Page 179 - 2021_10-Haematologica-web

Red Cell Biology & its Disorders
Fetal hemoglobin rescues ineffective erythropoiesis in sickle cell disease
Sara El Hoss,1,2,3 Sylvie Cochet,1,2,3,# Auria Godard,1,2,3,#° Hongxia Yan,4 Michaël Dussiot,5 Giacomo Frati,6,7 Bénédicte Boutonnat-Faucher,8 Sandrine Laurance,1,2,3 Olivier Renaud,9,10,11,12 Laure Joseph,13 Annarita Miccio,6,7 Valentine Brousse,1,2,3,8 Narla Mohandas4 and Wassim El Nemer1,2,3°
1Université de Paris, INSERM UMRS1134, BIGR, Paris, France; 2Institut National de la Transfusion Sanguine, Paris, France; 3Laboratoire d’Excellence GR-Ex, Paris, France; 4Red Cell Physiology Laboratory, New York Blood Center, New York, NY, USA; 5Institut Imagine, INSERM U1163, CNRS UMR8254, Université de Paris, Hôpital Necker Enfants Malades, Paris, France; 6Laboratory of Chromatin and Gene Regulation during Development, INSERM UMR1163, Paris, France; 7Université de Paris, Imagine Institute, Paris, France; 8Service de Pédiatrie Générale et Maladies Infectieuses, Hôpital Universitaire Necker Enfants Malades, Paris, France; 9Institut Curie, Paris Sciences et Lettres Research University, Paris, France; 10Institut National de la Santé et de la Recherche Médicale, INSERM U934, Paris, France;11Centre National de la Recherche Scientifique, INSERM UMR3215, Paris, France; 12Cell and Tissue Imaging Facility (PICT- IBiSA), Institut Curie, Paris, France and 13Service de Biothérapie, Hôpital Universitaire Necker Enfants Malades, Paris, France
°Present affiliation: Etablissement Français du Sang PACA-Corse, Aix Marseille Université, EFS, CNRS, ADES, “Biologie des Groupes Sanguins”, Marseille, France.
#SC and AG contributed equally as co-second authors.
ABSTRACT
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 associ- ated 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 lev- els is not only due to the increased life span of red cells but also a con- sequence of decreased ineffective erythropoiesis.
Introduction
Sickle cell disease (SCD) is an autosomal hereditary recessive disorder caused by a point mutation in the b-globin gene resulting in a Glu-to-Val substitution at the sixth position of the b-globin protein. The resulting abnormal hemoglobin (HbS) polymerizes under hypoxic conditions driving red blood cell (RBC) sickling.1 SCD is a multisystem disease characterized by hemolytic anemia, high susceptibility to infections, recurrent painful vaso-occlusive crises, strokes, acute chest syndrome and organ failure.2,3
While the pathobiology of circulating RBC has been extensively analyzed in SCD, erythropoiesis is surprisingly poorly documented. In b-thalassemia, ineffec- tive erythropoiesis is characterized by high levels of apoptotic erythroblasts dur- ing the late stages of terminal differentiation, due to an accumulation of free α- globin chains.4-6 Ineffective erythropoiesis is the major cause of anemia in b-tha-
Ferrata Storti Foundation
Haematologica 2021 Volume 106(10):2707-2719
Correspondence:
WASSIM EL NEMER
wassim.el-nemer@efs.sante.fr
Received: July 1, 2020 Accepted: August 17, 2020. Pre-published: August 27, 2020.
https://doi.org/10.3324/haematol.2020.265462 ©2021 Ferrata Storti Foundation
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