Stem cells
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Review
Concise review: Mesenchymal stem cells for acute lung injury: role of paracrine soluble factors.
Morbidity and mortality have declined only modestly in patients with clinical acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), despite extensive research into the pathophysiology. Current treatment remains primarily supportive with lung-protective ventilation and a fluid conservative strategy. Pharmacologic therapies that reduce the severity of lung injury in preclinical models have not yet been translated to effective clinical treatment options. ⋯ Cell-based therapy with mesenchymal stem cells (MSCs) is one attractive new therapeutic approach. MSCs have the capacity to secrete multiple paracrine factors that can regulate endothelial and epithelial permeability, decrease inflammation, enhance tissue repair, and inhibit bacterial growth. This review will focus on recent studies, which support the potential therapeutic use of MSCs in ALI/ARDS, with an emphasis on the role of paracrine soluble factors.
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The alpha-chemokine stromal-derived factor (SDF)-1 and the G-protein-coupled seven-span transmembrane receptor CXCR4 axis regulates the trafficking of various cell types. In this review, we present the concept that the SDF-1-CXCR4 axis is a master regulator of trafficking of both normal and cancer stem cells. Supporting this is growing evidence that SDF-1 plays a pivotal role in the regulation of trafficking of normal hematopoietic stem cells (HSCs) and their homing/retention in bone marrow. ⋯ Hence, we postulate that the metastasis of cancer stem cells and trafficking of normal stem cells involve similar mechanisms, and we discuss here the common molecular mechanisms involved in these processes. Finally, the responsiveness of CXCR4+ normal and malignant stem cells to an SDF-1 gradient may be regulated positively/primed by several small molecules related to inflammation which enhance incorporation of CXCR4 into membrane lipid rafts, or may be inhibited/blocked by small CXCR4 antagonist peptides. Consequently, strategies aimed at modulating the SDF-1-CXCR4 axis could have important clinical applications both in regenerative medicine to deliver normal stem cells to the tissues/organs and in clinical hematology/oncology to inhibit metastasis of cancer stem cells.
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Granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) are functionally related hematopoietins with overlapping but distinct hematopoietic effects. GM-CSF supports more myeloid progenitor cells, whereas IL-3 promotes more erythroid, megakaryocytic and multipotential progenitor cells. Their complementary in vivo biological effects and cross competition for receptor binding prompted the development of PIXY321, a synthetic hybrid protein of GM-CSF and IL-3. ⋯ Based on these preclinical observations, clinical trials have been initiated examining the therapeutic potential of this agent in ameliorating treatment- or disease-related hematopoietic suppression. The early results indicate that PIXY321 can stimulate multilineage hematopoiesis in vivo and enhance neutrophil and platelet recovery following chemotherapy and bone marrow transplantation (BMT). These results suggest that PIXY321 elicits the biological effects of both its component cytokines and represents a novel means of delivering two independent but interactive cytokines in combination.
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Peripheral blood stem cells (PBSC) have been studied for their use after high-dose chemotherapy. The combination of a standard-dose chemotherapy [VIP: VP16 (etoposide), ifosfamide, cisplatin] in combination with hematopoietic growth factors was shown to provide effective anti-cancer activity as well as to enable sufficient stem cell mobilization for clinical use. Different growth factor regimens [granulocyte-colony-stimulating factor (G-CSF), granulocyte-macrophage (GM)-CSF, interleukin (IL)-3/GM-CSF] resulted in a differential induction of high levels of circulating PBSC after VIP chemotherapy, with the sequential combination of IL-3 and GM-CSF inducing maximal numbers of CD34+ cells as well as clonogenic progenitors. ⋯ Positive selection of CD34+ cells by immunoadsorption that leads to an approximately three-log depletion of contaminating tumor cells therefore was investigated with regard to feasibility and capability as a source for PBSC transplantation. Twenty-one patients with advanced malignancies received autologous CD34+ cell transplantation after high-dose chemotherapy. Hematological recovery was as rapid as recorded for unseparated PBSC preparations, indicating that CD34+ cells can be safely used for autologous PBSC transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)