Functional C3a‐ and C5a‐Receptors on human Mesenchymal Stem Cells

The anaphylatoxin receptors, C3a‐receptor (C3aR) and C5a‐receptor (C5aR) are best known as receptors involved in leukocyte trafficking, but are much more widely expressed. Mesenchymal stem cells (MSCs) are among the cell types which express both C3aRs and C5aRs. Activation of the C3aR is often transient and weak compared with other G‐protein coupled receptors. In MSCs it was, however prolonged as determined by phosphorylation of ERK1/2 and Akt, which were phosphorylated for up to one hour in MSCs, but for at most 5 min in HEK293 cells. This prolonged activation of signaling pathways in MSCs was associated with translocation of the C3aR to the nucleus in MSCs, but not in other cell types tested. The signaling molecule ERK1/2 also translocated to the nucleus in MSCs, but only minimally in HEK293 cells. Translocation of these signaling molecules is important because it is associated with transcriptional activation as reflected by phosphorylation of the transcription factor Elk in C3a‐stimulated MSCs, but not in HEK293 cells. Functionally, both C3a and C5a chemo‐attracted MSCs, which may be an in vivo mechanism of MSC recruitment to areas of tissue injury. In summary, the C3aR in MSCs is translocated to the nucleus, which is associated with prolonged cell activation. Such distinct trafficking of a G‐protein coupled receptor depending on cellular context is a novel means of regulating cell activation.