Abstract
BackgroundStem 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.MethodsAdult male Sprague–Dawley rats were subjected to a transient middle cerebral artery occlusion (MCAO) and subsequently received an intra-arterial injection of 2 × 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.ResultsADSC 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.ConclusionsThese 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.
Highlights
Stem cell transplantation has been documented to promote functional recovery in animal models of stroke; the underlying mechanisms are not yet fully understood
Immunofluorescence staining showed that Adipose-derived stem cell (ADSC) at passages 3–4 were positive for surface antigens CD44 (Fig. 1b) and negative for CD34 (Fig. 1c) and CD45 (Fig. 1d), which is consistent with previous reports [7]
The results showed the number of von Willebrand factor (vWF)+ blood vessels was higher in the middle cerebral artery occlusion (MCAO) group, the MCAO + vehicle group, and the MCAO + ADSC group compared with the Sham group
Summary
Stem cell transplantation has been documented to promote functional recovery in animal models of stroke; the underlying mechanisms are not yet fully understood. Only intravenous recombinant tissue plasminogen activator (rtPA) is approved for the treatment of patients afflicted with ischemic stroke. Among various stem cell types, adiposederived stem cells (ADSCs) present several advantages and can serve as good candidates for cell therapy after stroke [6]. They are derived from adipose tissues and are abundant and easy to obtain [7]. Due to their relatively low immunogenicity, they are able to proliferate and differentiate without producing adverse side effects [4, 8]. The mechanisms of its protective effects are not yet fully understood and await further investigation [5]
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