Ischemia induces cytokine-mediated liberation of progenitor cells (PC) from the bone marrow (BM) to the circulation. Pain is an essential component of the alarm response to tissue injury. However, whether sensory signaling regulates PC mobilization remains unclear.Objective
To determine if substance P (SP) and Calcitonin Gene-Releated Peptide (CGRP) released from sensory nerves contribute to PC mobilization and tissue repair.Methods and Results
Sensory neurons showing immunoreactivity for SP and CGRP are present in mouse BM. Moreover, flow cytometry analyses showed that lineage negative, c-Kit/Sca-1 positive BM cells express the SP neurokinin receptor 1 (NK1) and CGRP receptor. In transwell migration assays, neuropeptides, cultured dorsal root ganglion neurons and their conditioned medium attract BM PC, which is prevented by SP and CGRP antagonists. Transplantation of migrated cells improves the blood flow recovery in a mouse model of limb ischemia. Moreover, acute myocardial infarction (aMI) mobilizes c-Kit/NK1 positive PC, this effect being associated with increased SP levels in peripheral blood and decreased SP immunoreactivity in BM. Moreover, human PC express neuropeptide receptors and neuropeptide-induced migration enriches for PC that enhance endothelial cell networking on matrigel. In aMI patients, the mobilization of CD34/KDR and CD34/CXCR4 PC co-expressing neuropeptide receptors is associated to increased SP levels in peripheral blood.Conclusions
Sensory fibers are localized in close proximity with PC niches and neurogenic mechanisms regulate PC mobilization and functions following ischemic insults. Nociceptive signaling might represent a novel target for modulation of PC homeostasis and reparative responses.