Sickle cell disease: old discoveries, new concepts, and future promise

Frenette, Paul S.; Atweh, George F.

doi:10.1172/jci30920

Cited by 321 publications

(309 citation statements)

References 132 publications

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“…protein depletion), and on a macroscopic scale, they could lead to a better understanding of factors regulating the functioning of the vascular system. This should not only be of potential value for a detailed understanding of the pathophysiology of diseases associated with abnormal RBC-EC interactions but might also be applicable to other cell-cell interactions such as leukocyte-endothelium adhesion, which has been correlated to abnormal RBC-EC adhesion (38).…”

Section: Discussionmentioning

confidence: 99%

Specific Binding of Red Blood Cells to Endothelial Cells Is Regulated by Nonadsorbing Macromolecules

Yang

Koo

Lin

et al. 2010

Journal of Biological Chemistry

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Abnormal adhesion of red blood cells to the endothelium has been linked to the pathophysiology of several diseases associated with vascular disorders. Various biochemical changes, including phosphatidylserine exposure on the outer membrane of red blood cells as well as plasma protein levels, have been identified as being likely to play a key role, but the detailed interplay between plasma factors and cellular factors remains unknown. It has been proposed that the adhesionpromoting effect of plasma proteins originates from ligand interaction, but evidence substantiating this assumption is often missing. In this work, we identified an alternative pathway by demonstrating that nonadsorbing macromolecules can also have a marked impact on the adhesion efficiency of red blood cells with enhanced phosphatidylserine exposure to endothelial cells. It is concluded that this adhesion-promoting effect originates from macromolecular depletion interaction and thereby presents an alternative mechanism by which plasma proteins could regulate cell-cell interactions. These findings should thus be of potential value for a detailed understanding of the pathophysiology of diseases associated with vascular complications and might be applicable to a wide range of cellcell interactions in plasma or plasma-like media. The adhesion of red blood cells (RBC)2 to endothelial cells (EC) is usually insignificant. However, increased RBC adhesion to endothelial cells has been observed in various clinical states such as sickle cell disease, ␤-thalassemia, and diabetes mellitus, and the degree of RBC-EC adhesiveness has been linked to the vascular complications associated with these diseases (1-5). There is now general agreement that various cell surface alterations control the increased RBC adhesiveness in such disease states. For example, an enhanced phosphatidylserine (PS) exposure on the outer leaflet of the RBC membrane has been linked to abnormal RBC-EC adhesion in sickle cell disease, hereditary hydrocytosis, and chronic uremia (6 -8). Usually this anionic phospholipid is located exclusively on the inner leaflet of the RBC membrane but is translocated to the outer leaflet in hemoglobinopathies and oxidative stress states (9). The role of PS in adhesion has not been fully understood, but RBC with enhanced PS exposure have been identified to establish specific interactions with EC or the endothelial matrix via several receptors including thrombospondin, ␣ V ␤ 3 , CD36, and PS receptor (6, 10, 11).Moreover, several plasma factors have been identified to be involved in abnormal RBC adhesion to EC. For example, fibrinogen enhances the adhesion of pathological RBC to EC (12, 13), which is consistent with the observation that the onset of vaso-occlusive crisis in sickle cell disease is always accompanied by a temporally elevated level of this acute phase protein (12,14). However, the underlying mechanisms behind the increased adhesion efficiency in the presence of this acute phase protein remain obscure. It has been suggested that fibrinogen acts...

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Section: Discussionmentioning

confidence: 99%

Specific Binding of Red Blood Cells to Endothelial Cells Is Regulated by Nonadsorbing Macromolecules

Yang

Koo

Lin

et al. 2010

Journal of Biological Chemistry

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“…Patients mostly present with hemolytic anemia, jaundice, repeated vaso-occlusive crises, hand foot syndrome, acute chest syndromes, and splenic sequestration crises etc. 10 They can also get repeated infections like pneumonia, osteomyelitis, dactylitis etc.…”

Section: Discussionmentioning

confidence: 99%

Death due to sickle cell anaemia, an autopsy diagnosis: a study at a tertiary care hospital

2015

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“…The now rigid blood cells block small capillaries, causing occlusion and ischemia. 37 One strategy to cure sickle cell anemia is to activate expression of fetal Hb, HbF, which does not require the b-globin subunit and therefore, does not cause sickling. HbF expression is normally downregulated after 6 weeks of age by a transcriptional repressor encoded by the BCL11A gene.…”

Section: Gene Therapy Protocols Using Genome Editing Technologiesmentioning

confidence: 99%

Gene Editing: Powerful New Tools for Nephrology Research and Therapy

Miyagi

Humphreys

2016

JASN

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Biologic research is experiencing a transformation brought about by the ability of programmable nucleases to manipulate the genome. In the recently developed CRISPR/ Cas system, short RNA sequences guide the endonuclease Cas9 to any location in the genome, causing a DNA double-strand break (DSB). Repair of DSBs allows the introduction of targeted genetic manipulations with high precision. Cas9-mediated gene editing is simple, scalable, and rapid, and it can be applied to virtually any organism. Here, we summarize the development of modern gene editing techniques and the biology of DSB repair on which these techniques are based. We discuss technical points in applying this technology and review its use in model organisms. Finally, we describe prospects for the use of gene editing to treat human genetic diseases. This technology offers tremendous promise for equipping the nephrology research community to better model and ultimately, treat kidney diseases.

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Sickle cell disease: old discoveries, new concepts, and future promise

Cited by 321 publications

References 132 publications

Specific Binding of Red Blood Cells to Endothelial Cells Is Regulated by Nonadsorbing Macromolecules

Specific Binding of Red Blood Cells to Endothelial Cells Is Regulated by Nonadsorbing Macromolecules

Death due to sickle cell anaemia, an autopsy diagnosis: a study at a tertiary care hospital

Gene Editing: Powerful New Tools for Nephrology Research and Therapy

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