Efficacy of Autologous Bone Marrow Mononuclear Cell Transplantation Therapy in Patients with Refractory Diabetic Peripheral Neuropathy
Diabetic peripheral neuropathy (DPN) is one of the most common and severe chronic complications in patients with type 2 diabetes mellitus (T2DM). It affects approximately half of the patients during the course of the disease and is characterized by the symmetrical loss of sensory perception in later stages, leading to an increased risk of foot ulceration and lower extremity amputation. This condition significantly contributes to the morbidity and mortality of diabetic patients, impairing their quality of life and causing a substantial societal burden. Currently, the treatment options for DPN are limited, with enhanced glucose control being the primary recommended strategy. However, this approach has shown only marginal effects in preventing the progression of diabetic neuropathy. Other therapies, such as aldose reductase inhibitors, α-lipoic acid, and transketolase activators, aim to relieve neuropathic symptoms but have limited efficacy due to the multifactorial nature of DPN pathogenesis. Therefore, there is a pressing need for novel therapeutic strategies, and stem cell-based therapies have emerged as a promising option.
The pathogenesis of DPN is complex and involves multiple factors, including inflammation, oxidative stress, and deficiencies in neurotrophic and angiogenic factors. Conventional treatments targeting a single pathway have shown limited success, highlighting the need for therapies that address the multifactorial nature of the disease. Stem cell-based therapies, particularly those involving bone marrow-derived stem cells (BMCs), have gained attention due to their potential to promote angiogenesis and neuron regeneration simultaneously. In response to exogenous cytokine stimulation, BMCs can be mobilized to perform repair functions. Recent studies have demonstrated that transplanted BMCs produce angiogenic and neuroprotective factors through paracrine mechanisms, ameliorating neuropathy symptoms in animal models. Among the various types of BMCs, bone marrow mononuclear cells (BMMNCs) have been the most commonly used for regenerative purposes. However, until recently, there had been no clinical applications of stem cells for treating DPN.
This study was designed to evaluate the safety and therapeutic efficacy of autologous BMMNCs transplantation in patients with refractory DPN. A total of 168 patients with refractory DPN were enrolled in the study from March 2014 to December 2017. The inclusion criteria included a diagnosis of T2DM according to the 2013 American Diabetes Association standards, a diagnosis of refractory DPN, and an age range of 30 to 80 years. Refractory DPN was defined as DPN lasting longer than two years, with insufficient relief of neuropathic symptoms or signs despite the use of conventional drugs for at least one year. The exclusion criteria included severe hepatic and renal dysfunction, hypercoagulable states, other causes of peripheral neuropathy, foot ulcers, limb deformity, pregnancy, and a history of malignancy within five years before the study.
All patients received autologous BMMNCs transplantation. To mobilize stem cells, patients were treated with 5 mg/kg/day recombinant human granulocyte colony-stimulating factor (G-CSF) via subcutaneous injection for three days. Following G-CSF mobilization, 200 mL of bone marrow was aspirated from the posterior superior iliac crest under aseptic and anesthetic conditions. The BMMNCs were prepared using Ficoll-Hypaque density-gradient centrifugation, and the mononuclear cell layer was harvested, washed, and resuspended in normal saline. The prepared BMMNCs were then injected intramuscularly into both thighs and legs at 50 sites, with each site receiving 1 mL of BMMNCs.
Patients were followed up at 1, 3, 6, 12, 18, 24, and 36 months after transplantation. Clinical data, including the Toronto Clinical Scoring System (TCSS) and nerve conduction studies (NCSs), were collected before and after transplantation. The TCSS was used to assess the severity of neuropathy, with scores ranging from 1 to 19. The NCSs included measurements of motor nerve conduction velocity (mNCV), sensory nerve conduction velocity (sNCV), compound muscle action potential (CMAP), and sensory nerve action potential (SNAP).
The results of the study showed significant improvements in the signs and symptoms of neuropathy following BMMNCs transplantation. The TCSS scores decreased significantly at 1 month (9.68 ± 2.49 vs. 12.55 ± 2.19, P < 0.001) and 3 months (8.47 ± 2.39 vs. 12.55 ± 2.19, P < 0.001) after transplantation compared to baseline values. This improvement persisted throughout the study period, with TCSS scores continuing to decrease until the end of the 36-month follow-up. The severity of neuropathy also improved significantly, with the proportion of patients with severe neuropathy decreasing from 69.6% at baseline to 28.6% at 1 month and further to 0.6% at 36 months. Conversely, the proportion of patients with no neuropathy increased from 0.0% at baseline to 36.0% at 36 months.
The NCS results revealed significant improvements in nerve conduction velocity and action potential after transplantation. At 3 months, mNCV increased from 38.21 ± 2.28 m/s at baseline to 40.24 ± 2.80 m/s, and sNCV increased from 36.96 ± 2.26 m/s to 39.15 ± 2.61 m/s. By 12 months, mNCV and sNCV had further increased to 41.00 ± 2.22 m/s and 40.41 ± 2.22 m/s, respectively. Similarly, CMAP improved from 4.67 ± 1.05 mV at baseline to 5.50 ± 1.20 mV at 3 months and 5.68 ± 1.08 mV at 12 months. SNAP also showed improvement, increasing from 4.29 ± 0.99 mV at baseline to 5.14 ± 1.26 mV at 3 months and 5.41 ± 1.14 mV at 12 months.
The study demonstrated that autologous BMMNCs transplantation is a safe and effective treatment for refractory DPN. No adverse events related to bone marrow aspiration or BMMNCs injection were observed during the follow-up period. Only 19 patients (11.31%) reported mild discomfort, such as slight pain or swelling at the injection sites, which resolved within three days. No cases of infection, bleeding, allergic reactions, rejection, or malignancy were detected.
The findings of this study suggest that autologous BMMNCs transplantation can improve the clinical manifestations of neuropathy and restore peripheral nerve function in patients with refractory DPN. The therapeutic efficacy of BMMNCs is likely due to their ability to produce neurotrophic and angiogenic factors through paracrine mechanisms, which promote nerve repair and regeneration. The study also highlights the safety of BMMNCs transplantation, with no serious adverse events reported during the 36-month follow-up period.
However, the study has some limitations. First, it did not include a control group, and the analysis was based on comparisons before and after transplantation. Future randomized double-blind controlled trials are needed to confirm the therapeutic efficacy of BMMNCs in DPN. Second, the study did not measure inflammation and anti-inflammation cytokines, neurotrophic factors, or angiogenic factors, which could provide further insights into the mechanisms underlying the therapeutic effects of BMMNCs. Despite these limitations, the study provides strong evidence that autologous BMMNCs transplantation is a promising treatment option for patients with refractory DPN.
In conclusion, this 36-month follow-up study demonstrates that autologous transplantation of BMMNCs mobilized by G-CSF stimulation is a safe and effective treatment for refractory DPN. The therapy significantly improves the clinical manifestations of neuropathy and restores peripheral nerve function, offering a promising option for patients who do not respond to conventional treatments. Further studies are needed to explore the mechanisms of action and to optimize the therapeutic efficacy of BMMNCs transplantation in DPN.
doi.org/10.1097/CM9.0000000000000009
Was this helpful?
0 / 0