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, 6 (11), e27458

Transplantation of Bone Marrow-Derived Mononuclear Cells Improves Mechanical Hyperalgesia, Cold Allodynia and Nerve Function in Diabetic Neuropathy

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Transplantation of Bone Marrow-Derived Mononuclear Cells Improves Mechanical Hyperalgesia, Cold Allodynia and Nerve Function in Diabetic Neuropathy

Keiko Naruse et al. PLoS One.

Abstract

Relief from painful diabetic neuropathy is an important clinical issue. We have previously shown that the transplantation of cultured endothelial progenitor cells or mesenchymal stem cells ameliorated diabetic neuropathy in rats. In this study, we investigated whether transplantation of freshly isolated bone marrow-derived mononuclear cells (BM-MNCs) alleviates neuropathic pain in the early stage of streptozotocin-induced diabetic rats. Two weeks after STZ injection, BM-MNCs or vehicle saline were injected into the unilateral hind limb muscles. Mechanical hyperalgesia and cold allodynia in SD rats were measured as the number of foot withdrawals to von Frey hair stimulation and acetone application, respectively. Two weeks after the BM-MNC transplantation, sciatic motor nerve conduction velocity (MNCV), sensory nerve conduction velocity (SNCV), sciatic nerve blood flow (SNBF), mRNA expressions and histology were assessed. The BM-MNC transplantation significantly ameliorated mechanical hyperalgesia and cold allodynia in the BM-MNC-injected side. Furthermore, the slowed MNCV/SNCV and decreased SNBF in diabetic rats were improved in the BM-MNC-injected side. BM-MNC transplantation improved the decreased mRNA expression of NT-3 and number of microvessels in the hind limb muscles. There was no distinct effect of BM-MNC transplantation on the intraepidermal nerve fiber density. These results suggest that autologous transplantation of BM-MNCs could be a novel strategy for the treatment of painful diabetic neuropathy.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Inhibitory effects of BM-MNC transplantation on mechanical hyperalgesia induced by STZ administration.
Number of foot withdrawals in response to the 93 (A) and 197 mN (B) von Frey hair (VFH) stimulation in diabetic rats is shown. Data are presented as mean ± SEM. Vertical axis, number of foot lifts; horizontal axis, order of the test (weeks after STZ injection). Broken line shows the time point of STZ administration and BM-MNC transplantation. In the treatment group (solid circles), BM-MNC injection was carried out just after the measurements at 2 weeks (2W) after the STZ injection (n = 8). In the control group (open circles), saline injection was done (n = 6). Repeated measures two-way ANOVA identified a significant difference in the day-effect between BM-MNC transplanted and control group. *P<0.05 compared with before (B) STZ injection (one-way ANOVA with Dunnett's tests).
Figure 2
Figure 2. BM-MNC transplantation inhibited mechanical hyperalgesia in the ipsilateral diabetic hind paw.
Number of foot withdrawals in response to the 93 (A) and 197 mN (B) von Frey hair (VFH) stimulation in both hind paws of diabetic rats are shown (n = 8). Data are presented as mean ± SEM. The form of presentation is the same as in Fig. 1. BM-MNC injection was carried out just after the measurements at 2 weeks (2W) after the STZ injection. Repeated measures two-way ANOVA identified a significant difference in the day-effect between both hind paws. *P<0.05 compared with before (B) STZ injection (one-way ANOVA with Dunnett's tests).
Figure 3
Figure 3. Inhibitory effects of BM-MNC transplantation on cold allodynia induced by STZ administration.
Number of foot withdrawals in response to the acetone application in diabetic rats is shown. Data are presented as mean ± SEM. Vertical axis, number of foot lifts; horizontal axis, order of the test (weeks after STZ injection). Black column, before STZ injection; white column, 2 weeks after STZ injection; shadow column, 3, 5, and 7 weeks after STZ injection. In the treatment group (left panel), BM-MNC injection was carried out just after the measurements at 2 weeks after the STZ injection (n = 9). In the control group (right panel), saline injection was done (n = 10). *P<0.05 compared with before (B) STZ injection (one-way ANOVA with Dunnett's tests).
Figure 4
Figure 4. Effects of BM-MNC transplantation on sciatic motor nerve conduction velocity and sensory nerve conduction velocity.
BM-MNCs were transplanted into unilateral hindlimb skeletal muscles 2 weeks after the STZ injection, and sciatic motor nerve conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV) were measured 2 weeks later. Results are means ± SEM. *P<0.001 vs. saline-injected side of control rats. **P<0.01 vs. saline-injected side of diabetic rats.
Figure 5
Figure 5. Effects of BM-MNC transplantation on sciatic nerve blood flow (SNBF).
BM-MNCs were transplanted into unilateral hindlimb skeletal muscles 2 weeks after the STZ injection, and SNBF was measured 2 weeks later. Results are means ± SEM. *P<0.05 vs. saline-injected side of control rats. **P<0.01 vs. saline-injected side of diabetic rats.
Figure 6
Figure 6. Capillary density and gene expressions in skeletal muscles.
A: Representative photomicrographs of histological sections in the saline-injected and BM-MNC-injected sides of the skeletal muscles of normal and diabetic rats. Arrowheads indicate vascular endothelial cells detected by immunostaining for vWF. Bar = 50 µm. B: Quantitative analyses for capillary/muscle fiber ratio of the saline-injected and BM-MNC-injected sides of the skeletal muscles in normal and diabetic rats. Results are means ± SEM. *P<0.001 vs. saline-injected side of control rats. **P<0.001 vs. saline-injected side of diabetic rats. C: bFGF and NT-3 mRNA expressions in saline and BM-MNC-injected muscle. Results are means ± SEM. *P<0.05 vs. saline-injected side of control rats. **P<0.05 vs. saline-injected side of diabetic rats.
Figure 7
Figure 7. Intraepidermal nerve fiver density (IENFD).
A: Representative photomicrographs of histological sections in the saline-injected and BM-MNC-injected sides of footpads of normal and diabetic rats. Arrowheads indicate intraepidermal nerve fiber detected by immunostaining for PGP 9.5. Bar = 10 µm. B: Quantitative analyses for IENFD in footpads of the saline-injected and BM-MNCs-injected sides in normal and diabetic rats. Results are means ± SEM. *P<0.05 vs. saline-injected side of control rats.

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