Abstract
Diabetes-triggered apoptosis of Schwann cells (SC) contributes to the degradation of diabetic peripheral neuropathy (DNP). In recent years, mesenchymal stem cells (MSC) were applied to DPN repair and it was demonstrated that paracrine secretion played a key role in neuroprotection exerted by MSC. Erythropoietin (EPO) is a potent cytokine capable of reducing apoptosis of SC. However, the expression of EPO in MSC is limited. In this study, we hypothesized that overexpression of EPO in MSC (EPO-MSC) may significantly improve their neuroprotective potentials. The EPO overexpression in MSC was achieved by lentivirus transduction. SC derived from the periphery nerve of diabetic rats were cocultured with MSC or EPO-MSC in normal or high glucose culture condition, respectively. In normal glucose culture condition, the overexpression of EPO in MSC promoted the MSC-induced restoration of SC from diabetic rats, including increases in GSH level and cell viability, decrease in TUNEL apoptosis, upregulation of antiapoptotic proteins, p-Akt, and Bcl-2, and downregulation of proapoptotic proteins, cleaved caspase-3, and Bax. The subsequent results in high glucose culture condition showed similar promotions achieved by EPO-MSC. Thus, it could be concluded that EPO-MSC possessed a potent potential in hampering apoptosis of SC, and the suppression was probably attributed to attenuating oxidative stress and regulating apoptosis related protein factors.
Highlights
Diabetic peripheral neuropathy (DPN) is the most common, but least recognized and understood long-term complication of diabetes [1], which is the main risk for foot ulceration and eventual limb amputation
With developing technologies of cell culture and genetic engineering [13, 14], the therapeutic effects of Mesenchymal stem cells (MSC) could be further promoted via integrating other wellestablished methods in vivo [15, 16] and in clinic [17], overcoming the serious side effects caused by clinical practice of monotherapy [18]
Diabetic model rats were established by STZ induction
Summary
Diabetic peripheral neuropathy (DPN) is the most common, but least recognized and understood long-term complication of diabetes [1], which is the main risk for foot ulceration and eventual limb amputation. Mesenchymal stem cells (MSC), one of widely used stem cells for their abundant autologous availability and delivery via an allogeneic fashion, possess multipotent differentiation properties [10, 11] and are capable of secreting several cytokines and growth factors [12], which are of great potential value to restore nerve functions. A variety of recent studies confirmed that MSC can repair DPN via differentiation into SC-like. Based on the feasibility of EPO to repair DPN though enhancing SC survival, we introduced EPO gene into MSC through lentivirus transduction, for the purpose of promoting therapeutic effects of MSC. We preliminarily studied the underlying mechanism of enhanced restoration of SC with EPO overexpression MSC enhanced, through the assessment of the level of antioxidant and the expression of apoptosis related proteins
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