ABSTRACT
E-cadherin is a crucial regulator of epithelial cell-to-cell adhesion and an established tumor suppressor. Aside epithelia, E-cadherin expression marks the erythroid cell lineage during human but not mouse hematopoiesis. However, the role of E-cadherin in human erythropoiesis remains unknown. Because rat erythropoiesis was postulated to reflect human erythropoiesis more closely than mouse erythropoiesis, we investigated E-cadherin expression in rat erythroid progenitors. E-cadherin expression is conserved within the erythroid lineage between rat and human. In response to anemia, erythroblasts in rat bone marrow (BM) upregulate E-cadherin as well as its binding partner ß-catenin. CRISPR/Cas9-mediated knock out of E-cadherin revealed that E-cadherin expression is required to stabilize ß-catenin in human and rat erythroblasts. Suppression of ß-catenin degradation by glycogen synthase kinase 3ß (GSK3ß) inhibitor CHIR99021 also enhances ß-catenin stability in human erythroblasts but hampers erythroblast differentiation and survival. In contrast, direct activation of ß-catenin signaling, using an inducible, stable ß-catenin variant, does not perturb maturation or survival of human erythroblasts but rather enhances their differentiation. Although human erythroblasts do not respond to Wnt ligands and direct GSK3ß inhibition even reduces their survival, we postulate that ß-catenin stability and signaling is mostly controlled by E-cadherin in human and rat erythroblasts. In response to anemia, E-cadherin-driven upregulation and subsequent activation of ß-catenin signaling may stimulate erythroblast differentiation to support stress erythropoiesis in the BM. Overall, we uncover E-cadherin/ß-catenin expression to mark stress erythropoiesis in rat BM. This may provide further understanding of the underlying molecular regulation of stress erythropoiesis in the BM, which is currently poorly understood.
Subject(s)
Anemia , beta Catenin , Humans , Rats , Mice , Animals , beta Catenin/metabolism , Erythropoiesis/physiology , Glycogen Synthase Kinase 3 beta , Cadherins/genetics , Cadherins/metabolismABSTRACT
E-cadherin is a key regulator of epithelial cell-cell adhesion, the loss of which accelerates tumor growth and invasion. E-cadherin is also expressed in hematopoietic cells as well as epithelia. The function of hematopoietic E-cadherin is, however, mostly elusive. In this study, we explored the validity of mouse models to functionally investigate the role of hematopoietic E-cadherin in human hematopoiesis. We generated a hematopoietic-specific E-cadherin knockout mouse model. In mice, hematopoietic E-cadherin is predominantly expressed within the basophil lineage, the expression of which is dispensable for the generation of basophils. However, neither E-cadherin mRNA nor protein were detected in human basophils. In contrast, human hematopoietic E-cadherin marks the erythroid lineage. E-cadherin expression in hematopoiesis thereby revealed striking evolutionary differences between the basophil and erythroid cell lineage in humans and mice. This is remarkable as E-cadherin expression in epithelia is highly conserved among vertebrates including humans and mice. Our study therefore revealed that the mouse does not represent a suitable model to study the function of E-cadherin in human hematopoiesis and an alternative means to study the role of E-cadherin in human erythropoiesis needs to be developed.
Subject(s)
Basophils , Hematopoiesis , Humans , Mice , Animals , Basophils/metabolism , Cell Lineage/genetics , Hematopoiesis/genetics , Cadherins/genetics , Cadherins/metabolism , Mice, KnockoutABSTRACT
Myeloid dysplastic syndrome (MDS) reflects a preleukemic bone marrow (BM) disorder with limited treatment options and poor disease survival. As only a minority of MDS patients are eligible for curative hematopoietic stem cell transplantation, there is an urgent need to develop alternative treatment options. Chronic activation of Wnt/ß-catenin has been implicated to underlie MDS formation and recently assigned to drive MDS transformation to acute myeloid leukemia. Wnt/ß-catenin signaling therefore may harbor a pharmaceutical target to treat MDS and/or prevent leukemia formation. However, targeting the Wnt/ß-catenin pathway will also affect healthy hematopoiesis in MDS patients. The control of Wnt/ß-catenin in healthy hematopoiesis is poorly understood. Whereas Wnt/ß-catenin is dispensable for steady-state erythropoiesis, its activity is essential for stress erythropoiesis in response to BM injury and anemia. Manipulation of Wnt/ß-catenin signaling in MDS may therefore deregulate stress erythropoiesis and even increase anemia severity. Here, we provide a comprehensive overview of the most recent and established insights in the field to acquire more insight into the control of Wnt/ß-catenin signaling in healthy and inefficient erythropoiesis as seen in MDS.