Effects of intra-arterial transplantation of adipose-derived stem cells on the expression of netrin-1 and its receptor DCC in the peri-infarct cortex after experimental stroke

Background: Stem cell transplantation has been documented to promote functional recovery in animal models of stroke; however, the underlying mechanisms are not yet fully understood. As netrin-1 and its receptor deleted in colorectal cancer (DCC) are important regulators in neuronal and vascular activities, the present study attempted to explore whether netrin-1 and DCC are involved in the neuroprotection of stem cell-based therapies in a rat ischemic stroke model. Methods: Adult male Sprague-Dawley rats were subjected to a transient middle cerebral artery occlusion (MCAO) and subsequently received an intra-arterial injection of 2 x 106 PKH26-labeled adipose-derived stem cells (ADSCs) or saline 24 h later. Neurological function was evaluated by behavioral tests before the rats were sacrificed at days 7 and 14 after MCAO. The migration of ADSCs and regeneration of neuronal fibers and blood vessels were determined by immunofluorescence staining. The expression of netrin-1 and DCC was analyzed by Western blot and immunofluorescence staining. Results: ADSC transplantation significantly improved the neurological recovery at days 7 and 14, and noticeably promoted the regeneration of neuronal fibers and blood vessels in the peri-infarct cortex at day 14. PKH26-labeled ADSCs located mainly in the peri-infarct area at days 7 and 14. In ADSC-treated rats, the expression of netrin-1 and DCC significantly increased in the peri-infarct cortex at days 7 and 14. Immunofluorescence staining showed that netrin-1 was mainly expressed by neuronal perikaryal in the peri-infarct cortex, and DCC was mainly expressed by neuronal fibers and was present around the blood vessels in the peri-infarct cortex. Conclusions: These findings suggest that ADSC transplantation facilitates the regeneration of neuronal fibers and blood vessels in the peri-infarct cortex and improves neurological functions, which may be attributed, at least in part, to the involvement of upregulated netrin-1 and DCC in the remodeling of neuronal and vascular networks in the peri-infarct cortex.