Autologous transplantation of bone marrow mononuclear cells improved ischemic peripheral neuropathy in humans.

Y Y Y Y M H K H T o the Editor: Ischemic peripheral neuropathy is a term used to escribe the neurological deficits of peripheral nerves in patients ith peripheral artery obstructive disease (1). Although ischemic eripheral neuropathy is a major complication of critical limb schemia resulting in impaired quality of life, effective treatment for schemic neuropathy is not available at present. Recently, it has been reported that therapeutic angiogenesis sing vascular endothelial growth factor (VEGF) gene transfer for ritical limb ischemia improves ischemic neuropathy in animals (2) nd humans (3). We reported that therapeutic angiogenesis using utologous transplantation of bone marrow mononuclear cells BM-MNCs) for peripheral artery disease increased limb perfuion and improved clinical conditions, such as ischemic pain, laudication, and ischemic ulcer (4,5). Therefore, we examined hether autologous transplantation of BM-MNCs would improve schemic neuropathy with critical limb ischemia in humans. We enrolled 14 patients with angiographically-proven critical imb ischemia (Table 1). In each patient, autologous transplantaion of BM-MNCs (4.89 5.21 10 cells) was performed in 1 schemic leg (treated limb), and saline was injected into another leg control limb). Before and 1 month after transplantation, we xamined subjective symptoms (visual analogue scale as an index of est pain severity, pain-free walking distance), ankle brachial ressure index, and digital subtraction angiography score. Tibial otor nerve conduction velocity (MNCV), sural sensory nerve onduction velocity (SNCV), compound muscle action potential CMAP), tibial and sural sensory nerve action potential (SNAP), nd quantitative vibration threshold time (QVT) were recorded. e also measured MNCV, SNCV, CMAP, and SNAP of 23 agend sex-similar healthy subjects. This study was blinded to the nvestigator who assessed nerve functions. The protocol was pproved by the institutional ethics committee of Kurume Uniersity. Written informed consent was obtained from all subjects. Treatment significantly improved subjective symptoms and eripheral blood perfusion only in the treated limb (Table 1). The NCV and CMAP could be measured in the treated limb of all atients, and in the control limb of 12 patients. Before treatment, oth MNCV and CMAP were significantly smaller in the treated imb than in the healthy group (Table 1). Treatment significantly ncreased both MNCV and CMAP only in the treated limb. reatment recovered MNCV and CMAP to the level of the ealthy group. The QVT was significantly improved only in the reated limb, but not in the control limb after treatment (Table 1). he SNCV and SNAP of the patients did not differ from those of he healthy group, and the treatment did not affect them (Table 1). The major findings of this study are as follows. First, autologous M-MNC transplantation improved subjective ischemic and neuopathic symptoms in patients with critical limb ischemia. Second, he treatment improved not only peripheral blood perfusion but lso peripheral nerve function. This study confirmed our previous ndings (4,5) that autologous BM-MNC transplantation imroved ankle brachial pressure index, digital subtraction angiograhy score, and subjective symptoms in treated limbs. Furthermore, M-MNC transplantation improved objective peripheral nerve unctions (MNCV, CMAP, and QVT) in the treated limb but not n the control limb, suggesting that the effects were not related to atural course or nonspecific effects. Thus, autologous BM-MNC ransplantation might improve not only peripheral blood perfusion ut also ischemic peripheral neuropathy. The improvement of peripheral nerve function may be caused y better blood perfusion after autologous BM-MNC transplanation. Simovic et al. (3) reported that VEGF gene transfer mproved the neuropathic symptoms, CMAP, and QVT. They peculated that the mechanisms of the nerve function improveent were related to the size of the vessels restored by VEGF. In act, angiogenic cytokine-induced neovascularization principally nvolves the small vessels including the vasa nervorum ( 180 m), he nutrient vessels of peripheral nerves. Thus, transplanted M-MNCs might have improved nerve perfusion and function irectly by contributing to neovascularization, and indirectly by ecreting a variety of angiogenic cytokines. In addition, because ransplanted BM-MNCs presumably contain various kinds of ells, such as bone marrow stromal cells, BM-MNC transplantaion might have regenerated the damaged peripheral motor nerve. This study has limitations. This study was an observational pen-label study with no placebo control group. In addition, the umber of patients enrolled in this study was small, and the uration of the follow-up was short.