The Differentiation Stage of Transplanted Stem Cells Modulates Nerve Regeneration

Abstract

In regenerative medicine applications, the differentiation stage of implanted stem cells must be optimized to control cell fate and enhance therapeutic efficacy. We investigated the therapeutic potential of human induced pluripotent stem cell (iPSC)-derived cells at two differentiation stages on peripheral nerve regeneration. Neural crest stem cells (NCSCs) and Schwann cells (NCSC-SCs) derived from iPSCs were used to construct a tissue-engineered nerve conduit that was applied to bridge injured nerves in a rat sciatic nerve transection model. Upon nerve conduit implantation, the NCSC group showed significantly higher electrophysiological recovery at 1 month as well as better gastrocnemius muscle recovery at 5 months than the acellular group, but the NCSC-SC group didn’t. Both transplanted NCSCs and NCSC-SCs interacted with newly-growing host axons, while NCSCs showed better survival rate and distribution. The transplanted NCSCs mainly differentiated into Schwann cells with no teratoma formation, and they secreted higher concentrations of brain-derived neurotrophic factor and nerve growth factor than NCSC-SCs. In conclusion, transplantation of iPSC-NCSCs accelerated functional nerve recovery with the involvement of stem cell differentiation and paracrine signaling. This study unravels the in vivo performance of stem cells during tissue regeneration, and provides a rationale of using appropriate stem cells for regenerative medicine.

The advances in nerve tissue engineering: From fabrication of nerve conduit toin vivonerve regeneration assays

“…Using a sciatic nerve gap in the mouse model, Ikeda et al () showed that peripheral nerve regeneration and functional recovery using nerve conduits are enhanced by a combination of iPSc‐derived neurospheres and a basic fibroblast growth factor drug delivery system. Huang et al () have also shown that transplantation of neural crest‐derived stem cells, which were differentiated from iPSCs into the conduit at the site of sciatic nerve injury, can increase motor recovery and restore muscle function.…”

Stem cells purified from human induced pluripotent stem cell-derived neural crest-like cells promote peripheral nerve regeneration

“…To date, Huang et al . evaluated whether the differentiation stage of transplanted stem cells modulates nerve regeneration 23 . They compared the transplantation performance of iPSC-derived neural crest stem cells (NCSCs) and Schwann cells from the NCSCs (NCSC-SCs) in rat sciatic nerve transection models.…”

“…Neural crest cells (NCCs) are known to derive from the ectoderm and can differentiate into neural lineage cells, including Schwann cells. Previous studies have reported the effectiveness of transplanting iPSC-derived NCCs for nerve regeneration 21 – 23 .…”

Strategies for Peripheral Nerve Repair

“…iPSCs can be differentiated into Schwann cells via a precursor stage [59,60], with Schwann cells being seen as the ideal cell type for therapy due to the key role they have in the repair process [45••, 46, 61]. The repair Schwann cells in the nerve autograft show greater similarity to ES cells than neural crest cells [62].…”

“…The repair Schwann cells in the nerve autograft show greater similarity to ES cells than neural crest cells [62]. For this reason, it is possible that cells at earlier stages of differentiation will support regeneration to a greater degree than terminally differentiated Schwann cells [60]. iPSC-derived Schwann cell precursors and Schwann cells have shown significant functional improvement compared to controls without cell therapy [59], with key outcomes being neurotrophic factor release and increased myelin formation.…”