E-cadherin controls erythropoiesis; a novel avenue to treat anaemia
In Western world aging-associated bone marrow (BM) dysplasia’s, such as Myelodysplastic-Syndrome (MDS), increasingly contribute to anaemia incidence. One major goal of MDS-treatment is treating anaemia with the aim of avoiding or delaying chronic transfusional support, to decrease the risk of transfusion–related complications and improve quality of life. When serum erythropoietin (EPO) is low, MDS-patients are treated with EPO and/or Sotatercept, displaying a ~50% response rate in terms of erythroid hematological improvement. Anaemia-treatment in MDS therefore urgently requires development of novel options to promote erythropoiesis. A fundamental requirement to develop novel treatment opportunities that promote erythropoiesis is to obtain improved understanding of the erythroid homeostatic responses in BM to anaemia.
The erythroid homeostatic response to anaemia has been extensively studied in vivo using mouse models. Erythropoiesis is an evolutionary conserved process. Yet the homeostatic response to anaemia, known as stress erythropoiesis, is significantly different in mice as compared to humans. Stress erythropoiesis in mice is mainly driven extramedullary, in the spleen, by activation of quiescent erythroid committed progenitor cells, whereas stress erythropoiesis in humans is mainly confined to BM. In humans, loss of RBCs induces 20-fold increase in BM erythropoiesis, in contrast to a 2-fold increase in BM erythropoiesis in mice. The underlying mechanism of stress erythropoiesis in human BM is mostly elusive. In contrast to mice, rat stress erythropoiesis is highly reminiscent to human as it primarily develops in BM. Therefore it has been suggested that rats are a superior model for human stress erythropoiesis.
Here, we identified Epithelial cadherin (E-cadherin) to selectively mark the erythroid differentiation trajectory in human BM. Additionally, our preliminary experiments reveal E-cadherin to control the expansion of erythroid progenitors as defined by Crispr-Cas9 knockout experiments of E-cadherin in human hematopoietic stem cells. This is striking, because E-cadherin is well-established to mediate epithelial integrity, as key component in adherens junctions. Here, E-cadherin functions as mechanosensor and crosstalks with signalling cascades, such as the Wnt pathway. Interestingly, we found that E-cadherin expression is conserved on erythroid progenitors in rat, but not in mouse. We therefore hypothesize that E-cadherin, as mediator of cell adhesion, mechanosensing and downstream signalling, displays an unanticipated BM-specific control on (stress) erythropoiesis that cannot be uncovered by exploring the anaemic response in mouse models, but may be revealed using a rat model instead. In extention, we suggest deficient E-cadherin to underlie inefficient stress erythropoiesis and anemia as we observe irregular E-cadherin mRNA and protein expression in the erythroid lineage in MDS patient BM.
Overall, E-cadherin signalling may underlie the erythroid homeostatic response to anaemia by controlling expansion of erythroid progenitors in human BM, and is an interesting candidate for targeted treatment of inefficient erythropoiesis.