Vitamin C promotes differentiation of stress-specific erythroid progenitors in stress erythropoiesis

We discovered that vitamin C import through the vitamin C transporter SLC23A2 in stress-specific erythroid progenitors represents a key regulatory nexus in the recovery of the erythron. In response to erythroid stress, such as blood loss, Epo induces the expression of Slc23a2 in stress erythroid progenitor cells, increasing intracellular vitamin C levels and promoting their differentiation into erythroblasts. Vitamin C-induced erythroid differentiation is blocked by Slc23a2 deletion or in EpoR mutant mice unable to induce Slc23a2. Both mice show attenuated erythron recovery in stress. These defects are rescued by exogenous expression of either SLC23A2 or the related vitamin C transporter SLC23A1, but not by a transport-defective SLC23A2 mutant. Mechanistically, intracellular vitamin C promotes erythroid progenitor differentiation independently of its antioxidant activity. Instead, it regulates 2-oxoglutarate-dependent dioxygenases, TET2, KDM6A and ALKBH8, facilitating the upregulation of the master erythroid transcription factor GATA1. These findings identify vitamin C uptake as an Epo-licensed, rate-limiting determinant of stress erythropoiesis.