received chemotherapy or radiotherapy and require autologous HSPC transplantation cannot mobilize the minimal threshold of mobilized HSPCs to achieve rapid and successful hematopoietic reconstitution. Although several alternatives to the G-CSF regime have been tested, few are used in the clinical setting. We have shown previously in mice that administration of prolyl 4-hydroxylase domain enzyme (PHD) inhibitors, which stabilize hypoxiainducible factor (HIF)-1a, synergize with G-CSF in vivo to enhance mouse HSPC mobilization into blood, leading to enhanced engraftment via an HSPC-intrinsic mechanism. To evaluate whether PHD inhibitors could be used to enhance mobilization of human HSPCs, we humanized nonobese, diabetic severe combined immune-deficient Il2rg L/L mice by transplanting them with human umbilical cord blood CD34 + HSPCs and then treating them with G-CSF with and without co-administration of the PHD inhibitor FG-4497. We observed that combination treatment with G-CSF and FG-4497 resulted in significant mobilization of human lineage-negative (Lin L ) CD34 + HSPCs and more primitive human Lin L CD34 + CD38 L HSPCs into blood and spleen, whereas mice treated with G-CSF alone did not mobilize human HSPCs significantly. These results suggest that the PHD inhibitor FG-4497 also increases human HSPC mobilization in a xenograft mouse model, suggesting the possibility of testing PHD inhibitors to boost HSPC mobilization in response to G-CSF in humans. Copyright Ó 2017 ISEH -International Society for Experimental Hematology. Published by Elsevier Inc. Granulocyte-stimulating factor (G-CSF) is used in the clinical setting to mobilize CD34þ hematopoietic stem and progenitor cells (HSPCs) into the blood for subsequent transplantation [1]. Autologous HSPC transplantations, which represent half of all HSC transplantations, increase survival rates of relapsed non-Hodgkin's lymphoma patients and multiple myeloma patients [2,3]. In the autologous transplantation setting, 20-60% of patients previously treated with repeated cycles of high-dose chemotherapy or radiotherapy fail to mobilize the minimum threshold of 2 Â 10 6 CD34 þ cells/kg required for rapid hematopoietic reconstitution [4], precluding potentially curative autologous HSPC transplantation. The synthetic CXCR4 chemokine receptor antagonist AMD3100/Plerixafor synergizes with G-CSF to promote HSPC mobilization and salvages mobilization in about 70% of poor mobilizers [5,6]. Because Plerixafor is the only drug approved by the U.S. Food and Drug Administration that boosts HSPC mobilization, there remains considerable scope to identify alternative strategies to further improve HSPC mobilization in poor mobilizers [4].Recently, we have demonstrated in mice that HSPCautonomous stabilizatio...

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Section: Resultssupporting

confidence: 87%

HIF-1α-stabilizing agent FG-4497 rescues human CD34+ cell mobilization in response to G-CSF in immunodeficient mice

Nowlan

Futrega

Brunck

et al. 2017

Experimental Hematology

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“…4,36,37 However, mobilization of normal hematopoietic stem/progenitor cells (HSPCs) to PB is not desired because it would accelerate BM aplasia and subsequent hematopoietic defects. Thus, we next analyzed whether lenalidomide also mobilizes normal HSPCs to PB.…”

Section: Resultsmentioning

confidence: 99%

“…Clearly, the CXCR4/SDF1 axis plays a major role in the interaction of HSPCs and leukemic cells within BM niches. CXCR4 is highly expressed in HSPCs/leukemic cells whereas SDF1 is a cytokine commonly released by BM-MSCs, 37,38 (Figure 5A). Consequently, we first treated both AML cell lines and primary non-del5q/5q- AML blasts with lenalidomide and pomalidomide and found a significant (25%–50%) reduction in the levels of CXCR4 in AML cells similar to treatment with the specific CXCR4 inhibitor AMD3100 (Figure 5B).…”

Section: Resultsmentioning

confidence: 99%

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IMiDs mobilize acute myeloid leukemia blasts to peripheral blood through downregulation of CXCR4 but fail to potentiate AraC/Idarubicin activity in preclinical models of non del5q/5q- AML

et al. 2018

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Treatment for acute myeloid leukemia (AML) remains suboptimal and many patients remain refractory or relapse upon standard chemotherapy based on nucleoside analogs plus anthracyclines. The crosstalk between AML cells and the BM stroma is a major mechanism underlying therapy resistance in AML. Lenalidomide and pomalidomide, a new generation immunomodulatory drugs (IMiDs), possess pleiotropic anti-leukemic properties including potent immune-modulating effects and are commonly used in hematological malignances associated with intrinsic dysfunctional BM such as myelodysplastic syndromes and multiple myeloma. Whether IMiDs may improve the efficacy of current standard treatment in AML remains understudied. Here, we have exploited in vitro and in vivo preclinical AML models to analyze whether IMiDs potentiate the efficacy of AraC/Idarubicin-based standard AML chemotherapy by interfering with the BM stroma-mediated chemoresistance. We report that IMiDs do not exert cytotoxic effects on either non-del5q/5q- AML cells nor BM-MSCs, but they enhance the immunomodulatory properties of BM-MSCs. When combined with AraC/Idarubicin, IMiDs fail to circumvent BM stroma-mediated resistance of non-del5q/5q- AML cells in vitro and in vivo but induce robust extramedullary mobilization of AML cells. When administered as a single agent, lenalidomide specifically mobilizes non-del5q/5q- AML cells, but not healthy CD34+ cells, to peripheral blood (PB) through specific downregulation of CXCR4 in AML blasts. Global gene expression profiling supports a migratory/mobilization gene signature in lenalidomide-treated non-del5q/5q- AML blasts but not in CD34+ cells. Collectively, IMiDs mobilize non-del5q/5q- AML blasts to PB through CXCR4 downregulation, but fail to potentiate AraC/Idarubicin activity in preclinical models of non-del5q/5q- AML.

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“…Winkler et al highlight the various cellular components of the BM niche including neutrophils, endothelial cells, mesenchymal stromal cells, osteoblasts, osteoclasts and sympathetic neurons and the role they play, either directly or indirectly, on HSC mobilization [10]. Bendall summarizes the role of the extracellular molecules within the niche that facilitate HSC mobilization, with particular emphasis on sphingosine 1 phosphate (S1P), complement cascade and the neurotransmitters [11]. Le Texeira et al review the potential of regulatory T-cells (T reg ) for improving allogeneic HSC transplantation [12] and Domingues et al provide an update on the latest HSC mobilization agents currently in development and their potential impact in clinical transplantation [13].…”

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confidence: 99%

Factors that influence a mobilized HSC product

Nilsson

2016

Int J Hematol

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and the subsequent mobilized product, which can ultimately have profound downstream effects on transplant outcomes.In this issue, four review articles will cover various factors that influence a mobilized product used in HSC transplant. Winkler et al. highlight the various cellular components of the BM niche including neutrophils, endothelial cells, mesenchymal stromal cells, osteoblasts, osteoclasts and sympathetic neurons and the role they play, either directly or indirectly, on HSC mobilization [10]. Bendall summarizes the role of the extracellular molecules within the niche that facilitate HSC mobilization, with particular emphasis on sphingosine 1 phosphate (S1P), complement cascade and the neurotransmitters [11]. Le Texeira et al. review the potential of regulatory T-cells (T reg ) for improving allogeneic HSC transplantation [12] and Domingues et al. provide an update on the latest HSC mobilization agents currently in development and their potential impact in clinical transplantation [13].A complete understanding of all factors that influence HSC mobilization is critical for development of an "optimal" mobilized blood product. Such an optimal mobilized product should not only enable rapid and long-term HSC engraftment, but should also provide accompanying benefits such as reduced transplant associated costs, minimized donor side effects, reducing relapse rates when used in the treatment of disease, as well as balancing the effects of graft vs leukaemia and graft vs host effects in allogeneic transplants. With these considerations in mind, it is anticipated that the development of novel HSC mobilization agents, as well as the "optimization" of a transplant product will continue in the future.The guest editor would like to thank all review authors for their contributions, Dr. Kitamura for the invitation to submit this Progress in Hematology and the Journal Office of International Journal of Hematology for their editorial work. Dear Editor,The presence of transplantable circulating peripheral blood (PB) hematopoietic stem cells (HSC) was first recognized in the 1960s [1], around the same time as the first described use of therapeutic apheresis [2], which is required to make PB HSC transplantation feasible. However, it was not until two decades later, after the discovery of granulocyte colony stimulating factor (G-CSF) [3], its isolation [4,5] and subsequent demonstration of its ability to increase the concentration of HSC in the PB through a process termed mobilization [6], that mobilized PB HSC became a routine source HSC for transplantation (reviewed in [7]). Nevertheless, G-CSF based mobilization is not without its drawbacks, proving to be ineffective in some patients and causing a variety of shortterm side effects in others, driving efforts to develop more improved mobilization strategies (reviewed in [7]).An improved understanding of how HSC are regulated and retained within the BM stem cell niche (reviewed in [8]) has enabled development of better HSC mobilization strategies. For example, the identific...

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Extracellular molecules in hematopoietic stem cell mobilisation

Cited by 15 publications

References 120 publications

HIF-1α-stabilizing agent FG-4497 rescues human CD34+ cell mobilization in response to G-CSF in immunodeficient mice

HIF-1α-stabilizing agent FG-4497 rescues human CD34+ cell mobilization in response to G-CSF in immunodeficient mice

IMiDs mobilize acute myeloid leukemia blasts to peripheral blood through downregulation of CXCR4 but fail to potentiate AraC/Idarubicin activity in preclinical models of non del5q/5q- AML

Factors that influence a mobilized HSC product

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