A ROLE FOR CD44 IN ERYHTROID IRON UPTAKE

Red blood cells (RBC) transport oxygen to cells by binding oxygen to the iron cation of heme. Consequently, RBC production requires iron. Erythroid cells can acquire iron through the transferrin-transferrin receptor (TFR1) endocytosis cycle. In addition to this well-established pathway, studies suggest that erythroid cells may also utilize non-transferrin-bound iron (NTBI). Importantly, in the context of cancer and immune cells, CD44, a major receptor of hyaluronates, mediates endocytosis of iron-bound hyaluronates into the cells

In this study, we selectively deleted Tfr1 or Cd44 in erythroid cells using Tfr1 and Cd44 flox mice crossed with EpoR-Cre mice to assess their respective roles in iron uptake and erythroid maturation. We observed that Tfr1EpoR/+ mice are viable, albeit they exhibit anemia. In these mice, erythroid cells that are deleted for Tfr1 develop and mature normally, and importantly maintain the capacity to produce hemoglobin. By measuring endosomal Fe2+ with a fluorescent probe, we demonstrated that erythroid cells lacking Tfr1 have the same ability to acquire iron than WT cells, indicating the utilization of an alternative mechanism for iron acquisition.

To investigate if Cd44 could be involved in this mechanism, we deleted Cd44 in erythroid cells in mice. We observed a reduced production of RBC and hemoglobin in Cd44EpoR/+ males. Females lacking Cd44 in erythroid cells exhibited delayed recovery during erythroid stress induced by phenylhydrazine injection, along with a reduction in RBC production compared to WT mice. Taken together, these results suggest that both Tfr1 and Cd44 contribute to iron acquisition in erythroid cells.