Introduction innovation

Red blood cells are by far the most abundant cells in the human body and mostly known for its pivotal role in systemic oxygen delivery and transfer. RBC transfusions are the oldest cellular therapy with the largest volumes distributed worldwide in absolute terms. Only recently, it became clear that ion channels and the membrane potential of red blood cells (RBCs) are highly relevant for human physiology and medicine; this includes the general scientific understanding of how RBCs are formed, how they survive, and how they influence physiological conditions going far beyond the blood3. These ion channels function independently alongside carriers like anion exchanger Band3 (AE1/SLC4A1) or ion pumps. Of note, the 2021 Nobel Prize for Physiology or Medicine for mechanosensing PIEZO ion channels, which are abundant on the RBC membrane, next to Ca2+-dependent Gárdos channels (KCNN4). Knowledge of the regulation of ion transport is urgently needed for the understanding, diagnosis, and treatment of RBC-related diseases: globally, one quarter of the world’s population suffers from anaemia4 and rare and congenital anaemias are an increasing health problem all over Europe. The large-scale in vitro production of RBCs with tailored properties can revolutionise transfusion medicine. Investigating and manipulating RBC ion-conducting properties bears the opportunity to treat numerous (initially unrelated) diseases by novel concepts of targeted drug delivery for gene therapy. Erythrocytes are very different from other cell types, which limits knowledge transfer from other cell types. The membrane potential of most cells is mainly determined by K+ conductance, which still holds true for RBC precursors. During differentiation, however, Cl- conductance becomes the major driver of the membrane potential. With the advance of automated high-throughput patch-clamp robots and progress in in vitro erythropoiesis, the large-scale analysis of ion channel activity and membrane potential during RBC maturation becomes feasible.