Growth Factor Directed Chondrogenic Differentiation of Porcine Bone Marrow–Derived Progenitor Cells

Abstract We previously showed that basic fibroblast growth factor (bFGF) is a potent mitogen for human bone marrow (BM) stromal cells and significantly delays their senescence. In the present study, we demonstrated that low concentrations of bFGF (0.2 to 2 ng/mL) enhance myelopoiesis in long-term human BM culture. Addition of bFGF to long- term BM cultures resulted in an increase in (a) the number of nonadherent cells (sixfold), particularly those of the neutrophil granulocyte series; (b) the number of nonadherent granulocyte colony- stimulating factor (G-CSF)- and granulocyte-macrophage colony- stimulating factor (GM-CSF)-responsive progenitor cells; (c) the number of adherent foci of hematopoietic cells (10-fold); and (d) the number of progenitor cells in the adherent stromal cell layer. These effects were not noted with higher concentrations of bFGF (20 ng/mL). Thus, low concentrations of bFGF effectively augment myelopoiesis in human long- term BM cultures, and bFGF may therefore be a regulator of the hematopoietic system in vitro and in vivo.

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Role of c-kit/Kit ligand signaling in regulating vasculogenesis

Thrombosis and Haemostasis ◽

10.1160/th03-03-0188 ◽

2003 ◽

Vol 90 (10) ◽

pp. 570-576 ◽

Cited By ~ 80

Author(s):

Beate Heissig ◽

Zena Werb ◽

Shahin Rafii ◽

Koichi Hattori

Keyword(s):

Bone Marrow ◽

Growth Factor ◽

Progenitor Cells ◽

International Workshop ◽

Medical Science ◽

Vascular Diseases ◽

Hematopoietic Stem ◽

Tumor Bed ◽

Kit Ligand ◽

Stromal Cell Derived Factor

SummaryMobilization into peripheral blood of bone marrow-derived cells including hematopoietic stem cells (HSCs) and endothelial progenitor cells (EPCs), is regulated by chemokines/cytokines. These cells can contribute to the formation of new blood vessels (vasculogenesis) under pathological conditions including atherosclerosis, wound healing and tumor growth. We will review how these cells are mobilized into circulation, and supplied to the sites, where vessel formation is needed (i.e. ischemic tissue or tumor bed).We will give evidence that matrix metalloproteinase-9 mediated Kit ligand (Stem cell factor) processing is essential for cell mobilization induced by chemo-/cyto-kines, like vascular endothelial growth factor (VEGF), Placental growth factor (PlGF), stromal cell derived factor-1 (SDF-1). These studies may provide the basis for the development of new therapeutic strategies for vascular diseases through targeting kit ligand mediated mobilization and homing of bone marrow-derived progenitor cells for cell therapy and cancer therapy.This publication was partially financed by Serono Foundation for the Advancement of Medical Science. Financial support: This work was supported by a grant from the Japanese Society for the Promotion of Science (B.H.) and by funds from the National Institutes of Health (CA 72006 and AR46238 to ZW). Part of this paper was originally presented at the 2nd International Workshop on New Therapeutic Targets in Vascular Biology from February 6-9, 2003 in Geneva, Switzerland.

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Human Stem/Progenitor Cells from Bone Marrow Enhance Glial Differentiation of Rat Neural Stem Cells: A Role for Transforming Growth Factor β and Notch Signaling

Stem Cells and Development ◽

10.1089/scd.2009.0444 ◽

2011 ◽

Vol 20 (2) ◽

pp. 289-300 ◽

Cited By ~ 28

Author(s):

Andrew P. Robinson ◽

Jessica E. Foraker ◽

Joni Ylostalo ◽

Darwin J. Prockop

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Growth Factor ◽

Neural Stem Cells ◽

Notch Signaling ◽

Progenitor Cells ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Glial Differentiation

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Transforming growth factor-β1 modulates responses of CD34+ cord blood cells to stromal cell-derived factor-1/CXCL12

Blood ◽

10.1182/blood-2004-10-4145 ◽

2005 ◽

Vol 106 (2) ◽

pp. 485-493 ◽

Cited By ~ 37

Author(s):

Sunanda Basu ◽

Hal E. Broxmeyer

Keyword(s):

Bone Marrow ◽

Growth Factor ◽

Cord Blood ◽

Progenitor Cells ◽

Stromal Cell ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β1 ◽

Cd34 Cells ◽

Stromal Cell Derived Factor ◽

Tgf Β1

Abstract Disruption of stromal cell-derived factor-1 (SDF-1/CXCL12 [CXC chemokine ligand 12]) interaction leads to mobilization of stem/progenitor cells from bone marrow to circulation. However, prolonged exposure of CD34+ cells to SDF-1 desensitizes them to SDF-1. So how do cells remain responsive to SDF-1 in vivo when they are continuously exposed to SDF-1? We hypothesized that one or more mechanisms mediated by cytokines exist that could modulate SDF-1 responsiveness of CD34+ cells and the desensitization process. We considered transforming growth factor-β1 (TGF-β1) a possible candidate, since TGF-β1 has effects on CD34+ cells and is produced by stromal cells, which provide niches for maintenance and proliferation of stem/progenitor cells. TGF-β1 significantly restored SDF-1–induced chemotaxis and sustained adhesion responses in cord blood CD34+ cells preexposed to SDF-1. Effects of TGF-β1 were dependent on the dose and duration of TGF-β1 pretreatment. Phosphorylation of extracellular signal-regulated kinase 1 (Erk1)/Erk2 was implicated in TGF-β1 modulation of migratory and adhesion responses to SDF-1. Our results indicate that low levels of TGF-β1 can modulate SDF-1 responsiveness of CD34+ cells and thus may facilitate SDF-1–mediated retention and nurturing of stem/progenitor cells in bone marrow.

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Vascular endothelial growth factor-A signaling in bone marrow-derived endothelial progenitor cells exposed to hypoxic stress

Physiological Genomics ◽

10.1152/physiolgenomics.00070.2013 ◽

2013 ◽

Vol 45 (21) ◽

pp. 1021-1034 ◽

Cited By ~ 22

Author(s):

Brian R. Hoffmann ◽

Jordan R. Wagner ◽

Anthony R. Prisco ◽

Agnieszka Janiak ◽

Andrew S. Greene

Keyword(s):

Bone Marrow ◽

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Signaling Pathways ◽

Progenitor Cells ◽

Endothelial Progenitor Cells ◽

Tube Formation ◽

Vascular Endothelial ◽

Endothelial Progenitor ◽

Endothelial Growth Factor

Bone marrow-derived endothelial progenitor cells (BM-EPCs) are stimulated by vascular endothelial growth factor-A (VEGF-A) and other potent proangiogenic factors. During angiogenesis, an increase in VEGF-A expression stimulates BM-EPCs to enhance endothelial tube formation and contribute to an increase in microvessel density. Hypoxia is known to produce an enhanced angiogenic response and heightened levels of VEGF-A have been seen in oxygen deprived epithelial and endothelial cells, yet the pathways for VEGF-A signaling in BM-EPCs have not been described. This study explores the influence of hypoxia on VEGF-A signaling in rat BM-EPCs utilizing a novel proteomic strategy to directly identify interacting downstream components of the combined VEGF receptor(s) signaling pathways, gene expression analysis, and functional phenotyping. VEGF-A signaling network analysis following liquid chromatographic separation and tandem mass spectrometry revealed proteins related to inositol/calcium signaling, nitric oxide signaling, cell survival, cell migration, and inflammatory responses. Alterations in BM-EPC expression of common angiogenic genes and tube formation in response to VEGF-A during hypoxia were measured and combined with the proteomic analysis to enhance and support the signaling pathways detected. BM-EPC tube formation assays in response to VEGF-A exhibited little tube formation; however, a cell projection/migratory phenotype supported the signaling data. Additionally, a novel assay measuring BM-EPC incorporation into preformed endothelial cell tubes indicated a significant increase of incorporated BM-EPCs after pretreatment with VEGF-A during hypoxia. This study verifies known VEGF-A pathway components and reveals several unidentified mechanisms of VEGF-A signaling in BM-EPCs during hypoxia that may be important for migration to sites of vascular regeneration.

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Partial purification and characterization of a growth factor for macrophage progenitor cells with high proliferative potential in mouse bone marrow

Blood ◽

10.1182/blood.v60.2.503.bloodjournal602503 ◽

1982 ◽

Vol 60 (2) ◽

pp. 503-508

Author(s):

AB Kriegler ◽

TR Bradley ◽

E Januszewicz ◽

GS Hodgson ◽

EF Elms

Keyword(s):

Bone Marrow ◽

Growth Factor ◽

Progenitor Cells ◽

Proteolytic Enzymes ◽

Partial Purification ◽

Proliferative Potential ◽

Mouse Bone Marrow ◽

Synergistic Activity ◽

Human Spleen

A population of macrophage progenitor cells, with high proliferative potential, has recently been demonstrated in postfluorouracil-treated and normal mouse bone marrow (BM) in vitro, when the newly discovered growth factor (synergistic activity, SA) is combined with a macrophage colony-stimulating factor (CSF) as a proliferative stimulus. SA, shown to be present in human spleen and placental conditioned media (HSCM and HPCM, respectively) have been studied and found to be unstable to trypsin digestion and to heating at 50 degrees C or above; stable between pH 4 and 9; nonadherent to Con-A-Sepharose; and to have an isoelectric point between pH 5 and 5.8 and a molecular weight of between 14,000 and 21,000 as indicated by gel filtration chromatography. SAs from both HSCM and HPCM have been purified 89- and 122-fold, respectively, by precipitation of extraneous proteins at pH 5 followed by chromatographing twice on Sephacryl S200. Neither of these partially purified SAs contain any CSF for mouse BM. These results indicate that the SAs from HSCM and HPCM may be closely related and that they are structurally different from CSFs derived from various murine sources that have been shown to be stable to proteolytic enzymes and heat.

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