Optimal electrical stimulation boosts stem cell therapy in nerve regeneration

• Published in: Biomaterials 2018-10, Vol.181, p.347-359
• Main Authors: Du, Jian, Zhen, Gehua, Chen, Huanwen, Zhang, Shuming, Qing, Liming, Yang, Xiuli, Lee, Gabsang, Mao, Hai-Quan, Jia, Xiaofeng
• Format: Article
• Language: English
• Subjects: Animals; Cell Differentiation - physiology; Cells, Cultured; Electric Stimulation - methods; Electrical stimulation; Human neural crest stem cell; Humans; Immunohistochemistry; Nerve regeneration; Nerve Regeneration - physiology; Neural Crest - cytology; Neural Stem Cells - cytology; Neural Stem Cells - physiology; Neurogenesis - physiology; Peripheral Nerve Injuries - therapy; Peripheral nerve injury; Pluripotent stem cells; Rats; Stem Cell Transplantation - methods
• ISSN: 0142-9612; 1878-5905
• DOI: 10.1016/j.biomaterials.2018.07.015

Peripheral nerve injuries often lead to incomplete recovery and contribute to significant disability to approximately 360,000 people in the USA each year. Stem cell therapy holds significant promise for peripheral nerve regeneration, but maintenance of stem cell viability and differentiation potential in vivo are still major obstacles for translation. Using a made-in-house 96-well vertical electrical stimulation (ES) platform, we investigated the effects of different stimulating pulse frequency, duration and field direction on human neural crest stem cell (NCSC) differentiation. We observed dendritic morphology with enhanced neuronal differentiation for NCSCs cultured on cathodes subject to 20 Hz, 100μs pulse at a potential gradient of 200 mV/mm. We further evaluated the effect of a novel cell-based therapy featuring optimized pulsatile ES of NCSCs for in vivo transplantation following peripheral nerve regeneration. 15 mm critical-sized sciatic nerve injuries were generated with subsequent surgical repair in sixty athymic nude rats. Injured animals were randomly assigned into five groups (N = 12 per group): blank control, ES, NCSC, NCSC + ES, and autologous nerve graft. The optimized ES was applied immediately after surgical repair for 1 h in ES and NCSC + ES groups. Recovery was assessed by behavioral (CatWalk gait analysis), wet muscle-mass, histomorphometric, and immunohistochemical analyses at either 6 or 12 weeks after surgery (N = 6 per group). Gastrocnemius muscle wet mass measurements in ES + NCSC group were comparable to autologous nerve transplantation and significantly higher than other groups (p