Fine-tuned Calcium Homeostasis is Crucial for Murine Erythropoiesis

Intracellular calcium (Ca) is a crucial signaling molecule involved in multiple cellular processes. However, the functional role of Ca in terminal erythropoiesis remains unclear. Here, we uncovered the dynamics of intracellular Ca levels during mouse erythroid development. By using the calcium ionophore ionomycin, we found that low Ca levels are required for the expansion of erythroid progenitors, whereas higher Ca levels led to the differentiation and proliferation of early-stage erythroblasts. Intracellular Ca levels were then gradually reduced, which is required for the nuclear condensation and polarisation at the late stage of erythroid differentiation. However, elevated Ca levels in late-stage erythroblasts, achieved by using ionomycin, promoted erythroid enucleation via calmodulin (CaM)/calcium/calmodulin-dependent protein kinase kinase 1 (CaMKK1)/AMPK signaling. These data suggest that the reduction of intracellular Ca plays a double-edged role at the late stage of erythroid differentiation, which is beneficial for nuclear condensation but compromises terminal enucleation. Our study highlighted the importance of the fine-tuned regulation of intracellular Ca during terminal erythropoiesis, providing cues for the efficient generation of mature and enucleated erythrocytes in vitro.