SDF1/CXCR4 contributes to neural regeneration in hemiplegic mice with a monkey ES-cell-derived neural graft

Abstract

We induced neural cells by treating cynomolgus monkey embryonic stem cells with retinoic acid. The retinoic acid-treated cells had elongated axons and expressed βIII tubulin, neurofilament middle chain (NFM) and Islet1 in vitro, suggesting their differentiation into motoneurons. The monkey ES derived neural cells were transplanted to hemiplegic mice with experimental brain injury. Injured mice with the neural cell graft gradually recovered motor function, whereas injured mice with vehicle (PBS) injection and injured mice with undifferentiated monkey ES cell graft remained hemiplegic. After transplantation into hemiplegic mice, the neural cells that had grafted into the periventricular area migrated and located near the corpus callosum by day 7. The neural cells distributed over the injured cortex at day 21. The cells expressed CXCR4, a receptor for chemokine SDF1. In a microchemotaxis assay, the neural cells responded to SDF1, and AMD3100, an antagonist of CXCR4, abrogated their migration. The injured cortex initially produced SDF1, and the graft expressed CXCR4 in the brain. SDF1 accelerated NCAM mRNA expression in the neural cells in vitro. The neural cells distributed over the cortex expressed L1CAM, NCAM, and N-Cadherin extensively after reaching the injured cortex. Administration of AMD3100 forced the graft to stay at the injection site. Thus, chemokine, chemokine receptor, and neural cell adhesion molecules seem to be involved in the regeneration of neural networks and functional recovery of hemiplegic mice.