TY - JOUR
T1 - E-cadherin/β-catenin expression is conserved in human and rat erythropoiesis and marks stress erythropoiesis
AU - Krimpenfort, Rosa A
AU - van der Meulen, Santhe A
AU - Verhagen, Han
AU - Driessen, Michel
AU - Filonova, Galina
AU - Hoogenboezem, Mark
AU - van den Akker, Emile
AU - von Lindern, Marieke
AU - Nethe, Micha
N1 - Funding Information: This research has been funded by the Landsteiner foundation for blood transfusion research (LSBR) fellowship grant, LSBR 2007F. Publisher Copyright: © 2023 by The American Society of Hematology.
PY - 2023/12/12
Y1 - 2023/12/12
N2 - 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 β-catenin. CRISPR/Cas9-mediated knock out of E-cadherin revealed that E-cadherin expression is required to stabilize β-catenin in human and rat erythroblasts. Suppression of β-catenin degradation by glycogen synthase kinase 3β (GSK3β) inhibitor CHIR99021 also enhances β-catenin stability in human erythroblasts but hampers erythroblast differentiation and survival. In contrast, direct activation of β-catenin signaling, using an inducible, stable β-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 GSK3β inhibition even reduces their survival, we postulate that β-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 β-catenin signaling may stimulate erythroblast differentiation to support stress erythropoiesis in the BM. Overall, we uncover E-cadherin/β-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.
AB - 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 β-catenin. CRISPR/Cas9-mediated knock out of E-cadherin revealed that E-cadherin expression is required to stabilize β-catenin in human and rat erythroblasts. Suppression of β-catenin degradation by glycogen synthase kinase 3β (GSK3β) inhibitor CHIR99021 also enhances β-catenin stability in human erythroblasts but hampers erythroblast differentiation and survival. In contrast, direct activation of β-catenin signaling, using an inducible, stable β-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 GSK3β inhibition even reduces their survival, we postulate that β-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 β-catenin signaling may stimulate erythroblast differentiation to support stress erythropoiesis in the BM. Overall, we uncover E-cadherin/β-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.
KW - Anemia
KW - Animals
KW - Cadherins/genetics
KW - Erythropoiesis/physiology
KW - Glycogen Synthase Kinase 3 beta
KW - Humans
KW - Mice
KW - Rats
KW - beta Catenin/metabolism
UR - http://www.scopus.com/inward/record.url?scp=85179491806&partnerID=8YFLogxK
U2 - https://doi.org/10.1182/BLOODADVANCES.2023010875
DO - https://doi.org/10.1182/BLOODADVANCES.2023010875
M3 - Article
C2 - 37792794
SN - 2473-9529
VL - 7
SP - 7169
EP - 7183
JO - Blood advances
JF - Blood advances
IS - 23
ER -