Page 15 - Haematologica March 2020

Editorials
Figure 1. Schematic representation of the various developmental stages of hematopoietic stem cells during erythroid differentiation. The multipotent hematopoi- etic stem cell first commits to the erythroid lineage to generate erythroid progenitors, which are recognized by their ability to form erythroid colonies in a semisolid methylcellulose culture system in response to interleukin-3, stem cell factor and erythropoietin. They cannot be distinguished based on their morphology. It is esti- mated that hematopoietic stem cells undergo approximately eight to ten cell divisions prior to the generation of the first morphologically recognizable erythroid cell in the bone marrow, the proerythroblast. During terminal erythroid differentiation, the proerythroblast undergoes five mitoses to generate an orthochromatic ery- throblast. This ordered progression during normal erythropoiesis may be disturbed at any of the different developmental stages in various pathological states, leading to ineffective erythropoiesis. HSC: hematopoietic stem cell; BFU-E: burst-forming unit–erythroid; CFU-E: colony-forming unit–erythroid; ProE: proerythroblast; EBaso: early basophilic erythroblast; LBaso: late basophilic erythroblast; Poly: polychromatic erythroblast; Ortho: orthochromatic erythroblast.
throid cell line model or in primary normal HSC repressed erythroid differentiation. Importantly, the authors also showed that there was delayed erythroid differentiation of HSC from patients carrying PIEZO1 mutations. Delayed erythroid differentiation due to PIEZO1 activation was shown to be dependent on calci- um entry and transcriptional control through the phos- phorylation of transcription factors NFAT, STAT5 and ERK1/2.
These findings provide unexpected and novel insights into the role of ion channels in regulating human ery- thropoiesis. Although the reported findings represent an important step in our understanding of the role of PIEZO1 in regulating human erythropoiesis and ineffec- tive erythropoiesis in hereditary xerocytosis, a number of questions remain unanswered. The variability in the delayed erythoid differentiation among different patients has not been defined. Furthermore, while ineffective ery- thropoiesis has been documented to be a feature of ter- minally differentiating erythroblasts, it is less clear at what specific stage of terminal erythroid differentiation apoptosis dominates. There is also no information about whether ineffective erythropoiesis is a feature of ery- throid progenitors. It is anticipated that these important issues will be pursued in future studies.
In spite of some of these unanswered questions, the studies by Caulier and colleagues are significant in that they provide new and previously unsuspected insights into the role of ion channels in regulating human ery- thropoiesis. These valuable insights expand our current understanding of the role not only of growth factors and cytokines but also of ion channels in human erythroid differentiation. It is likely that the experimental strate- gies used in the study will be useful in furthering our understanding of the regulation of human erythropoiesis
in general and the contribution of ineffective erythro- poiesis to anemia in various human red cell disorders.
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