Fate and contribution of induced pluripotent stem cell-derived neurospheres transplanted with nerve conduits to promote peripheral nerve regeneration in mice

Article type: Research Article

Authors: Yokoi, Takuya^a | Uemura, Takuya^{a; b;} | Takamatsu, Kiyohito^{a; c} | Shintani, Kosuke^d | Onode, Ema^a | Hama, Shunpei^a | Miyashima, Yusuke^a | Okada, Mitsuhiro^a | Nakamura, Hiroaki^a

Affiliations: [a] Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan | [b] Department of Orthopaedic Surgery, Osaka General Hospital of West Japan Railway Company, Osaka, Japan | [c] Department of Orthopaedic Surgery, Yodogawa Christian Hospital, Osaka, Japan | [d] Department of Pediatric Orthopaedic Surgery, Osaka City General Hospital, Osaka, Japan

Correspondence: [*] Corresponding author: Takuya Uemura, Department of Orthopaedic Surgery, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno-ku, Osaka, 545-8585, Japan. Tel.: +81 6 6645 3851; Fax: +81 6 6646 6260; E-mail: t-uemura@med.osaka-cu.ac.jp

Abstract: BACKGROUND:We previously demonstrated that a bioabsorbable nerve conduit coated with mouse induced pluripotent stem cell (iPSC)-derived neurospheres accelerated peripheral nerve regeneration in mice. OBJECTIVE:We examined the fate and utility of iPSC-derived neurospheres transplanted with nerve conduits for the treatment of sciatic nerve gaps in mice. METHODS: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. RESULTS: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. CONCLUSIONS: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.

Keywords: Induced pluripotent stem cells, nerve conduit, sciatic nerve, scaffold, regenerative medicine, neurospheres, neural stem/progenitor cells, cell viability, transcription factor, neurotrophic factor

DOI: 10.3233/BME-201182

Journal: Bio-Medical Materials and Engineering, vol. 32, no. 3, pp. 171-181, 2021