Dual Contribution of Mesenchymal Stem Cells Employed for Tissue Engineering of Peripheral Nerves: Trophic Activity and Differentiation into Connective-Tissue Cells

Abstract

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.

Allogeneic bone marrow mesenchymal stem cells in the epineurium and perineurium of the recipient rat

“…On the other hand, the effect is related to the possible differentiation of MSCs into Schwann cells under the influence of trophic factors released from the proximal end of the cut nerve. However, this assumption does not always find experimental confirmation (Shen et al, 2010;Evaristo-Mendonca et al, 2018). In this study, we were also unable to show the possibility of differentiating MSCs into Schwann cells.…”

“…There is evidence of vascularization improvement in the damaged nerve due to the use of cellular therapy (Tamaki et al, 2014; Petrova, Isaeva, Kolos, and Korzhevskii, 2018; Evaristo-Mendonca et al, 2018). In our previous work, we showed that the number of microvessels in the damaged rat nerve trunk increases one and a half times after the application of MSCs (Petrova, 2018;Evaristo-Mendonca et al, 2018). Our current explanation of this fact is that MSCs produce angiogenic factors.…”

“…The question of how long exogenous MSCs can maintain their viability in recipient tissues is debatable. Some authors have detected pre-labeled MSCs even a few months after transplantation (Evaristo-Mendonca et al, 2018). However, other authors note that MSCs survive about 10 days after transplantation into the brain, and by 20 days they have completely degenerated (Loseva et al, 2012).…”

Adipose‐derived stem cells: From mice to man

“…Instead, investigators have focused on the regenerative potential of adult stem cell lineages. Mesenchymal stem cells are an easily expandable, multipotent cell population that may differentiate into Schwann cell‐like cells and are capable of releasing a range of neurotrophins, growth factors, and interleukins . There are many sources, including bone marrow stromal cells (BMSC), from which mesenchymal stem cells can be harvested .…”

“…Mesenchymal stem cells are an easily expandable, multipotent cell population that may differentiate into Schwann cell-like cells and are capable of releasing a range of neurotrophins, growth factors, and interleukins. 3 There are many sources, including bone marrow stromal cells (BMSC), from which mesenchymal stem cells can be harvested. [4][5][6][7] However, the practical difficulty of harvesting BMSCs, including donor site pain and morbidity, limits the feasibility of using it in clinical practice.…”