Erythroid Ca²⁺ Channel 2 (ECC2) inhibits erythroid maturation while promoting globin transcription.

Abstract

Ca²⁺ influx plays a crucial role during erythropoiesis. To gain deeper insights into how Ca²⁺ signaling impacts erythropoiesis, we investigated the role of Erythroid Calcium Channel 2 (ECC2), a regulator of calcium influx, using induced pluripotent stem cell (iPSC) and human umbilical cord blood-derived erythroid progenitor (HUDEP, Immortalized Human Erythroid Progenitor Cell Lines) cell lines. Our findings revealed a significant upregulation of ECC2 mRNA levels as cells transitioned from the undifferentiated iPSCs to the CD71+ erythroid progenitors. This upregulation was accompanied by an increase in ECC2 mediated Ca2+ influx at the CD71+ erythroid progenitors. Additionally, ECC2 mRNA levels continued to increase from the CD71+ to the CD71−CD235a+ mature RBC. To clarify the specific role of ECC2 in erythropoiesis, we employed a dominant-negative ECC2 mutation (DN) in HUDEP-2 cells. DN cells exhibited a significant reduction in Ca²⁺ influx. Furthermore, erythropoiesis efficiency was enhanced in DN cells compared to the control, suggesting that ECC2 inhibits terminal erythroid differentiation. Additionally, DN cells showed a decrease in globin gene family expression, indicating that ECC2 functions as a positive regulatory factor in globin gene transcription. Overall, we identified two distinct functional roles of the ECC2 Ca²⁺ channel in erythroid maturation: delaying maturation and inducing globin transcription. These findings offer valuable insights into the role of ECC2-mediated Ca²⁺ signaling in erythropoiesis.