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At least 163 records · Page 9Linked to original sources
PubMed2002

Treatment of high-risk acute myelogenous leukaemia by myeloablative chemoradiotherapy followed by co-infusion of T cell-depleted haematopoietic stem cells and culture-expanded marrow mesenchymal stem cells from a related donor with one fully mismatched human leucocyte antigen haplotype.

A 20-year-old woman with high-risk acute myelogenous leukaemia was transplanted with granulocyte colony stimulating factor (G-CSF)-mobilized peripheral blood CD34+ haematopoietic stem cells and bone-marrow-derived mesenchymal stem cells (MSC) from her human leucocyte antigen haplotype-mismatched father after myeloablative conditioning therapy. The patient engrafted rapidly and had no acute or chronic graft-versus-host disease. Since transplantation, the patient has shown an enduring trilineage haematological complete response without any evidence of leukaemia relapse at 31 months. We suggest that MSC can be used effectively for genetically haploidentical haematopoietic stem cell transplantation for acute leukaemia.

Adult↗
PubMed2006

The therapeutic potential of human olfactory-derived stem cells.

Stem cells from fetal and adult central nervous system have been isolated and characterized, providing populations for potential replacement therapy for traumatic injury repair and neurodegenerative diseases. The regenerative capacity of the olfactory system has attracted scientific interest. Studies focusing on animal and human olfactory bulb ensheathing cells (OECs) have heightened the expectations that OECs can enhance axonal regeneration and repair demyelinating diseases. Harvest of OECs from the olfactory bulb requires highly invasive surgery, which is a major obstacle. In contrast, olfactory epithelium (OE) has a unique regenerative capacity and is readily accessible from its location in the nasal cavity, allowing for harvest without lasting damage to the donor. Adult OE contains progenitors responsible for the normal life-long continuous replacement of neurons and supporting cells. Culture techniques have been established for human OE that generate populations of mitotically active neural progenitors that form neurospheres (Roisen et al., 2001; Winstead et al., 2005). The potential application of this technology includes autologous transplantation where minimal donor material can be isolated, expanded ex vivo, and lineage restricted to a desired phenotype prior to/or after re-implantation. Furthermore, these strategies circumvent the ethical issues that arise with embryonic or fetal tissues. The long term goal is to develop procedures through which a victim of a spinal cord injury or neurodegenerative condition would serve as a source of progenitors for his/her own regenerative grafts, avoiding the need for immunosuppression and ethical controversy. In addition, these cells can provide populations for pharmacological and/or diagnostic evaluation.

Cells, Cultured↗
PubMed2001

Lyn is required for normal stem cell factor-induced proliferation and chemotaxis of primary hematopoietic cells.

Stem cell factor (SCF) binds to c-Kit and is an important mediator of survival, growth, and function of hematopoietic progenitor cells and mast cells. Lyn and other Src family members are activated by SCF and associate with phosphorylated tyrosine residues in the c-Kit juxtamembrane region. However, studies using c-Kit mutants incapable of directly recruiting Src family members suggest this kinase family plays a minimal role in c-Kit stimulus-response coupling mechanisms. The objective of this study was to specifically target Lyn and subsequently address its role in SCF-mediated responses of primary hematopoietic progenitor cells and mast cells. To this end, a dominant-inhibitory Lyn mutant and Lyn-deficient mice were used. Transfection of normal murine mast cells with kinase-inactive Lyn impaired SCF-induced growth. Further, SCF-induced proliferation and chemotaxis of Lyn-deficient mast cells were less than for wild-type mast cells. SCF-induced growth of progenitor cells lacking Lyn was also reduced compared with that of wild-type progenitor cells. Impairment of SCF-mediated responses of Lyn-deficient mast cells and progenitor cells did not result from reductions in surface expression of c-Kit. These studies demonstrate that Lyn is required for normal SCF-mediated responses of primary progenitors and for a differentiated lineage.

Animals↗
PubMed2000

Stem cell factor enhances IgE-mediated histamine and TNF-alpha release from dispersed canine cutaneous mast cells.

Stem cell factor (SCF), the c-kit receptor ligand, plays a critical role in mast cell (MC) development and differentiation. In addition, SCF has recently been found to both modulate and induce MC activation. To investigate the effect of SCF on canine cutaneous MC function, we have characterized the ability of SCF to modulate the release by mature canine MC of preformed (histamine) and newly generated (TNF-alpha) mediators. Mature MC were isolated from skin and cultured in the absence or presence of exogenous SCF (6 ng/ml) for up to 5 days and then challenged with anti-IgE (1 microg/ml) alone for 30 min or with a combination of SCF (50 ng/ml) and anti-IgE. SCF alone failed to trigger either histamine or TNF-alpha release at any time. However, we observed that SCF used as a co-stimulus significantly potentiated histamine and TNF-alpha release in canine MC activated through Fc epsilon RI regardless of whether or not SCF was added to the medium during culturing. Thus, the mean histamine release (%) and TNF-alpha production (pg/ml) were found to be significantly higher if cells were maintained in culture in SCF-supplemented medium compared with cells cultured in the absence of exogenous SCF. We also observed that MC responsiveness to immunological stimulation increased with culture time, the percentage of histamine released being higher in cells cultured for at least 3 days when compared to freshly isolated MC. Taken together these findings suggest that canine skin MC releasability can be enhanced independently either through prolonged incubation with SCF and/or through anti-IgE and SCF co-stimulation.

Animals↗
PubMed1999

CNS development: The obscure origins of adult stem cells.

Stem cells of the adult central nervous system are the focus of a great deal of attention because of their potential for making new neural cells. A recent study has claimed to identify their in vivo location, but this important issue remains controversial.

Adult↗
PubMed2002

The changes of serum leptin and soluble leptin receptor levels in patients undergoing mobilization of peripheral blood stem cells before autologous stem cells transplantation.

BACKGROUND AND OBJECTIVES: Leptin was demonstrated to stimulate the proliferation of hematopoietic stem cells in vitro, but there is scarce information concerning serum leptin levels in patients with hematological diseases. The aim of our study was to measure serum leptin levels in patients undergoing mobilization of peripheral blood stem cells (PBSC) before autologous stem cell transplantation (ASCT). DESIGN AND METHODS: Eighteen patients indicated for ASCT were included in the study. The blood samples were obtained before the initiation of mobilization chemotherapy, at the phase of maximal leukopenia and on the second day of stem cell harvest. Serum leptin levels, soluble leptin receptor, cortisol, insulin, tumor necrosis factor alpha (TNFalpha), and interleukin-1 receptor antagonist (IL-1ra) levels were measured in the withdrawn samples. RESULTS: The basal values of parameters measured except for higher levels of IL-1ra in mobilized group did not differ significantly from those of a control group of healthy subjects. Serum leptin levels decreased significantly at the leukopenia phase and remained suppressed in the stem cell harvest phase (means +/- standard error means (SEM): 12.2 +/- 2.4 vs. 7.7 +/- 1.5 vs. 9.3 +/- 1.9 ng mL(-1)). No significant changes were found in soluble leptin receptor, insulin, cortisol, and TNFalpha levels throughout three measurements, while IL-1ra levels increased significantly in the SC harvest phase compared to the previous two measurements. INTERPRETATION AND CONCLUSIONS: As no metabolic variations explaining suppressed leptin levels were found, this suppression could be the result either of G-CSF administration or increased leptin consumption by activated stem cells.

Adult↗
PubMed1995

Mixed haematopoietic colony formation via immature blast cell clusters on foetal mesenchymal cell layers distinguishes stem cells from peripheral blood, cord blood, bone marrow and blood stem cells mobilized by granulocyte-macrophage colony-stimulating factor.

Multilineage colony formation was evaluated from healthy donors' bone marrow (BM), peripheral blood (PB) and cord blood (CB) and compared with blood stem cell (BSC) harvests of sarcoma patients mobilized with granulocyte-macrophage colony-stimulating factor (GM-CSF). The test was a modified CFU-blast assay performed with and without an irradiated foetal mesenchymal cell layer (HFFF). These non-transformed mesenchymal cells served as a good source of haematopoietically active stroma cells in that cytokine expression patterns (interleukin (IL)-6, granulocyte (G)-CSF, GM-CSF) and adhesion molecules on HFFF cells were qualitatively identical to BM-derived fibroblasts, but the expression density of adhesion receptors was significantly higher. This HFFF layer stimulated blood stem cells of GM-CSF-treated patients significantly more than a cocktail of exogenous growth factors with IL-1, IL-6, and stem cell factor (SCF). The reverse was true for multilineage colonies from healthy donors' PB, BM, and CB. According to these results, stem cells of GM-CSF-treated patients are functionally distinct due to their dependence on stroma-derived factors and/or matrix-adhesion interactions and can be reproducibly evaluated on these mesenchymal cells.

Blood Cells↗
PubMed2004

Mesenchymal stem cells and haematopoietic stem cell transplantation.

The bone marrow serves as a reservoir for different classes of stem cells. In addition to haemopoietic stem cells, the bone marrow comprises a population of marrow stromal cells or mesenchymal stem cells (MSCs). These cells exhibit multilineage differentiation capacity, and are able to generate progenitors with restricted developmental potential, including fibroblasts, osteoblasts, adipocytes and chondrocyte progenitors. In addition, MSCs have been shown to possess immunosuppressive activity in vitro and in vivo. Clinical trials are underway to test whether MSCs are beneficial in patients undergoing allogeneic bone marrow transplantation. With the expanding role of stem cell transplants in different areas of medicine, including cardiology and orthopaedics, MSCs may become very important in the next few years.

Animals↗
PubMed2004

Gene expression analysis in SV40-immortalized human breast luminal epithelial cells with stem cell characteristics using a cDNA microarray.

The epithelial compartment of the human breast comprises two distinct cell types. Type I human breast epithelial cells (HBECs) are expressing luminal epithelial cell markers and stem cell characteristics, whereas Type II HBECs show basal epithelial cell phenotypes. When defined in terms of markers for normal cell lineages, most invasive breast cancer cells correspond to the phenotype of the common luminal epithelial cell. We had developed simian virus 40-immortalized cell lines from normal HBECs with luminal and stem cell characteristics. To identify molecular changes involved in immortalization, we analyzed the differential gene expression profiles of normal and non-tumorigenic immortalized Type I HBECs using cDNA microarray with 7,448 sequence-verified clones. Out of the 7,448 genes screened, consistent gene expression changes among biological replicates included 67 in Type I HBECs and 86 in Type II HBECs for 4-fold change criteria. Surprisingly, we identified 148 genes (>2.0-fold) as being either up- or down-regulated related to immortalization: 67 genes (MYBL2, UCHL1 et al) were up-regulated, and 81 genes (IGFBP3, CDKN1A et al) were down-regulated significantly. The altered expression levels of the selected genes were subsequently confirmed by semiquantitative RT-PCR. Our studies suggest that the immortalization of Type I HBECs might be an early step in the initiation of a subset of breast cancer. Furthermore, these results will open up an avenue for more detailed understanding of breast stem cell and tumor biology.

Biomarkers↗
PubMed1996

Airway epithelial cells produce stem cell factor.

Airway epithelial cells modulate the inflammatory response in asthmatic, allergic and fibrotic lung diseases through the secretion of cytokines that regulate the movement and activation of inflammatory cells. Mast cells play an important role in the pathogenesis of these lung diseases. In this study we report that normal airway epithelial cells express stem cell factor which is a critical mediator of mast cell growth and differentiation and that transforming growth factor-beta inhibits secretion of stem cell factor by airway epithelial cells.

Bronchi↗
PubMed2002

The chiaroscuro stem cell: a unified stem cell theory.

Hematopoiesis has been considered hierarchical in nature, but recent data suggest that the system is not hierarchical and is, in fact, quite functionally plastic. Existing data indicate that engraftment and progenitor phenotypes vary inversely with cell cycle transit and that gene expression also varies widely. These observations suggest that there is no progenitor/stem cell hierarchy, but rather a reversible continuum. This may, in turn, be dependent on shifting chromatin and gene expression with cell cycle transit. If the phenotype of these primitive marrow cells changes from engraftable stem cell to progenitor and back to engraftable stem cell with cycle transit, then this suggests that the identity of the engraftable stem cell may be partially masked in nonsynchronized marrow cell populations. A general model indicates a marrow cell that can continually change its surface receptor expression and thus responds to external stimuli differently at different points in the cell cycle.

Animals↗
PubMed2004

The happy destiny of frozen haematopoietic stem cells: from immature stem cells to mature applications.

Forty years ago, van Putten described in the European Journal of Cancer (see this issue) quantitative studies on the optimal storage techniques of mouse and monkey bone marrow suspensions. Survival of the animals after irradiation following injection with stored bone marrow cell suspensions was the endpoint. He observed some species differences, but based on the data obtained considered a careful trial of the glycerol-polyvinylpyrrolide (PVP) combination for storage of marrow in man was indicated. In spite of this, dimethyl sulphoxide has become the 'standard' cryopreservant for human marrow stem cells. Over the last 40 years, there has been a tremendous increase in knowledge about haematopoietic stem cells and their use in the clinic. Haematopoietic stem cells are now known to travel between the bone marrow and peripheral blood and are the best-characterised adult stem cells. These cells are currently widely used for transplantations in the clinic and are obtained from a wide variety of sources. These include the bone marrow, peripheral blood, cord blood, autologous as well as allogeneic stem cells from related or unrelated donors. Increasingly, data has become available that adult haematopoietic stem cells can generate differentiated cells belonging to other cell types, a process called "developmental plasticity". Thus, they may contribute to non-haematopoietic tissue repair in multiple organ systems. This has created a whole new potential therapeutic armamentarium for the application of haematopoietic stem cells outside of the area of malignancies and haematopoietic disorders.

Adult↗
PubMed2005

Transforming growth factor-beta2 enhances differentiation of cardiac myocytes from embryonic stem cells.

Stem cell therapy holds great promise for the treatment of injured myocardium, but is challenged by a limited supply of appropriate cells. Three different isoforms of transforming growth factor-beta (TGF-beta) -beta1, -beta2, and -beta3 exhibit distinct regulatory effects on cell growth, differentiation, and migration during embryonic development. We compared the effects of these three different isoforms on cardiomyocyte differentiation from embryonic stem (ES) cells. In contrast to TGF-beta1, or -beta3, treatment of mouse ES cells with TGF-beta2 isoform significantly increased embryoid body (EB) proliferation as well as the extent of the EB outgrowth that beat rhythmically. At 17 days, 49% of the EBs treated with TGF-beta2 exhibited spontaneous beating compared with 15% in controls. Cardiac myocyte specific protein markers sarcomeric myosin and alpha-actin were demonstrated in beating EBs and cells isolated from EBs. In conclusion, TGF-beta2 but not TGF-beta1, or -beta3 promotes cardiac myocyte differentiation from ES cells.

Animals↗
PubMed2004

Nitric oxide facilitates cardiomyogenesis in mouse embryonic stem cells.

Stem cell therapy holds great promise for the replacement of damaged or dysfunctional myocardium. Nitric oxide (NO) has been shown to promote embryonic stem (ES) cell differentiation in other systems. We hypothesized that NO, through NO synthase gene transfer or exogenous NO exposure, would promote the differentiation of mouse ES cells into cardiomyocytes (CM). In our study, NO treatment increased both the number and the size of beating foci in embryoid body (EB) outgrowths. Within 2 weeks, 69% of the inducible NO synthase-transduced EB displayed spontaneously beating foci, as did 45% of the NO donor-treated EB, compared with only approximately 15% in controls. Cardiac-specific genes and protein expression were significantly increased in NO-treated ES. Electron microscopy and immunocytochemistry revealed that these NO-induced contracting cells exhibited characteristics consistent with CM. At day 7 in culture, troponin T was expressed in 45.6 +/- 20.6% of the NO-treated ES cells but in only 9.25 +/- 1.77% of control cells. Interestingly, 50.4 +/- 18.4% of NO-treated ES cells were troponin T-negative and annexin V-positive. This apoptotic phenotype was seen in <1% of the control ES cells. These data strongly support our hypothesis that mouse ES cells can be accelerated to differentiate into CM by NO treatment. NO may influence cardiac differentiation by both inducing a switch toward a cardiac phenotype and inducing apoptosis in cells not committed to cardiac differentiation.

Animals↗
PubMed1997

Lyn associates with the juxtamembrane region of c-Kit and is activated by stem cell factor in hematopoietic cell lines and normal progenitor cells.

Stem cell factor (SCF) is a cytokine critical for normal hematopoiesis. The receptor for SCF is c-Kit, a receptor tyrosine kinase. Our laboratory is interested in delineating critical components of the SCF signal transduction pathway in hematopoietic tissue. The present study examines activation of Src family members in response to SCF. Stimulation of cell lines as well as normal progenitor cells with SCF rapidly increased tyrosine phosphorylation of the Src family member Lyn. Peak responses were noted 10-20 min after SCF treatment, and phosphorylation of Lyn returned to basal levels 60-90 min after stimulation. SCF also induced increases in Lyn kinase activity in vitro. Lyn coimmunoprecipitated with c-Kit, and studies with GST fusion proteins demonstrated that Lyn readily associated with the juxtamembrane region of c-Kit. Treatment of cells with either Lyn antisense oligonucleotides or PP1, a Src family inhibitor, resulted in dramatic inhibition of SCF-induced proliferation. These data demonstrate that SCF rapidly activates Lyn and suggest that Lyn is critical in SCF-induced proliferation in hematopoietic cells.

Binding Sites↗
PubMed2003

Genetic and functional differences between multipotent neural and pluripotent embryonic stem cells.

Stem cells (SCs) are functionally defined by their abilities to self-renew and generate differentiated cells. Although much effort has been focused on defining the common characteristics among various types of SCs, the genetic and functional differences between multipotent and pluripotent SCs have garnered less attention. We report a direct genetic and functional comparison of molecularly defined and clonally related populations of neural SCs (NSCs) and embryonic SCs (ESCs), using the Sox2 promoter for isolation of purified populations by fluorescence-activated cell sorting. A stringent expression profile comparison of promoter-defined NSCs and ESCs revealed a striking dissimilarity, and subsequent chimera analyses confirmed the fundamental differences in cellular potency between these populations. This direct comparison elucidates the molecular basis for the functional differences in pluripotent ESCs and multipotent NSCs.

Animals↗
PubMed1984

Influence of a fibroblastoid cell line derived from murine bone marrow (H-1 cells) on stem cell proliferation.

A murine fibroblastoid cell line (H-1) with properties similar to those of adventitial reticular cells can support granulopoiesis and the development of mononuclear phagocytes in vitro. In the current study the effect of these cells on stem cell maintenance in vitro was assessed. The H-1 cells were unable to support CFUs replication in liquid culture, while treatment of some stem cells with H-1 conditioned medium appeared to inhibit their proliferation.

Animals↗
PubMed2002

Cyclophosphamide, etoposide and G-CSF to mobilize peripheral blood stem cells for autologous stem cell transplantation in patients with lymphoma.

We aimed to assess the effectiveness of cyclophosphamide, etoposide and G-CSF (C+E) to mobilize peripheral blood stem cells for autologous stem cell transplantation in patients with lymphoma. A matched cohort study was performed comparing patients mobilized with C+E to patients mobilized with cyclophosphamide and G-CSF (C alone). Patients were matched for disease, prior radiotherapy and a chemotherapy score reflecting the amount and type of prior chemotherapy. Thirty-eight consecutive patients mobilized with C+E were compared with 38 matched controls. C+E was equivalent to C alone in terms of numbers of patients achieving a minimum threshold of > or =2 x 10(6)/kg CD34(+)cells (82% vs 79%, P = 0.74). C+E was superior, however, in terms of total CD34(+) yield (6.35 vs 3.3 x 10(6)/kg, P < 0.01), achieving a target graft of > or =5 x 10(6)/kg (55% vs 34%, P = 0.04) and obtaining both a minimum (61% vs 32%, P < 0.01) and target (45% vs 13%, P < 0.01) graft in one apheresis. This superiority was largely confined to patients with lower chemotherapy scores. There was no difference in neutrophil and platelet recovery or transfusion requirements for those who subsequently received high-dose therapy and stem cell transplantation. Thus, C+E improves the efficiency of peripheral blood stem cell collection, but does not increase the number of patients who can proceed to transplantation. Most of the benefit of the regimen was confined to patients who had not received extensive prior therapy. Novel strategies are required to increase the collection efficiency of 'hard to mobilize' patients.

Antineoplastic Combined Chemotherapy Protocols↗