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Editorials
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Staying hydrated is important also for erythroblasts
Anupama Narla1 and Narla Mohandas2
1Department of Pediatrics, Stanford University, School of Medicine, Stanford, CA and 2Laboratory of Red Cell Physiology, New York Blood Center, New York, NY, USA
E-mail: ANUPAMA NARLA - anunarla@stanford.edu or NARLA MOHANDAS - mnarla@nybc.org doi:10.3324/haematol.2019.233999
In this edition of Haematologica, Caulier and colleagues provide new insights into the role of PIEZO1, a mechanosensitive ion channel, in regulating normal human erythropoiesis.1 Defects in PIEZO1 have also been shown to lead to disordered erythropoiesis in hereditary xerocytosis, an inherited red cell disorder leading to red cell dehydration.2,3 Using in vitro cellular models of human erythropoiesis, the authors documented that the chemi- cal activation of PIEZO1 either in an erythroid cell line model or in normal human hematopoietic stem cells (HSC) repressed erythroid differentiation. Importantly, they further documented that there was delayed ery- throid differentiation in HSC from patients with PIEZO1 mutations. These findings provide unexpected and novel insights into the role of ion channels in the regulation of human erythropoiesis.1
Anemia is a significant health problem that affects near- ly two billion people around the world. The major causes of anemia are: (i) an increased rate of destruction of circu- lating red cells in disorders that include red cell membrane disorders, sickle cell disease, immune hemolytic anemia, nutritional anemias and malaria; (ii) acute blood loss or splenic sequestration; and (iii) decreased production of red cells in the bone marrow due to ineffective erythro- poiesis,which includes thalassemias, inherited bone mar- row failure syndromes, infiltrative processes such as myelodysplastic syndrome and acute myeloid leukemia and suppression of erythropoiesis due to infection and medications. While significant progress has been made over the years to improve our understanding of the contri- bution of increased red cell destruction to anemia, much less is known about the extent of the effect of ineffective erythropoiesis and its contribution to anemia in the vari- ous red cell disorders. This is particularly true in the case of inherited red blood cell membrane disorders. The lack
of progress has been due in part to a lack of an adequate and easily implementable methodology to study the com- plex process of human erythroid differentiation.
The generation of enucleated circulating human red cells is a complex biological process that begins in the bone marrow with the commitment of pluripotent HSC to the erythroid lineage (Figure 1). Subsequent stages of maturation include erythroid progenitors, burst-forming unit–erythroid and colony-forming unit–erythroid (CFU- E), which can be identified by their development into representative clonal colonies of red cells in vitro. The CFU-E then undergoes terminal differentiation, progress- ing through four to five morphological stages, each hav- ing characteristic light microscopic and ultrastructural features. During terminal erythroid differentiation there is an increasing amount of hemoglobin synthesis accom- panied by nuclear chromatin condensation and in the final stage of differentiation there is nuclear extrusion to generate an anucleate reticulocyte which over 2 to 3 days matures, first in the marrow and then in the circulation, into the discoid erythrocyte.
Significant progress has been made during the last decade in developing culture systems to study the differ- entiation of human CD34 cells intto enucleate reticulo- cytes and using various cell surface markers to monitor the progression through all stages of erythroid differentia- tion.4-7 These developments are enabling detailed charac- terization of normal and disordered human erythro- poiesis.8-13 Importantly, as a result of this progress it is now possible to obtain insights into at what stage of the com- plex process of erythroid differentiation various genes contribute to ineffective erythropoiesis.
Using these in vitro cellular models of human erythro- poiesis, the study by Caulier and colleagues documented that the chemical activation of PIEZO1 either in an ery-
haematologica | 2020; 105(3)