Evidence of in vivo exogen protein uptake by red blood cells: a putative therapeutic concept

For some molecular players in red blood cells, the functional indications and molecular evidence are discrepant. One such protein is transient potential receptor channel of canonical type 6 (TRPC6). Transcriptome analysis of reticulocytes revealed the presence of TRPC6 in mouse red blood cells and its absence in human red blood cells. We transfused TRPC6 knockout (KO) red blood cells into wild-type (WT) mice and performed functional tests; we observed the 'rescue' of TRPC6 within 10 days but slower TRPC6 'rescue' in splenectomized mice. The latter finding led us to mimic the mechanical challenge with the cantilever of an atomic force microscope (AFM) and simultaneously carry out imaging by confocal (3D) microscopy. We observed the strong interaction of red blood cells with the opposed surface in the range of 200 pN and the formation of tethers. The results of both the transfusion experiments and the atomic force spectroscopy suggest mechanically stimulated protein transfer to red blood cells as a protein source in the absence of the translational machinery. This protein transfer mechanism has the potential to be utilized in therapeutic contexts, especially for hereditary diseases involving red blood cells, such as hereditary xerocytosis or Gárdos channelopathy.