Abstract
BackgroundDiabetic peripheral neurovascular diseases (DPNVs) are complex, lacking effective treatment. Autologous/allogeneic transplantation of adipose-derived stem cells (ADSCs) is a promising strategy for DPNVs. Nonetheless, the transplanted ADSCs demonstrate unsatisfying viability, migration, adhesion, and differentiation in vivo, which reduce the treatment efficiency. Netrin-1 secreted as an axon guidance molecule and served as an angiogenic factor, demonstrating its ability in enhancing cell proliferation, migration, adhesion, and neovascularization.MethodsADSCs acquired from adipose tissue were modified by Netrin-1 gene (NTN-1) using the adenovirus method (N-ADSCs) and proliferation, migration, adhesion, and apoptosis examined under high-glucose condition. The sciatic denervated mice (db/db) with type 2 diabetes mellitus (T2DM) were transplanted with N-ADSCs and treatment efficiency assessed based on the laser Doppler perfusion index, immunofluorescence, and histopathological assay. Also, the molecular mechanisms underlying Netrin-1-mediated proliferation, migration, adhesion, differentiation, proangiogenic capacity, and apoptosis of ADSCs were explored.ResultsN-ADSCs improved the proliferation, migration, and adhesion and inhibited the apoptosis of ADSCs in vitro in the condition of high glucose. The N-ADSCs group demonstrated an elevated laser Doppler perfusion index in the ADSCs and control groups. N-ADSCs analyzed by immunofluorescence and histopathological staining demonstrated the distribution of the cells in the injected limb muscles, indicating chronic ischemia; capillaries and endothelium were formed by differentiation of N-ADSCs. The N-ADSCs group showed a significantly high density of the microvessels than the ADSCs group. The upregulation of AKT/PI3K/eNOS/P-38/NF-κB signaling pathways and secretion of multiple growth factors might explain the positive effects of Netrin-1 on ADSCs.ConclusionThe overexpression of Netrin-1 in ADSCs improves proliferation, migration, and treatment effect in type 2 diabetic mice with sciatic denervation, which directs the clinical treatment of patients with DPNVs.
Highlights
Diabetic peripheral neurovascular diseases (DPNVs) are complex, lacking effective treatment
Phenotypic analysis by flow cytometry demonstrated that the P3 adipose-derived stem cells (ADSCs) were strongly double-positive for the stem cell surface antigens, such as CD90 (99.2 ± 3.73%) and Sca-1 (99.6 ± 3.08%) (Fig. 1), and negative for CD11b, CD31, CD34, CD45, CD133, and MHC-II
Effects of Netrin-1 on migration, adhesion, and tube formation of ADSCs under high glucose As the injected stem cells in vivo would gradually migrate to the injured area, we examined the effect of Netrin-1 overexpression on the migration ability of ADSCs under high glucose
Summary
Diabetic peripheral neurovascular diseases (DPNVs) are complex, lacking effective treatment. Autologous/allogeneic transplantation of adipose-derived stem cells (ADSCs) is a promising strategy for DPNVs. the transplanted ADSCs demonstrate unsatisfying viability, migration, adhesion, and differentiation in vivo, which reduce the treatment efficiency. As the most common chronic complication in diabetic patients, diabetic peripheral neurovascular disease (DPNV) is characterized by high incidence, early onset, long duration, and refractoriness [3]. With an abundant natural source in T2DM patients due to their obesity, adipose-derived stem cells (ADSCs) have the advantage of convenience and highly expressed stemness, rendering them as the optimal therapy for ischemic disease than endothelial progenitor cells (EPCs) and bone marrow-derived stem cells (BMSCs). The treatment efficiency of ADSCs was impaired by T2DM, primarily reflected in the ability of proliferation, adhesion, and angiogenic potential [9,10,11,12]. The mechanisms underlying the survival, differentiation of ADSCs under hyperglycemia, and promotion of angiogenesis after DPNV injury are yet to be elucidated
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