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Sci Rep. 2017 Mar 28;7:45396. doi: 10.1038/srep45396.

Nerve regeneration by human corneal stromal keratocytes and stromal fibroblasts.

Author information

Tissue Engineering and Stem Cell Group, Singapore Eye Research Institute, Singapore.
Ophthalmology and Visual Science Academic Clinical Research Program, Duke-National University of Singapore Graduate Medical School, Singapore.
Cornea and External Eye Disease Service Team, Singapore National Eye Centre, Singapore.
Singapore Eye Research Institute, Singapore.
Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Department of Ophthalmology, RWTH Aachen University, Aachen, Germany.
School of Materials Science and Engineering, Nanyang Technological University, Singapore.


Laser refractive surgeries reshape corneal stroma to correct refractive errors, but unavoidably affect corneal nerves. Slow nerve regeneration and atypical neurite morphology cause desensitization and neuro-epitheliopathy. Following injury, surviving corneal stromal keratocytes (CSKs) are activated to stromal fibroblasts (SFs). How these two different cell types influence nerve regeneration is elusive. Our study evaluated the neuro-regulatory effects of human SFs versus CSKs derived from the same corneal stroma using an in vitro chick dorsal root ganglion model. The neurite growth was assessed by a validated concentric circle intersection count method. Serum-free conditioned media (CM) from SFs promoted neurite growth dose-dependently, compared to that from CSKs. We detected neurotrophic and pro-inflammatory factors (interleukin-8, interleukin-15, monocyte chemoattractant protein-1, eotaxin, RANTES) in SFCM by Bio-Plex Human Cytokine assay. More than 130 proteins in SFCM and 49 in CSKCM were identified by nanoLC-MS/MS. Proteins uniquely present in SFCM had reported neuro-regulatory activities and were predicted to regulate neurogenesis, focal adhesion and wound healing. Conclusively, this was the first study showing a physiological relationship between nerve growth and the metabolically active SFs versus quiescent CSKs from the same cornea source. The dose-dependent effect on neurite growth indicated that nerve regeneration could be influenced by SF density.

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