The mobilization of hematopoietic progenitors to peripheral blood is predictive of the hematopoietic syndrome after total or partial body irradiation of mice

Grande, Teresa; Bueren, Juan A.

doi:10.1016/j.ijrobp.2005.09.036

Cited by 16 publications

(14 citation statements)

References 43 publications

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“…In addition, irradiation of mice before transplantation could further account for poor HSPC mobilization [4,15]. Indeed, total body irradiation and cytotoxic drugs damage the BM stroma in humans [4,16,17] and mice [18,19] in a similar manner and decrease subsequent HSPC mobilization.…”

Section: Resultsmentioning

confidence: 99%

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: Resultsmentioning

confidence: 99%

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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“…The spleen, as a part of hematopoietic system, involves the regulatory mechanism of BM hemopoiesis; spleen index reflects its function status [31]. It is generally agreed that impairment of BM hematopoietic function and PB cells ultimately lead to hemorrhage and infection [19]. Accordingly, endoCFUs counts, BMNC counts and PB leukocyte counts were used to evaluate hemopoiesis.…”

Section: Discussionmentioning

confidence: 99%

“…After exposure to 4Gy of irradiation, bone marrow (BM) cells were obtained from anesthetized mice by aseptic isolation of the femurs followed by a flushing of the marrow with RPMI 1640 medium, using a 25-gauge needle, and single cell suspensions were made as described previously [19]. BM cells were counted immediately using a hemocytometer.…”

Section: Methodsmentioning

confidence: 99%

“…Peripheral blood (PB) samples were obtained from the tail vein of mice at different days after irradiation as described previously [19]. Numbers of PB leukocyte were determined with a hemocytometer.…”

Section: Methodsmentioning

confidence: 99%

“…Less than about 2% of men who received total-body IR are able to father children later in life [5]. The hematopoietic system is also known to be sensitive to IR, and myelosuppression is a critical issue for individuals exposed to IR [6]. Hemorrhage and infection are serious complications in hematopoietic syndrome.…”

Section: Introductionmentioning

confidence: 99%

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Hydrogen-rich saline protects spermatogenesis and hematopoiesis in irradiated BALB/c mice

et al. 2012

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SummaryBackgroundRecent studies show that molecular hydrogen (dihydrogen, H2) has potential as an effective and safe radioprotective agent through reducing oxidative stress. The aim of this study was to investigate whether H2 is able to protect spermatogenesis and hematopoiesis from radiation-induced injuries.Material/MethodsH2 was dissolved in physiological saline using an apparatus produced by our department. 60Co-gamma rays in the irradiation centre were used for irradiation. Spermatid head counts and histological analysis were used to evaluate spermatogenesis. Endogenous hematopoietic spleen colony formation (endoCFUs), bone marrow nucleated cells (BMNC) and peripheral blood (PB) leukocytes were used to evaluate hemopoiesis.ResultsThis study demonstrates that treating mice with H2 before ionizing radiation (IR) can increase the spermatid head count and protect seminiferous epithelium from IR. This study also demonstrates that H2 could significantly increase the number of endoCFUs, BMNC and PB leukocyte.ConclusionsThis study suggests that hydrogen-rich saline could partially protect spermatogenesis and hematopoiesis in irradiated mice.

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Development of Radiation Countermeasures

Pellmar

2008

Wiley Handbook of Science and Technology for Homeland Security

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Medical countermeasures are required to address the emerging radiological and nuclear threats. Radiation injury can result from exposure to external, penetrating radiation or internalized radionuclides. Countermeasures for internal contamination focus on decorporation and protecting the primary site of activity. No countermeasures are currently approved for the acute radiation syndrome that results from external exposures, but significant efforts are ongoing to develop new agents to counter the cascade of damage from ionizing radiation. Antioxidants and enzyme mimics are directed toward prevention of free radical damage to macromolecules. Other agents target the affected cell‐signaling pathways: preventing apoptosis, triggering cell cycle arrest, or modulating the inflammatory response. To counter the loss of progenitor cells, particularly in the bone marrow and the gut, drugs such as the cytokines and other immunomodulators are developed to promote proliferation of new cells. If radiation injury proceeds to organ failure and infection, supportive care and antibiotics provide significant therapeutic value. In addition to the radiation dose, several factors impact the severity of the injury. Among these are radiation quality (e.g. neutron–gamma mixed fields) and dose rate, combined injuries, and partial‐body exposures. In future efforts, it will be important to consider these factors, which can modulate the radiation response and possibly affect the efficacy of the treatments. Although an ideal countermeasure that is inexpensive, stable with a long shelf‐life, easily administered, nontoxic, and efficacious is yet to be attained, new options continue to arise. Many promising drugs are in the pipeline.

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The mobilization of hematopoietic progenitors to peripheral blood is predictive of the hematopoietic syndrome after total or partial body irradiation of mice

Cited by 16 publications

References 43 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

Hydrogen-rich saline protects spermatogenesis and hematopoiesis in irradiated BALB/c mice

Development of Radiation Countermeasures

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