Bioabsorbable nerve conduits three-dimensionally coated with human induced pluripotent stem cell-derived neural stem/progenitor cells promote peripheral nerve regeneration in rats

Abstract

Peripheral nerve regeneration using nerve conduits has been less effective than autogenous nerve grafts. To overcome this hurdle, we developed a tissue-engineered nerve conduit coated with mouse induced pluripotent stem cell (iPSC)-derived neurospheres, for the first time, which accelerated nerve regeneration in mice. We previously demonstrated the long-term efficacy and safety outcomes of this hybrid nerve conduit for mouse peripheral nerve regeneration. In this study, we investigated the therapeutic potential of nerve conduits coated with human iPSC (hiPSC)-derived neurospheres in rat sciatic nerve defects, as a translational preclinical study. The hiPSC-derived quaternary neurospheres containing neural stem/progenitor cells were three-dimensionally cultured within the nerve conduit (poly l-lactide and polycaprolactone copolymer) for 14 days. Complete 5-mm defects were created as a small size peripheral nerve defect in sciatic nerves of athymic nude rats and reconstructed with nerve conduit alone (control group), nerve conduits coated with hiPSC-derived neurospheres (iPS group), and autogenous nerve grafts (autograft group) (n = 8 per group). The survival of the iPSC-derived neurospheres was continuously tracked using in vivo imaging. At 12 weeks postoperatively, motor and sensory function and histological nerve regeneration were evaluated. Before implantation, the hiPSC-derived quaternary neurospheres that three-dimensional coated the nerve conduit were differentiated into Schwann-like cells. The transplanted hiPSC-derived neurospheres survived for at least 56 days after implantation. The iPS group showed non-significance higher sensory regeneration than the autograft group. Although there was no actual motor functional nerve regeneration in the three groups: control, iPS, and autograft groups, the motor function in the iPS group recovered significantly better than that in the control group, but it did not recover to the same level as that in the autograft group. Histologically, the iPS group demonstrated significantly higher axon numbers and areas, and lower G-ratio values than the control group, whereas the autograft group demonstrated the highest axon numbers and areas and the lowest G-ratio values. Nerve conduit three-dimensionally coated with hiPSC-derived neurospheres promoted axonal regeneration and functional recovery in repairing rat sciatic nerve small size defects. Transplantation of hiPSC-derived neurospheres with nerve conduits is a promising clinical iPSC-based cell therapy for the treatment of peripheral nerve defects.

Newly Generated 3D Schwann-Like Cell Spheroids From Human Adipose-Derived Stem Cells Using a Modified Protocol

“…To further verify the function of 3D SLCs, a widely used sciatic nerve injury model was used to explore their effect on PNI repair in vivo 29 , 34 . The results showed that ADSC, conventional SLC, and 3D SLC transplantation could improve the SFI and prevent denervation-induced gastrocnemius muscle atrophy.…”

Peripheral Nerve Injury Treatments and Advances: One Health Perspective

“…The results from the autograft were slightly better than the therapeutic option. However, the group with the cells showed higher axon number and good outcomes making this other promising cell-based therapy using NGCs in the PNI treatment [78].…”

Polymeric Scaffolds for Regeneration of Central/Peripheral Nerves and Soft Connective Tissues

“…f ) Reproduced with permission. [93] Copyright 2021, Springer Nature. [99] , and b) Representative stressstrain curves of the shell, core, and tendon scaffold in a) and the H&E staining images of the regenerated tissues near shell and in core.…”

“…d) Cross-sectional H&E staining images of regenerated nerves obtained [8]. e) Fabricated NGC (left top), the cross-sectional SEM image (right top), the neurospheres derived from the hiPSCs (left bottom), and the seeding of hiPSC-derived neurospheres on the NGC in vitro (right bottom) [93]. f ) Bar graphs of regenerated axon numbers and axon area from the control group (NGC alone), iPSC-scaffold, and autograft [93].…”