Abstract 18521: Sensory Neuropathy Jeopardizes Nociceptive-mediated Liberation and Homing of Stem Cells in Mice and Patients With Diabetes

Abstract

Introduction: Diabetic sensory neuropathy (SN) causes either unbearable pain or lack of ischemic pain perception. It remains unknown if SN affects bone marrow (BM) with consequence for stem cell (SCs) liberation upon tissue injury. We reported that ischemia induces the liberation of Lineage - Sca-1 + c-kit + (LSK)SCs co-expressing the SP receptor NK1 (LSK-NK1) via a neuronal circuitry projecting to the BM and a humoral mechanism consisting of the generation of a chemoattractant gradient of Substance P (SP) between the circulation and BM. We hypothesize that SN might contribute to faulty SC liberation in diabetes. Results: Nociceptive fibers coexpressing SP and NGF are reduced in BM of type 1 (T1D, streptozotocin-induced) and type 2 diabetic (T2D, Leptin-receptor knockout) mice compared with controls. BM SN was prevented by systemic AAV-mediated NGF gene therapy. Upon induction of limb ischemia, a gradient of SP is created between skeletal muscle>circulation>BM in non-diabetic mice, which associates with LSK-NK1 cell liberation and homing to the ischemic limb. These phenomena are abrogated in T1D mice. Furthermore, in vitro SP-induced migration of BM LSK-NK1 cells is reduced in T1D mice ( P <0.05 vs. ND mice). For clinical translation, we studied the association of SN and SC liberation in T2D with or without vascular complications. Sensory fibers were found reduced in BM of T2D patients. In addition, critical limb ischemia fails to create an SP gradient and induce CD34+NK1+ SC release. Pain is an acknowledged side effect of BM stimulation by granulokines. We found that BM stimulation with G-CSF fails to induce CD34+NK1+ SC liberation in T2D patients, with this phenomenon being directly correlated to pain score and increase in SP levels. Conclusions: We are the first to show that diabetes is associated with NGF-sensitive BM SN in animal models and humans. Two nociceptive mechanisms fail following ischemia or granulokine stimulation: the ability of nerve terminals to coordinate SP release between periphery and BM and responsiveness of NK1 SCs to SP-induced chemoattraction. These findings open new avenues to rescue diabetic SC mobilopathy and thereby encourage vascular repair.