E-钙粘蛋白是上皮细胞-细胞粘附的重要调节剂，也是一种已确定的肿瘤抑制因子。除了上皮细胞外，E-钙粘蛋白的表达还标志着人类而非小鼠造血过程中的红细胞谱系。然而，E-钙粘蛋白在人类红细胞生成中的作用仍不清楚。由于假定大鼠红细胞生成比小鼠红细胞生成更接近地反映人类红细胞生成，因此我们研究了大鼠红系祖细胞中的 E-钙粘蛋白表达。 E-钙粘蛋白的表达在大鼠和人类的红系谱系中是保守的。为了应对贫血，大鼠骨髓 (BM) 中的成红细胞上调 E-钙粘蛋白及其结合伙伴 β-连环蛋白。 CRISPR/Cas9 介导的 E-钙粘蛋白敲除表明，E-钙粘蛋白表达是稳定人和大鼠成红细胞中 β-连环蛋白所必需的。 GSK3β 抑制剂 CHIR99021 抑制 β-连环蛋白降解也增强了人成红细胞中 β-连环蛋白的稳定性，但阻碍了成红细胞分化和存活。相比之下，使用可诱导的、稳定的β-连环蛋白变体直接激活β-连环蛋白信号传导，不会干扰人类成红细胞的成熟或存活，而是增强其分化。尽管人类成红细胞对 WNT 配体没有反应，并且直接抑制 GSK3β 甚至会降低其存活率，但我们假设人类和大鼠成红细胞中的 β-连环蛋白稳定性和信号传导主要由 E-钙粘蛋白控制。为了应对贫血，E-钙粘蛋白驱动的上调和随后的 β-连环蛋白信号激活可能会刺激成红细胞分化，以支持 BM 中的应激性红细胞生成。总体而言，我们发现 E-钙粘蛋白/β-连环蛋白表达可标记大鼠 BM 中的应激性红细胞生成。这可能有助于进一步了解 BM 应激性红细胞生成的潜在分子调节，目前对此知之甚少。版权所有 © 2023 美国血液学会。

E-cadherin is a crucial regulator of epithelial cell-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 then 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 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. Whereas 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 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 BM, which is currently poorly understood.Copyright © 2023 American Society of Hematology.