Fetal hemoglobin rescues ineffective erythropoiesis in sickle cell disease

While ineffective erythropoiesis has long been recognized as a key contributor to anemia in thalassemia, its role in anemia of sickle cell disease (SCD) has not been critically explored. Using in vitro and in vivo derived human erythroblasts we assessed the extent of ineffective erythropoiesis in SCD. Modeling the bone marrow hypoxic environment, we found that hypoxia induces death of sickle erythroblasts starting at the polychromatic stage, positively selecting cells with high levels of fetal hemoglobin (HbF). Cell death was associated with cytoplasmic sequestration of heat shock protein 70 and was rescued by induction of HbF synthesis. Importantly, we document that in the bone marrow of SCD patients similar cell loss occurs during the final stages of terminal differentiation. Our study provides evidence for ineffective erythropoiesis in SCD and highlights an anti-apoptotic role for HbF during the terminal stages of erythroid differentiation. These findings imply that the beneficial effect on anemia of increased HbF levels is not only due to the increased life span of red cells but also a consequence of decreased ineffective erythropoiesis

Approche pharmacogénomique du traitement de la drépanocytose (analyse globale de l'effet de l'hydroxyurée sur le transcriptome de cellules endothéliales humaines)

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Red Blood Cells: A Newly Described Partner in Central Retinal Vein Occlusion Pathophysiology?

Central retinal vein occlusion (CRVO) is a frequent retinal disorder inducing blindness due to the occlusion of the central vein of the retina. The primary cause of the occlusion remains to be identified leading to the lack of treatment. To date, current treatments mainly target the complications of the disease and do not target the primary dysfunctions. CRVO pathophysiology seems to be a multifactorial disorder; several studies did attempt to decipher the cellular and molecular mechanisms underlying the vessel obstruction, but no consensual mechanism has been found. The aim of the current review is to give an overview of CRVO pathophysiology and more precisely the role of the erythroid lineage. The review presents emerging data on red blood cell (RBC) functions besides their role as an oxygen transporter and how disturbance of RBC function could impact the whole vascular system. We also aim to gather new evidence of RBC involvement in CRVO occurrence

Gas6 promotes inflammatory (CCR2hiCX3CR1lo) monocyte recruitment in venous thrombosis

Objective - Coagulation and inflammation are inter-related. Gas6 (growth arrest-specific 6) promotes venous thrombosis and participates to inflammation through endothelial-innate immune cell interactions. Innate immune cells can provide the initiating stimulus for venous thrombus development. We hypothesize that Gas6 promotes monocyte recruitment during venous thrombosis. Approach and Results - Deep venous thrombosis was induced in wild-type and Gas6-deficient (-/-) mice using 5% FeCl and flow reduction in the inferior vena cava. Total monocyte depletion was achieved by injection of clodronate before deep venous thrombosis. Inflammatory monocytes were depleted using an anti-C-C chemokine receptor type 2 (CCR2) antibody. Similarly, injection of an anti-chemokine ligand 2 (CCL2) antibody induced CCL2 depletion. Flow cytometry and immunofluorescence were used to characterize the monocytes recruited to the thrombus. In vivo, absence of Gas6 was associated with a reduction of monocyte recruitment in both deep venous thrombosis models. Global monocyte depletion by clodronate leads to smaller thrombi in wild-type mice. Compared with wild type, the thrombi from Gas6 mice contain less inflammatory (CCR2CXCR1) monocytes, consistent with a Gas6-dependent recruitment of this monocyte subset. Correspondingly, selective depletion of CCR2CXCR1 monocytes reduced the formation of venous thrombi in wild-type mice demonstrating a predominant role of the inflammatory monocytes in thrombosis. In vitro, the expression of both CCR2 and CCL2 were Gas6 dependent in monocytes and endothelial cells, respectively, impacting monocyte migration. Moreover, Gas6-dependent CCL2 expression and monocyte migration were mediated via JNK (c-Jun N-terminal kinase). Conclusions - This study demonstrates that Gas6 specifically promotes the recruitment of inflammatory CCR2CXCR1 monocytes through the regulation of both CCR2 and CCL2 during deep venous thrombosis