Abstract
BackgroundNerve injuries are debilitating, leading to long-term motor deficits. Remyelination and axonal growth are supported and enhanced by growth factor and cytokines. Combination of nerve guidance conduits (NGCs) with adipose-tissue-derived multipotent mesenchymal stromal cells (AdMSCs) has been performing promising strategy for nerve regeneration.Methods3D-printed polycaprolactone (PCL)-NGCs were fabricated. Wistar rats subjected to critical sciatic nerve damage (12-mm gap) were divided into sham, autograft, PCL (empty NGC), and PCL + MSCs (NGC multi-functionalized with 106 canine AdMSCs embedded in heterologous fibrin biopolymer) groups. In vitro, the cells were characterized and directly stimulated with interferon-gamma to evaluate their neuroregeneration potential. In vivo, the sciatic and tibial functional indices were evaluated for 12 weeks. Gait analysis and nerve conduction velocity were analyzed after 8 and 12 weeks. Morphometric analysis was performed after 8 and 12 weeks following lesion development. Real-time PCR was performed to evaluate the neurotrophic factors BDNF, GDNF, and HGF, and the cytokine and IL-10. Immunohistochemical analysis for the p75NTR neurotrophic receptor, S100, and neurofilament was performed with the sciatic nerve.ResultsThe inflammatory environment in vitro have increased the expression of neurotrophins BDNF, GDNF, HGF, and IL-10 in canine AdMSCs. Nerve guidance conduits multi-functionalized with canine AdMSCs embedded in HFB improved functional motor and electrophysiological recovery compared with PCL group after 12 weeks. However, the results were not significantly different than those obtained using autografts. These findings were associated with a shift in the regeneration process towards the formation of myelinated fibers. Increased immunostaining of BDNF, GDNF, and growth factor receptor p75NTR was associated with the upregulation of BDNF, GDNF, and HGF in the spinal cord of the PCL + MSCs group. A trend demonstrating higher reactivity of Schwann cells and axonal branching in the sciatic nerve was observed, and canine AdMSCs were engrafted at 30 days following repair.Conclusions3D-printed NGCs multi-functionalized with canine AdMSCs embedded in heterologous fibrin biopolymer as cell scaffold exerted neuroregenerative effects. Our multimodal approach supports the trophic microenvironment, resulting in a pro-regenerative state after critical sciatic nerve injury in rats.
Highlights
Nerve injuries are debilitating, leading to long-term motor deficits
Nerve guidance conduits multi-functionalized with canine adipose-tissue-derived multipotent mesenchymal stromal cells (AdMSCs) embedded in heterologous fibrin biopolymer (HFB) improved functional motor and electrophysiological recovery compared with PCL group after 12 weeks
Increased immunostaining of brainderived neurotrophic factor (BDNF), Glial cell-derived neurotrophic factor (GDNF), and growth factor receptor p75 neurotrophin receptor (p75NTR) was associated with the upregulation of BDNF, GDNF, and hepatocyte growth factor (HGF) in the spinal cord of the PCL + mesenchymal stromal cells (MSCs) group
Summary
Nerve injuries are debilitating, leading to long-term motor deficits. Remyelination and axonal growth are supported and enhanced by growth factor and cytokines. The distal stump in lesions with long-gap defects does not respond to trophic signals released by the proximal stump, resulting in poor nerve regrowth [9] This regenerative response is associated with a complex interaction between the Wallerian degeneration process, the immunological response, Schwann cells, and pro-regenerative molecules such as neurotrophic factors and cytokines [9]. Autografting is the current standard treatment for nerve injuries, resulting in long-gap defects [10] This procedure has several disadvantages, such as additional damage to donor nerves, and insufficient revascularization [10]. These limitations have led to the development of nerve guidance conduits (NGCs) for nerve repair that guide regenerating axons, support vascularization, increase the concentration of trophic factors, and avoid the formation of scarred tissue [11, 12]
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