Abstract
Although autologous nerve grafting is widely accepted as the gold standard treatment for segmental nerve defects, harvesting autologous nerves is highly invasive and leads to functional loss of the ablated part. In response, artificial nerve conduits made of artificial materials have been reported, but the efficacy of the nerve regeneration still needs improvement. The purpose of this study is to investigate the efficacy and mechanism of the Bio three-dimensional (3D) conduit composed of xeno-free human induced pluripotent stem cell–derived mesenchymal stem cells (iMSCs). The 5-mm nerve gap of the sciatic nerve in immunodeficient rats was bridged with the Bio 3D conduit or silicone tube. Functional and histological recovery were assessed at 8 weeks after surgery. The regenerated nerve in the Bio 3D group was significantly superior to that in the silicone group based on morphology, kinematics, electrophysiology, and wet muscle weight. Gene expression analyses demonstrated neurotrophic and angiogenic factors. Macroscopic observation revealed neovascularization both inside and on the surface of the Bio 3D conduit. Upon their subcutaneous implantation, iMSCs could induce angiogenesis. The Bio 3D conduit fabricated from iMSCs are an effective strategy for nerve regeneration in animal model. This technology will be useful in future clinical situations.
Highlights
Peripheral nerve injury is often accompanied by trauma or tumor resection
We used induced pluripotent stem cell–derived mesenchymal stem cells (iMSCs) induced from human induced pluripotent stem cell (iPSC) of a neural crest lineage under xeno-free conditions. iMSCs were cultured on temperature-responsive plates to generate cell sheets, and the cell sheets were transferred to lowadhesion plates to generated clumps of iMSCs (C-iMSCs) (Fig. 1A,B)[20]
Principal component analysis (PCA) and a heatmap of pluripotent stem cell (PSC), neural crest cell (NCC), and mesenchymal stromal/stem cells (MSCs) gene expressions revealed that the gene expression patterns of iMSCs, cell sheets, C-iMSCs, and the Bio 3D conduits were similar to bone marrow mesenchymal stem cells (BM-MSCs), and distinct of iPSC and iPSC-derived NCCs (Fig. 2A,B)
Summary
Peripheral nerve injury is often accompanied by trauma or tumor resection. The gold standard treatment when tensionless direct repair cannot be achieved is autologous nerve g rafting[1,2]. As the development of tissue engineering progresses, several studies have reported well-devised nerve conduits with improvements in the supportive cells, scaffolds, growth factors, and v ascularity[7,8] Most of these conduits consist of artificial materials and are faced with the inevitable problems of low biocompatibility, foreign body reactions, and risk of infection. We have established a robust and simple protocol to induce mesenchymal stromal/stem cells (MSCs) from iPSCs through neural crest cell (NCC) lineage (iMSCs, hereafter)[14] This stepwise induction protocol makes it possible to control and evaluate the quality and quantity of iMSCs. compared to fibroblasts, MSCs are able to differentiate into a broad spectrum of end-stage cells, secrete a wide variety of immunomodulatory molecules, assemble exosomes, and repair damaged tissue via a mitochondrial transfer mechanism[15,16]. Our results indicate that the engrafted iMSCs accelerate nerve regeneration in terms of supportive cells, growth factors, and especially vascularity
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