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We previously demonstrated that a bioabsorbable nerve conduit coated with mouse induced pluripotent stem cell (iPSC)-derived neurospheres accelerated peripheral nerve regeneration in mice.We examined the fate and utility of iPSC-derived neurospheres transplanted with nerve conduits for the treatment of sciatic nerve gaps in mice.Complete 5 mm defects were created in sciatic nerves and reconstructed using nerve conduits that were either uncoated or coated with mouse iPSC-derived neurospheres. The survival of the neurospheres on the nerve conduits was tracked using an in vivo imaging. The localization of the transplanted cells and regenerating axons was examined histologically. The gene expression levels in the nerve conduits were evaluated.The neurospheres survived for at least 14 days, peaking at 4–7 days after implantation. The grafted neurospheres remained as Schwann-like cells within the nerve conduits and migrated into the regenerated axons. The expression levels of ATF3, BDNF, and GDNF in the nerve conduit coated with neurospheres were upregulated.Mouse iPSC-derived neurospheres transplanted with nerve conduits for the treatment of sciatic nerve defects in mice migrated into regenerating axons, survived as Schwann-like cells, and promoted axonal growth with an elevation in the expression of nerve regeneration-associated trophic factors. [ABSTRACT FROM AUTHOR]

The induced pluripotent stem cell (iPSc) offers great potential for cell-based therapy in regenerative medicine. We previously developed tissue-engineered bioabsorbable nerve conduits coated with iPSc-derived neurospheres for use in peripheral nerve repair. Here, we examine the long-term efficacy and safety of using nerve conduits with iPSc technology for peripheral nerve repair in mice. The nerve conduit consisted of an outer layer of a poly L-lactide mesh and an inner layer of porous sponge composed of 50% L-lactide and 50% ε-caprolactone. Secondary neurospheres were derived from mouse iPScs, resuspended and cultured within the conduit for 14 days. Conduits were implanted within surgically administered 5-mm defects in the left sciatic nerve of mice (iPSc group; n = 14). The defects in the control group (n = 13) were reconstructed using the nerve conduit alone. At 4, 8, 12, 24 and 48 weeks postsurgery, motor and sensory functional recovery in the iPSc group had improved significantly more than in the control group. At 24 and 48 weeks, histological analysis revealed axonal regeneration in the nerve conduits of both groups. However, axonal regeneration and myelination were significantly enhanced in the iPSc group. No teratomas were identified in the iPSc group at any time point. Therefore, we here demonstrate that bioabsorbable nerve conduits coated with iPSc-derived neurospheres promote enhanced regeneration of peripheral nerves and functional recovery without teratoma formation in the long term. This combination of iPSc technology and bioabsorbable nerve conduits has the potential to be a safe future tool for the treatment of peripheral nerve defects. © 2015 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Various modifications including addition of Schwann cells or incorporation of growth factors with bioabsorbable nerve conduits have been explored as options for peripheral nerve repair. However, no reports of nerve conduits containing both supportive cells and growth factors have been published as a regenerative therapy for peripheral nerves. In the present study, sciatic nerve gaps in mice were reconstructed in the following groups: nerve conduit alone (control group), nerve conduit coated with induced pluripotent stem cell (iPSc)-derived neurospheres (iPSc group), nerve conduit coated with iPSc-derived neurospheres and basic fibroblast growth factor (bFGF)-incorporated gelatin microspheres (iPSc + bFGF group), and autograft. The fastest functional recovery and the greatest axon regeneration occurred in the autograft group, followed in order by the iPSc + bFGF group, iPSc group, and control group until 12 weeks after reconstruction. Thus, peripheral nerve regeneration using nerve conduits and functional recovery in mice was accelerated by a combination of iPSc-derived neurospheres and a bFGF drug delivery system. The combination of all three fundamental methodologies, iPSc technology for supportive cells, bioabsorbable nerve conduits for scaffolds, and a bFGF drug delivery system for growth factors, was essential for peripheral nerve regenerative therapy. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 1370-1378, 2014. [ABSTRACT FROM AUTHOR]

Abstract: In spite of the extensive research using induced pluripotent stem (iPS) cells, the therapeutic potential of iPS cells in the treatment of peripheral nerve injury is largely unknown. In this study, we repaired peripheral nerve gaps in mice using tissue-engineered bioabsorbable nerve conduits coated with iPS cell-derived neurospheres. The secondary neurospheres derived from mouse iPS cells were suspended in each conduit (4000,000 cells per conduit) and cultured in the conduit in three-dimensional (3D) culture for 14days. We then implanted them in the mouse sciatic nerve gaps (5mm) (iPS group; n =10). The nerve conduit alone was implanted in the control group (n =10). After 4, 8 and 12weeks, motor and sensory functional recovery in mice were significantly better in the iPS group. At 12weeks, all the nerve conduits remained structurally stable without any collapse and histological analysis indicated axonal regeneration in the nerve conduits of both groups. However, the iPS group showed significantly more vigorous axonal regeneration. The bioabsorbable nerve conduits created by 3D-culture of iPS cell-derived neurospheres promoted regeneration of peripheral nerves and functional recovery in vivo. The combination of iPS cell technology and bioabsorbable nerve conduits shows potential as a future tool for the treatment of peripheral nerve defects. [Copyright &y& Elsevier]

We previously reported a bioabsorbable nerve conduit coated with Schwann cells for the treatment of peripheral nerve defects. Since there have been dramatic developments in induced pluripotent stem (iPS) cells in recent years, the purpose of the present study was to create a tissue-engineered nerve conduit coated with iPS cell-derived neurospheres. Such a conduit was constructed by three-dimensional (3D)-culture of these cells using a bioabsorbable polymer conduit as a scaffold. The nerve conduit was composed of a mesh of poly L-lactide, and a porous sponge of 50% poly L-lactide and 50% poly ε-caprolactone. The primary and secondary neurospheres (PNS and SNS, respectively) induced from iPS cells were suspended in individual conduits. The conduits were incubated for 7 or 14 days in vitro and then evaluated using immunohistochemistry. All of the 7- and 14-day differentiated PNS and SNS were observed to have adhered to the inner surface of the conduits and to have migrated into the inner porous sponge. The engrafted cells were positive for anti-Tuj1, -S-100 and -GFAP antibodies, indicating that their pluripotent ability to form neural or glial cells was maintained. These findings indicate the feasibility of creating nerve conduits coated with a 3D-culture of iPS cell-derived neurospheres for the treatment of peripheral nerve defects. [ABSTRACT FROM AUTHOR]