Abstract
IntroductionSevere spinal cord injury often causes temporary or permanent damages in strength, sensation, or autonomic functions below the site of the injury. So far, there is still no effective treatment for spinal cord injury. Mesenchymal stem cells (MSCs) have been used to repair injured spinal cord as an effective strategy. However, the low neural differentiation frequency of MSCs has limited its application. The present study attempted to explore whether the grafted MSC-derived neural-like cells in a gelatin sponge (GS) scaffold could maintain neural features or transdifferentiate into myelin-forming cells in the transected spinal cord.MethodsWe constructed an engineered tissue by co-seeding of MSCs with genetically enhanced expression of neurotrophin-3 (NT-3) and its high-affinity receptor tropomyosin receptor kinase C (TrkC) separately into a three-dimensional GS scaffold to promote the MSCs differentiating into neural-like cells and transplanted it into the gap of a completely transected rat spinal cord. The rats received extensive post-operation care, including cyclosporin A administrated once daily for 2 months.ResultsMSCs modified genetically could differentiate into neural-like cells in the MN + MT (NT-3-MSCs + TrKC-MSCs) group 14 days after culture in the GS scaffold. However, after the MSC-derived neural-like cells were transplanted into the injury site of spinal cord, some of them appeared to lose the neural phenotypes and instead transdifferentiated into myelin-forming cells at 8 weeks. In the latter, the MSC-derived myelin-forming cells established myelin sheaths associated with the host regenerating axons. And the injured host neurons were rescued, and axon regeneration was induced by grafted MSCs modified genetically. In addition, the cortical motor evoked potential and hindlimb locomotion were significantly ameliorated in the rat spinal cord transected in the MN + MT group compared with the GS and MSC groups.ConclusionGrafted MSC-derived neural-like cells in the GS scaffold can transdifferentiate into myelin-forming cells in the completely transected rat spinal cord.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0100-7) contains supplementary material, which is available to authorized users.
Highlights
Severe spinal cord injury often causes temporary or permanent damages in strength, sensation, or autonomic functions below the site of the injury
The cortical motor evoked potential and hindlimb locomotion were significantly ameliorated in the rat spinal cord transected in the MN + MT group compared with the gelatin sponge (GS) and mesenchymal stem cell (MSC) groups
Neural marker expression of the mesenchymal stem cells in GS scaffold To investigate whether NT-3-MSCs could promote tropomyosin receptor kinase C (TrkC)-MSCs differentiating into neural-like cells in GS scaffold after 14 days of culture in vitro, the immature neuron marker β-tubulin III (Tju-1), mature neuron marker microtubule-associated protein 2 (Map2), astrocyte marker glial fibrillary acidic protein (GFAP), and oligodendrocyte marker adenomatous polyposis coli (APC) were used to detect the differentiating MSCs by immunofluorescence staining (IFS)
Summary
Severe spinal cord injury often causes temporary or permanent damages in strength, sensation, or autonomic functions below the site of the injury. With the development of regenerative medicine, tissue-engineered exogenous stem cell transplantation has become a promising strategy to restore the structure and function of injured spinal cord [9]. Mesenchymal stem cells (MSCs), as important seed cells of tissue engineering, have received the most attention for treatment of central nervous system injury in view of their ease of culturing and low immunogenicity, immunoregulation, pro-survival, and neurogenic differentiation properties [10, 11]. We reported that neurotrophin-3 (NT-3)/TrkC signal pathway promotes MSC differentiation This was strongly evidenced by the fact that Schwan cells (SCs) modified by NT-3 gene could induce MSCs overexpressing NT-3 receptor-TrkC to differentiate into neural cells in twodimensional (2D) and three-dimensional (3D) culture in vitro [26, 27]. Given that cells in a 3D environment in vitro would closely mimic cells in vivo and that they present predominant properties compared with those in a 2D environment, such as metabolism [28, 29], gene expression and protein synthesis [30, 31], proliferation [32], and differentiation [27, 33], the 3D gelatin sponge (GS) scaffold was constructed and adopted to support the growth and neural differentiation of MSCs [34]
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