• Filgrastim
• G-CSF
• Hematopoietic stem cell mobilization
• Posology

• Apheresis
• Autologous hematopoietic stem cell transplant (AHSCT)
• Flow and mass cytometry
• Hematological malignancies
• Immunophenotyping

• CD34
• absolute cell count
• allowable total error
• flow cytometry
• measurement uncertainty

• HSPC
• exercise
• interval cycling
• natural killer cell
• peripheral blood stem cell donation
• transplantation

• breast cancer
• cancer immunotherapy
• chemotherapy

• K08 CA259533 NCI NIH HHS
• P30 CA008748 NCI NIH HHS

• anemia
• inflammation
• polytrauma
• pseudofracture
• shock

• Animals
• Shock, Hemorrhagic/complications
• Rats, Sprague-Dawley
• Male
• Disease Models, Animal
• Anemia/etiology
• Anemia/pathology
• Multiple Trauma/complications
• Multiple Trauma/pathology
• Rats
• Bone Marrow/pathology
• Toll-Like Receptor 4/metabolism
• Lung Injury/etiology
• Lung Injury/pathology
• Granulocyte Colony-Stimulating Factor/blood
• Hemoglobins

• R01 GM105893 NIGMS NIH HHS
• NIH NIGMS T32 GM-008721 NIGMS NIH HHS
• NIH NIGMS R01 GM105893 NIGMS NIH HHS
• National Institute of General Medical Sciences

• IDO-1
• TDO2
• Tryptophan metabolism
• aryl hydrocarbon receptor
• cancer stem cells
• hematopoietic stem cells
• human diseases
• induced pluripotent stem cells
• kynurenine pathway
• mesenchymal stromal cells
• neural stem cells

• St. Vincent’s Clinic Foundation
• Multiple Sclerosis Australia
• St Vincent’s Curran Foundation

• Mice
• Animals
• Humans
• Hematopoietic Stem Cells/metabolism
• Bone Marrow
• Genetic Therapy/methods
• Lentivirus/genetics

• R01 HL136135 NHLBI NIH HHS

• exosomes
• trauma
• injury
• bone marrow dysfunction
• hematopoietic progenitor

• Humans
• Exosomes
• Cohort Studies
• Prospective Studies
• Hematopoietic Stem Cells
• Cytokines
• Granulocytes
• Cells, Cultured

• R01 GM105893 NIGMS NIH HHS
• T32 GM008721 NIGMS NIH HHS

• delivery
• gene therapy
• hematopoietic stem cells
• imaging
• nanoparticles
• targeting

• Health∼Holland

Severe traumatic injury results in a cascade of systemic changes which negatively affect normal erythropoiesis. Immediately after injury, acute blood loss leads to anemia, however, patients can remain anemic for as long as 6 months after injury. Research on the underlying mechanisms of such alterations of erythropoiesis after trauma has focused on the prolonged hypercatecholaminemia seen after trauma. Supraphysiologic elevation of catecholamines leads to an inhibitive effect on erythropoiesis. There is evidence to show that alleviation of the neuroendocrine stress response following trauma reduces these inhibitory effects. Both beta blockade and alpha-2 adrenergic receptor stimulation have demonstrated increased growth of hematopoietic progenitor cells as well as increased pro-erythropoietic cytokines after trauma. This review will describe prior research on the neuroendocrine stress response after trauma and its consequences on erythropoiesis, which offer insight into underlying mechanisms of prolonged anemia postinjury. We will then discuss the beneficial effects of adrenergic modulation to improve erythropoiesis following injury and propose future directions for the field.

• alpha agonist
• beta blockade
• bone marrow
• catecholamine
• erythropoiesis
• trauma

High-dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplantation has been explored and has played an important role in the management of patients with high-risk germ cell tumors (GCTs) who failed to be cured by conventional chemotherapy. Hematopoietic stem cells (HSCs) collected from the peripheral blood, after appropriate pharmacologic mobilization, have largely replaced bone marrow as the principal source of HSCs in transplants. As it is currently common practice to perform tandem or multiple sequential cycles of HDCT, it is anticipated that collection of large numbers of HSCs from the peripheral blood is a prerequisite for the success of the procedure. Moreover, the CD34+ cell dose/kg of body weight infused after HDCT has proven to be a major determinant of hematopoietic engraftment, with patients who receive > 2 × 10⁶ CD34+ cells/kg having consistent, rapid, and sustained hematopoietic recovery. However, many patients with relapsed/refractory GCTs have been exposed to multiple cycles of myelosuppressive chemotherapy, which compromises the efficacy of HSC mobilization with granulocyte colony-stimulating factor with or without chemotherapy. Therefore, alternative strategies that use novel agents in combination with traditional mobilizing regimens are required. Herein, after an overview of the mechanisms of HSCs mobilization, we review the existing literature regarding studies reporting various HSC mobilization approaches in patients with relapsed/refractory GCTs, and finally report newer experimental mobilization strategies employing novel agents that have been applied in other hematologic or solid malignancies.

• Hematopoietic stem cells
• Germ cell tumors
• Hematopoietic stem cell transplantation
• Granulocyte colony-stimulating factor
• Plerixafor

The global SARS-CoV-2 pandemic starting in 2019 has already reached more than 2.3 million deaths. Despite the scientific community’s efforts to investigate the COVID-19 disease, a drug for effectively treating or curing patients yet needs to be discovered. Hematopoietic stem cells (HSC) differentiating into immune cells for defense express COVID-19 entry receptors, and COVID-19 infection hinders their differentiation. The importance of purinergic signaling in HSC differentiation and innate immunity has been recognized. The metabotropic P2Y14 receptor subtype, activated by UDP-glucose, controls HSC differentiation and mobilization. Thereon, the exacerbated activation of blood immune cells amplifies the inflammatory state observed in COVID-19 patients, specially through the continuous release of reactive oxygen species and extracellular neutrophil traps (NETs). Further, the P2Y14 subtype, robustly inhibits the infiltration of neutrophils into various epithelial tissues, including lungs and kidneys. Here we discuss findings suggesting that antagonism of the P2Y14 receptor could prevent the progression of COVID-19-induced systemic inflammation, which often leads to severe illness and death cases. Considering the modulation of neutrophil recruitment of extreme relevance for respiratory distress and lung failure prevention, we propose that P2Y14 receptor inhibition by its selective antagonist PPTN could limit neutrophil recruitment and NETosis, hence limiting excessive formation of oxygen reactive species and proteolytic activation of the kallikrein-kinin system and subsequent bradykinin storm in the alveolar septa of COVID-19 patients.

• Bradykinin storm
• COVID-19
• Hematopoietic stem cells
• Neutrophils
• P2Y14 receptor
• Purinergic signaling
• SARS-CoV-2

• Bone marrow
• Hematopoietic stem cell
• In vitro bone model
• Mesenchymal stem cell
• Peripheral blood
• Personalized medicine

• Bone Marrow Cells/metabolism
• Cell Differentiation
• Cell Proliferation
• Cells, Cultured
• Humans
• In Vitro Techniques
• Models, Biological
• Osteoblasts/metabolism
• Osteoclasts/metabolism
• Osteocytes/metabolism
• Osteogenesis/physiology
• Stem Cells/metabolism
• Tissue Engineering/methods

• Ministry of Education, culture and science, gravitation program (Materials Driven Regeneration)
• Dutch organization for scientific research (NWO)

• G-CSF
• HMGB1
• Hematopoietic progenitor cell mobilization
• Neutrophil elastase
• Trauma
• VCAM-1

• GCS-F
• amyotrophic lateral sclerosis
• haematopoietic stem cells
• randomised clinical trial

• Amyotrophic Lateral Sclerosis/drug therapy
• Clinical Trials, Phase II as Topic
• Double-Blind Method
• Filgrastim/therapeutic use
• Humans
• Italy
• Multicenter Studies as Topic
• Quality of Life
• Randomized Controlled Trials as Topic

• Agenzia Italiana del Farmaco, Ministero della Salute

• Cytokine humanization
• Hematopoietic stem cell
• Humanized mice
• Immunodeficient mouse models
• Myeloid differentiation
• Xenotransplantation

• Animals
• Animals, Newborn
• Antigens, CD34/metabolism
• Cell Lineage
• Cell Separation
• Hematopoietic Stem Cells/metabolism
• Humans
• Mice
• Transplantation, Heterologous

• U54 DK106857 NIDDK NIH HHS

Albumin, the most abundant plasma protein, not only controls osmotic blood pressure, but also serves as a carrier for various small molecules, including pharmaceuticals. Its impact on pharmacological properties of many drugs has been extensively studied over decades. Here, we focus on its interaction with the following mobilizing agents: Granulocyte-colony stimulating factor (G-CSF) and AMD3100, where such analyses are lacking. These compounds are widely used for hematopoietic stem cell mobilization of healthy donors or patients. Using albumin-deficient (Alb−/−) mice, we studied the contribution of albumin to mobilization outcomes. Mobilization with the bicyclam CXCR4 antagonist AMD3100 was attenuated in Alb−/− mice compared to wild-type littermates. By contrast, mobilization with recombinant human G-CSF (rhG-CSF), administered twice daily over a five-day course, was significantly increased in Alb−/− mice. In terms of a mechanism, we show that rhG-CSF bioavailability in the bone marrow is significantly improved in Alb−/− mice, compared to wild-type (WT) littermates, where rhG-CSF levels dramatically drop within a few hours of the injection. These observations likely explain the favorable mobilization outcomes with split-dose versus single-dose administration of rhG-CSF to healthy donors.

• AMD3100
• Plerixafor
• granulocyte-colony stimulating factor
• hematopoietic stem cell mobilization
• hematopoietic stem cell transplantation
• pharmacodynamics
• serum albumin deficiency

The bone marrow (BM) microenvironment plays a crucial role in the maintenance and regeneration of hematopoietic stem (HSC) and progenitor cells (HSPC). In particular, the vascular niche is responsible for regulating HSC maintenance, differentiation, and migration of cells in and out of the BM. Damage to this niche upon exposure to ionizing radiation, whether accidental or as a result of therapy, can contribute to delays in HSC recovery and/or function. The ability of BM derived-endothelial cells (BMEC) to alter and/or protect HSPC after exposure to ionizing radiation was investigated. Our data show that exposure of BMEC to ionizing radiation resulted in alterations in Akt signaling, increased expression of PARP-1, IL6, and MCP-1, and decreased expression of MMP1 and MMP9. In addition, global analysis of gene expression of HSC and BMEC in response to mixed neutron/gamma field (MF) radiation identified 60 genes whose expression was altered after radiation in both cell types, suggesting that a subset of genes is commonly affected by this type of radiation. Focused gene analysis by RT-PCR revealed two categories of BMEC alterations: (a) a subset of genes whose expression was altered in response to radiation, with no additional effect observed during coculture with HSPC, and (b) a subset of genes upregulated in response to radiation, and altered when cocultured with HSPC. Coculture of BMEC with CD34+ HSPC induced HSPC proliferation, and improved BM function after MF radiation. Nonirradiated HSPC exhibited reduced CD34 expression over time, but when irradiated, they maintained higher CD34 expression. Nonirradiated HSPC cocultured with nonirradiated BMEC expressed lower levels of CD34 expression compared to nonirradiated alone. These data characterize the role of each cell type in response to MF radiation and demonstrate the interdependence of each cell’s response to ionizing radiation. The identified genes modulated by radiation and coculture provide guidance for future experiments to test hypotheses concerning specific factors mediating the beneficial effects of BMEC on HSPC. This information will prove useful in the search for medical countermeasures to radiation-induced hematopoietic injury.

• R01 DK074720 NIDDK NIH HHS
• T32 HL134644 NHLBI NIH HHS
• P30 GM127211 NIGMS NIH HHS
• R56 HL124266 NHLBI NIH HHS
• R01 HL112788 NHLBI NIH HHS
• P20 GM103527 NIGMS NIH HHS

• Angiopoietins
• Bone cells
• Bone markers
• Hematopoietic stem cells
• Mobilization

• Adolescent
• Adult
• Aged
• Biomarkers/blood
• Biomarkers/metabolism
• Bone and Bones/metabolism
• Cytokines/blood
• Cytokines/metabolism
• Female
• Hematopoietic Stem Cell Mobilization
• Humans
• Male
• Middle Aged
• Neovascularization, Physiologic
• Osteoblasts/metabolism
• Osteoclasts/metabolism
• Osteoprotegerin/metabolism
• RANK Ligand/metabolism
• Time Factors
• Young Adult

• S10 OD016230 NIH HHS

• bone marrow microenvironment
• hematopoietic stem cells
• leukemia
• uPAR
• urokinase receptor

• CD44
• EMT
• apoptosis resistance
• cancer initiating cells
• metastasis
• migration
• tumor exosomes

• Intraosseal
• Intravenous
• Mobilization
• Viral vectors

• Blood
• CXCL12/SDF1/CXCR4
• Cell-to-cell signaling
• Differentiation
• Lymphocytes
• Myeloid cells
• Neutrophils
• Niches
• Stromal cells

• Animals
• Bone Marrow/metabolism
• Cell Differentiation
• Ephrins/metabolism
• Hematopoiesis/physiology
• Hematopoietic Stem Cells/cytology
• Hematopoietic Stem Cells/metabolism
• Humans
• Ligands
• Receptors, Eph Family/metabolism

• adipocyte
• fibrin matrix
• hematopoietic-to-mesenchymal transition
• integrin
• macrophage

• Bone marrow
• Cytokine
• Engraftment
• Extracellular matrix protein
• Hematopoietic stem cell
• Mesenchymal stem cell
• Microenvironment
• Mobilization
• Niche
• Osteolineage cells
• Perivascular cell
• Reconstitution
• Stroma
• Transgenic mouse model
• Transplantation

• CXCL12/CXCR4
• HSC mobilization
• aPC/EPCR/PAR1 signaling
• bone marrow retention
• hematopoietic stem cells
• nitric oxide
• thrombomodulin

• Animals
• Antineoplastic Agents/adverse effects
• Cells, Cultured
• Female
• Granulocyte Colony-Stimulating Factor/pharmacology
• Hematopoietic Stem Cells/cytology
• Hematopoietic Stem Cells/drug effects
• Hematopoietic Stem Cells/metabolism
• Humans
• Mice
• Mice, Inbred C57BL
• Osteoblasts/cytology
• Osteoblasts/drug effects
• Osteoblasts/metabolism
• Parathyroid Hormone/pharmacology
• RANK Ligand/pharmacology
• Stem Cell Niche

The use of high-dose chemotherapy with autologous support of hematopoietic progenitor cells is an effective strategy to treat various hematologic neoplasms, such as non-Hodgkin lymphomas and multiple myeloma. Mobilized peripheral blood progenitor cells are the main source of support for autologous transplants, and collection of an adequate number of hematopoietic progenitor cells is a critical step in the autologous transplant procedure. Traditional strategies, based on the use of growth factors with or without chemotherapy, have limitations even when remobilizations are performed. Granulocyte colony-stimulating factor is the most widely used agent for progenitor cell mobilization. The association of plerixafor, a C-X-C Chemokine receptor type 4 (CXCR4) inhibitor, to granulocyte colony stimulating factor generates rapid mobilization of hematopoietic progenitor cells. A literature review was performed of randomized studies comparing different mobilization schemes in the treatment of multiple myeloma and lymphomas to analyze their limitations and effectiveness in hematopoietic progenitor cell mobilization for autologous transplant. This analysis showed that the addition of plerixafor to granulocyte colony stimulating factor is well tolerated and results in a greater proportion of patients with non-Hodgkin lymphomas or multiple myeloma reaching optimal CD34⁺ cell collections with a smaller number of apheresis compared the use of granulocyte colony stimulating factor alone.

• Autologous transplant
• Hematopoietic progenitor cell mobilization
• Multiple myeloma
• Non-Hodgkin lymphoma
• Plerixafor

CD44 is an adhesion molecule that varies in size due to glycosylation and insertion of so-called variant exon products. The CD44 standard isoform (CD44s) is highly expressed in many cells and most abundantly in cells of the hematopoietic system, whereas expression of CD44 variant isoforms (CD44v) is more restricted. CD44s and CD44v are known as stem cell markers, first described for hematopoietic stem cells and later on confirmed for cancer- and leukemia-initiating cells. Importantly, both abundantly expressed CD44s as well as CD44v actively contribute to the maintenance of stem cell features, like generating and embedding in a niche, homing into the niche, maintenance of quiescence, and relative apoptosis resistance. This is surprising, as CD44 is not a master stem cell gene. I here will discuss that the functional contribution of CD44 relies on its particular communication skills with neighboring molecules, adjacent cells and, last not least, the surrounding matrix. In fact, it is the interaction of the hyaluronan receptor CD44 with its prime ligand, which strongly assists stem cells to fulfill their special and demanding tasks. Recent fundamental progress in support of this “old” hypothesis, which may soon pave the way for most promising new therapeutics, is presented for both hematopoietic stem cell and leukemia-initiating cell. The contribution of CD44 to the generation of a stem cell niche, to homing of stem cells in their niche, to stem cell quiescence and apoptosis resistance will be in focus.

• CD44
• adhesion
• apoptosis resistance
• bone marrow niche
• dormancy
• hematopoietic stem cells
• homing
• leukemia-initiating cells

• Animals
• Clinical Trials as Topic
• Hematopoietic Stem Cell Mobilization
• Hematopoietic Stem Cell Transplantation
• Humans
• Lymphoma/therapy
• Multiple Myeloma/therapy
• Stem Cell Niche

The chemokine receptor CXCR4 and its ligand CXCL12 play an important homeostatic function by mediating the homing of progenitor cells in the bone marrow and regulating their mobilization into peripheral tissues upon injury or stress. Although the CXCL12/CXCR4 interaction has long been regarded as a monogamous relation, the identification of the pro-inflammatory chemokine macrophage migration inhibitory factor (MIF) as an important second ligand for CXCR4, and of CXCR7 as an alternative receptor for CXCL12, has undermined this interpretation and has considerably complicated the understanding of CXCL12/CXCR4 signaling and associated biological functions. This review aims to provide insight into the current concept of the CXCL12/CXCR4 axis in myocardial infarction (MI) and its underlying pathologies such as atherosclerosis and injury-induced vascular restenosis. It will discuss main findings from in vitro studies, animal experiments and large-scale genome-wide association studies. The importance of the CXCL12/CXCR4 axis in progenitor cell homing and mobilization will be addressed, as will be the function of CXCR4 in different cell types involved in atherosclerosis. Finally, a potential translation of current knowledge on CXCR4 into future therapeutical application will be discussed.

• CXCL12
• CXCR4
• CXCR7
• MIF
• atherosclerosis
• cardiovascular disease
• myocardial infarction
• restenosis

Mobilized peripheral blood (PB) is widely used as source of stem cells (PBSCs) for autologous stem cell transplantation (ASCT). The use of cytokines, alone or in combination with chemotherapy (chemomobilization), is the most common strategy applied to mobilize and collect PBSCs. However, a significant proportion of cancer patients fail to mobilize enough PBSCs to proceed to ASCT. Plerixafor is a small molecule that reversibly and transiently disrupts the interaction between the chemokine receptor CXCR4 and its ligand CXCL12 (formerly known as stroma derived factor 1, SDF-1) leading to the rapid release of CD34⁺ hematopoietic stem cells from the bone marrow (BM) to PB. Plerixafor has been recently approved to enhance PBSC mobilization in adult patients with multiple myeloma or non-Hodgkin lymphoma and has been shown to be more effective than G-CSF alone. There is limited experience on combining plerixafor with chemotherapy plus G-CSF in patients who mobilize poorly. Current evidence suggests that the addition of plerixafor is safe and effective in the large majority of the patients with low blood CD34⁺ cell count after mobilization and/or poor yield after the first collection(s). Circulating CD34⁺ cells can be increased by several folds with plerixafor and the majority of the patients considered “poor mobilizers” can be successfully collected. Overall, its mechanism of action inducing the rapid release of CD34⁺ cells from the BM to the circulation makes plerixafor suitable for the ‘preemptive’ use in patients who are hard-to-mobilize.