Dual Contribution of Mesenchymal Stem Cells Employed for Tissue Engineering of Peripheral Nerves: Trophic Activity and Differentiation into Connective-Tissue Cells
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Adult peripheral nerves in vertebrates can regrow their axons and re-establish function after crush lesion. However, when there is extensive loss of a nerve segment, due to an accident or compressive damage caused by tumors, regeneration is strongly impaired. In order to overcome this problem, bioengineering strategies have been employed, using biomaterials formed by key cell types combined with biodegradable polymers. Many of these strategies are successful, and regenerated nerve tissue can be observed 12 weeks after the implantation. Mesenchymal stem cells (MSCs) are one of the key cell types and the main stem-cell population experimentally employed for cell therapy and tissue engineering of peripheral nerves. The ability of these cells to release a range of different small molecules, such as neurotrophins, growth factors and interleukins, has been widely described and is a feasible explanation for the improvement of nerve regeneration. Moreover, the multipotent capacity of MSCs has been very often challenged with demonstrations of pluripotency, which includes differentiation into any neural cell type. In this study, we generated a biomaterial formed by EGFP-MSCs, constitutively covering microstructured filaments made of poly-ε-caprolactone. This biomaterial was implanted in the sciatic nerve of adult rats, replacing a 12-mm segment, inside a silicon tube. Our results showed that six weeks after implantation, the MSCs had differentiated into connective-tissue cells, but not into neural crest-derived cells such as Schwann cells. Together, present findings demonstrated that MSCs can contribute to nerve-tissue regeneration, producing trophic factors and differentiating into fibroblasts, endothelial and smooth-muscle cells, which compose the connective tissue.
KeywordsMesenchymal stem cells PCL filaments Tissue engineering Nerve regeneration Peripheral nervous system
alpha smooth muscle actin
analysis of variance
brain-derived neurotrophic factor, CD-90, 45, 34, 29 and 31, cluster of differentiation 90, 45, 34, 29 and 31
Dulbecco’s modified Eagle medium
dorsal root ganglia;
enhanced green fluorescent protein
human adipose-derived stromal cells
mesenchymal stem cells
nerve growth factor
phosphate buffered saline
peripheral nervous system
vascular endothelial growth factor
We thank Dr. Burkhard Schlosshauer from the NMI Reutlingen at Tübingen University for kindly donating the PCL filaments. This study was supported by grants and fellowships from the Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ) to V.T.R.R., F.E.M., and A.C.R.; and the Instituto Nacional de Neurociências Translacional (INNT) and the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) to V.T.R.R.
FEM: performed cell and embryonic cultures, generation of in-vivo experimental model, histology procedures, fluorescent imaging, statistical analysis, interpretation of experimental results, and manuscript development and writing. ACR: Performed histology, confocal microscopy, culture procedures, interpretation of experimental results and development and writing of the manuscript. RSS: Established DRG explants culture system, contributed to the interpretation of experimental results, and manuscript development and writing. VTRR: Director of the project. Contributed to the general administration, cell culture, generation of in-vivo experimental model, histology and staining procedures, fluorescence and electron microscopy, statistical analysis, interpretation of experimental results, and manuscript development and writing. All authors read and approved the manuscript.
Compliance with Ethical Standards
The authors declare that they have no competing interests.
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