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Biomedical subjects

Dominique Bonnet

Publications and source records attributed to Dominique Bonnet.

26 records · Page 2Linked to original sources
PubMed2003

Hematopoietic stem cells.

Considerable effort has been made in recent years in defining the embryonic origin of the hematopoietic stem cell (HSC). Using transgenic mouse models, a number of genes that regulate the formation, self-renewal, or differentiation of HSCs have been identified. Of particular interest, it has recently been shown that key regulators of definitive blood formation played a crucial role in adult HSC development. Specifically, the use of some of these regulatory molecules has dramatically improved the potential of adult HSC expansion. Furthermore, the elucidation of the molecular phenotype of the HSC has just begun. Finally, unexpected degrees of HSC developmental or differentiation plasticity have emerged. In this review, we will summarize the recent advances made in the human HSC field, and we will examine the impacts these discoveries may have clinically and on our understanding of the organization of the human hematopoietic system.

Animals↗
PubMed2002

Haematopoietic stem cells.

Considerable efforts have been made in recent years in determining the composition of the cell types that constitute the human haematopoietic stem cell (HSC) compartment. These studies have emphasized the heterogeneity of the human HSC in terms of proliferative and self-renewal capacities. Recent studies have indicated that CD34 is not the universal marker of all human HSCs. New markers for purifying HSCs have been described. A number of genes that regulate the formation, self-renewal, or differentiation of HSCs has been identified. The elucidation of the molecular phenotype of the HSC has just begun. Finally, an unexpected degree of developmental or differentiation plasticity of HSC has emerged. This review summarizes all the recent advances made in the human HSC field and examines the impacts that these discoveries may have both clinically and in understanding the organization of the human haematopoietic system.

Animals↗
PubMedDate not supplied

Stem cells of the alveolar epithelium.

Elucidation of the biology of stem cells of the lung parenchyma could revolutionise treatment of patients with lung disorders such as cancer, acute respiratory distress syndrome, emphysema, and fibrotic lung disease. How close is this goal? Despite remarkable observations and ensuing advances, more questions than answers have been generated. Progenitors of the alveolar epithelium remain largely mysterious, so the prospect of isolating enough of these cells and delivering them effectively to cure disease remains remote. Similarly, the bone-marrow-derived cell that might most effectively engraft the lung remains unknown. If this mechanism is an important process for lung repair, why will the administration of additional cells be more effective? Finally, there is an issue of control of multipotent cells to avoid the generation of multiple teratomas, longevity of the graft, and possible immunological reactions to gene products inserted to replace a deficiency. The biology is exciting but not yet well enough understood to support therapeutic advances.

Animals↗
PubMedDate not supplied

Simultaneous lipidation of a characterized peptide mixture by chemoselective ligation.

The modification of a peptide antigen by a fatty acid such as palmitic acid is now recognized as a mean to induce cellular responses. Mixtures of lipopeptides, obtained by combining individually synthesized compounds, were shown to be promising synthetic vaccine candidates. Usually, in lipopeptide synthesis, the fatty acyl moiety is introduced on the crude peptide chain using solid-phase methods. The separation of the target compound from impurities by RP-HPLC is often complicated by the amphiphilic properties of lipopeptides and results in low overall yields. To overcome the difficulties associated with lipopeptide synthesis and mixture preparation, we have developed a method where the fatty acyl moiety is site-specifically and collectively introduced in solution onto a mixture of individually prepurified peptides. The lipidation is based on the quasistoichiometric and high-yielding ligation of a glyoxylyl lipid with hydrazinoacetyl peptides. The hydrazone constructs were prepared in a salt-free medium and could be isolated by direct lyophilization of the reaction mixture. This process is compatible with cysteinyl peptides, and no aggregation nor degradation could be observed.

Amino Acid Sequence↗
PubMedDate not supplied

A rapid and versatile method to label receptor ligands using "click" chemistry: Validation with the muscarinic M1 antagonist pirenzepine.

Tagged biologically active molecules represent powerful pharmacological tools to study and characterize ligand-receptor interactions. However, the labeling of such molecules is not trivial, especially when poorly soluble tags have to be incorporated. The classical method of coupling usually necessitates a tedious final purification step to remove the excess of reagents and to isolate tagged molecules. To overcome this limitation, Cu(I)-catalyzed 1,3-dipolar cycloaddition, referred to as "click" chemistry, was evaluated as a tool to facilitate the access to labeled molecules. In order to validate the approach, we focused our attention on the incorporation of a fluorophore (Lissamine Rhodamine B), a nonfluorescent dye (Patent Blue VF), or biotin into a muscarinic antagonist scaffold derived from pirenzepine. The reaction performed in acetonitrile/water, in the presence of CuSO4 and Cu wire, allowed us to obtain three novel pirenzepine derivatives with high purity and in good yield. No coupling reagents were needed, and the quasi-stoichiometric conditions of the reaction enabled the straightforward isolation of the final product by simple precipitation and its use in bioassays. The affinity of the compounds for the human M1 muscarinic receptor fused to EGFP was checked under classical radioligand and FRET binding conditions. The three pirenzepine constructs display a nanomolar affinity for the M1 receptor. In addition, both dye-labeled derivatives behave as potent acceptors of energy from excited EGFP with a very high quenching efficiency.

Catalysis↗
PubMedDate not supplied

Effect of glycoamphiphiles on the solubilization and dendritic cell uptake of a lipopeptide: a preliminary study.

The selective delivery of antigens to professional antigen-presenting cells represents a promising approach to improve vaccine efficacy. Addition of a glycoamphiphile to a lipopeptide, whose interest for vaccination is now well-established, greatly favors its solubilization in aqueous solutions through the formation of mixed vesicles. Flow cytometry experiments indicate that this formulation does not diminish the uptake of the lipopeptide by the dendritic cells (DCs). These preliminary results suggest a possible straightforward, noncovalent targeting of cocktail-lipopeptide vaccines to the DCs via carbohydrate receptor-mediated endocytosis.

Biological Transport↗
PubMedDate not supplied

Characterization of cells with a high aldehyde dehydrogenase activity from cord blood and acute myeloid leukemia samples.

Aldehyde dehydrogenase (ALDH) is a cytosolic enzyme that is responsible for the oxidation of intracellular aldehydes. Elevated levels of ALDH have been demonstrated in murine and human progenitor cells compared with other hematopoietic cells, and this is thought to be important in chemoresistance. A method for the assessment of ALDH activity in viable cells recently has been developed and made commercially available in a kit format. In this study, we confirmed the use of the ALDH substrate kit to identify cord blood stem/progenitor cells. Via multicolor flow cytometry of cord blood ALDH+ cells, we have expanded on their phenotypic analysis. We then assessed the incidence, morphology, phenotype, and nonobese diabetic/ severe combined immunodeficiency engraftment ability of ALDH+ cells from acute myeloid leukemia (AML) samples. AML samples had no ALDH+ cells at all, an extremely rare nonmalignant stem/progenitor cell population, or a less rare, leukemic stem cell population. Hence, in addition to identifying nonmalignant stem cells within some AML samples, a high ALDH activity also identifies some patients' CD34+/ CD38- leukemic stem cells. The incidence of normal or leukemic stem cells with an extremely high ALDH activity may have important implications for resistance to chemotherapy. Identification and isolation of leukemic cells on the basis of ALDH activity provides a tool for their isolation and further analysis.

ADP-ribosyl Cyclase↗