Netrin-1 improves adipose-derived stem cell proliferation, migration, and treatment effect in type 2 diabetic mice with sciatic denervation

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.

Adipose-Derived Mesenchymal Stem Cells Isolated from Patients with Abdominal Aortic Aneurysm Exhibit Senescence Phenomena

“…A growing body of evidence from preclinical studies and clinical trials has shown the promising results of autologous ASC transplantation in various disorders including cardiovascular diseases and AAA [30–33]. Nevertheless, the function of ASCs is adversely influenced by a patient's comorbid conditions, thus affecting their therapeutic efficiency.…”

<p>Cdc42 Promotes ADSC-Derived IPC Induction, Proliferation, And Insulin Secretion Via Wnt/β-Catenin Signaling</p>

“…41 ADSCs are a feasible source of IPCs, for the advantages of more convenient acquisition. [42][43][44][45] Activation of crucial signaling pathways in the induction of ADSCs into IPCs is a suitable way to improve differentiation protocols. 46 In summary, we demonstrated for the first time that there exists a direct link between Cdc42 and induction of ADSCs into IPCs; additionally, our main outcome is that Cdc42/Wnt/β-catenin signaling plays a critical role in regulating the induction of ADSCs into IPCs and proliferation and insulin secretion of ADSCs-derived IPCs.…”

Netrin-1: A Modulator of Macrophage Driven Acute and Chronic Inflammation

“…A major clinical challenge in diabetes is the diabetic peripheral neurovascular diseases (DPNVs), for which no effective treatment is currently available. In this framework Zhang et al [ 102 ] showed that netrin-1 might mitigate DPNVs. In their study, transplanted adipose-derived stem cells, which have potential for differentiation and tissue restoration, were exposed to netrin-1 differentiated into endothelial cells and formed small capillaries [ 102 ].…”

“…In this framework Zhang et al [ 102 ] showed that netrin-1 might mitigate DPNVs. In their study, transplanted adipose-derived stem cells, which have potential for differentiation and tissue restoration, were exposed to netrin-1 differentiated into endothelial cells and formed small capillaries [ 102 ]. Netrin-1 not only promotes neuronal migration but also regulates the survival, adhesion, migration, proliferation, and differentiation of endothelial cells.…”