External muscle stimulation differentiates circulating hematopoietic stem cells in diabetes patients

Introduction: External electric muscle stimulation (EMS) can reduce pain resulting from diabetic neuropathy (DN), a vascular complication of diabetes. It was hypothesized that EMS-treatment activated circulating CD34+ hematopoietic stem cells (HSC), which can participate in vessel repair by differentiating into endothelial progenitor cells (EPC).

Methods: 24 DN patients were evaluated for neuropathic symptoms using Diabetic Neuropathy Symptom Score (NSS) and Neuropathy Disability Score (NDS) after three 60 minutes EMS-treatments. The frequency of CD34+ HCS and expression of surface markers were determined by flow cytometry.

Results: Median NSS was reduced from 8 to 6 (p = 0.001) and NDS from 5.5 to 5 (p = 0.027). EMS-treatment also caused HSC to immediately disappear from the blood, reducing the HSC remaining in circulation of participants with DN (median -20%, p < 0.001) and healthy controls (median -17%, p = 0.015). HSC remaining in blood of 9 EMS-treated DN patients showed significant increases of surface molecules required for binding to vessel walls (JAM-A and CD31), homing toward hypoxic tissue (CXCR4) and differentiation into endothelial cells (CD31). The proportion of HSC expressing vascular endothelial growth factor receptor 2 (VEGFR2), defining the cells as EPC, was increased by a median of 36% (p = 0.011).

Conclusion: EMS-treatment improves symptoms of DN and causes HSC in circulation to differentiate and disappear from the blood. While the connection between these two observations is unclear, both symptom release and HSC activation are of benefit to diabetes patients. To our knowledge, this is the first protocol described for in vivo differentiation of HSC in diabetes patients.