Identification of signalling cascades involved in red blood cell shrinkage and vesiculation

Kostova, Elena; Beuger, Boukje M.; Klei, Thomas R.; Halonen, Pasi; Lieftink, Cor; Beijersbergen, Roderick L.; Berg, Timo K. van den; Bruggen, Robin van

doi:10.1042/bsr20150019

Cited by 39 publications

(44 citation statements)

References 107 publications

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“…Wild-type blood incubated with 5 μM calcium ionophore A23187 (Sigma) and 5 mM CaCl 2 (Merck) was used as positive control to induce vesiculation [19] (data not shown). For enriched cortical oligodendrocytes, CG-4 cells and myelin, supernatant was collected, centrifuged at 100 g for 10 min at room temperature to pellet cells and debris bigger than 5 μm.…”

Section: Methodsmentioning

confidence: 99%

Psychosine enhances the shedding of membrane microvesicles: Implications in demyelination in Krabbe’s disease

et al. 2017

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In prior studies, our laboratory showed that psychosine accumulates and disrupts lipid rafts in brain membranes of Krabbe’s disease. A model of lipid raft disruption helped explaining psychosine’s effects on several signaling pathways important for oligodendrocyte survival and differentiation but provided more limited insight in how this sphingolipid caused demyelination. Here, we have studied how this cationic inverted coned lipid affects the fluidity, stability and structure of myelin and plasma membranes. Using a combination of cutting-edge imaging techniques in non-myelinating (red blood cell), and myelinating (oligodendrocyte) cell models, we show that psychosine is sufficient to disrupt sphingomyelin-enriched domains, increases the rigidity of localized areas in the plasma membrane, and promotes the shedding of membranous microvesicles. The same physicochemical and structural changes were measured in myelin membranes purified from the mutant mouse Twitcher, a model for Krabbe’s disease. Areas of higher rigidity were measured in Twitcher myelin and correlated with higher levels of psychosine and of myelin microvesiculation. These results expand our previous analyses and support, for the first time a pathogenic mechanism where psychosine’s toxicity in Krabbe disease involves deregulation of cell signaling not only by disruption of membrane rafts, but also by direct local destabilization and fragmentation of the membrane through microvesiculation. This model of membrane disruption may be fundamental to introduce focal weak points in the myelin sheath, and consequent diffuse demyelination in this leukodystrophy, with possible commonality to other demyelinating disorders.

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Section: Methodsmentioning

confidence: 99%

Psychosine enhances the shedding of membrane microvesicles: Implications in demyelination in Krabbe’s disease

et al. 2017

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“…The mitogen-activated protein kinase ERK 1/2 and the upstream kinase responsible for its activation, MEK 1/2, are constitutively activated in sickle red cells, leading to increased adhesion. [60][61][62] The selectins E-selectin and P-selectin are upregulated in sickle cell disease and also mediate adhesion, with the degree of red cell adhesion correlating with greater severity of disease. 63 In addition to these changes, the cell containing sickle hemoglobin is stiffer than a normal red cell would be in circulation.…”

Section: Pathophysiology Of Sickle Cell Diseasementioning

confidence: 99%

Sickle Cell Disease: Advances in Treatment

Gardner

2018

TOJ

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Background: Sickle cell disease causes significant morbidity and mortality and affects the economic and healthcare status of many countries. Yet historically, the disease has not had commensurate outlays of funds that have been aimed at research and development of drugs and treatment procedures for other diseases. Methods: This review examines several treatment modalities and new drugs developed since the late 1990s that have been used to improve outcomes for patients with sickle cell disease. Results: Targeted therapies based upon the pathophysiologic mechanisms of sickle cell disease that result in organ dysfunction and painful episodes include hydroxyurea, L-glutamine, crizanlizumab, and other drugs that are currently on the market or are on the verge of becoming available. These agents have the potential to improve survival and quality of life for individuals with sickle cell disease. Also discussed is stem cell transplantation that, to date, is the only curative approach for this disease, as well as the current status of gene therapy. Conclusion:These examples demonstrate how the current knowledge of sickle cell disease pathophysiology and treatment approaches intersect. Although interest in sickle cell research has blossomed, many more clinical trials need to be initiated and subjected to more strenuous examination and analysis than have been used in the past.

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“…19 GpC-ex3 erythrocytes were kindly provided by the Department of Serology, Sanquin (Amsterdam, The Netherlands).…”

Section: Methodsmentioning

confidence: 99%

Glycophorin-C sialylation regulates Lu/BCAM adhesive capacity during erythrocyte aging

et al. 2018

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Key Points• The Lu/BCAM adhesion molecule is gradually activated during erythrocyte aging due to loss of sialic acid on glycophorin-C.• Upon activation, Lu/ BCAM engages a sialic acid-dependent interaction with the extracellular matrix protein laminin-a5.Lutheran/basal cell adhesion molecule (Lu/BCAM) is a transmembrane adhesion molecule expressed by erythrocytes and endothelial cells that can interact with the extracellular matrix protein laminin-a5. In sickle cell disease, Lu/BCAM is thought to contribute to adhesion of sickle erythrocytes to the vascular wall, especially during vaso-occlusive crises.On healthy erythrocytes however, its function is unclear. Here we report that Lu/BCAM is activated during erythrocyte aging. We show that Lu/BCAM-mediated binding to laminin-a5 is restricted by interacting, in cis, with glycophorin-C-derived sialic acid residues. Following loss of sialic acid during erythrocyte aging, Lu/BCAM is released from glycophorin-C and allowed to interact with sialic acid residues on laminin-a5.

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Identification of signalling cascades involved in red blood cell shrinkage and vesiculation

Cited by 39 publications

References 107 publications

Psychosine enhances the shedding of membrane microvesicles: Implications in demyelination in Krabbe’s disease

Psychosine enhances the shedding of membrane microvesicles: Implications in demyelination in Krabbe’s disease

Sickle Cell Disease: Advances in Treatment

Glycophorin-C sialylation regulates Lu/BCAM adhesive capacity during erythrocyte aging

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