Abstract
Purpose: Skin-derived Precursor Schwann cells (SKP-SCs) have been reported to provide neuroprotection for the injured and dysmyelinated nervous system. However, little is known about SKP-SCs on acute ischemic stroke (AIS). We aimed to explore the efficacy and the potential mechanism of action of SKP-SCs on AIS in a rat ischemic stroke model.Methods: Adult male Sprague–Dawley rats were subjected to a middle cerebral artery occlusion (MCAO) for 1.5 h on Day 0 and subsequently received an intracarotid injection of 2 × 106 green fluorescent protein (GFP) -labeled SKP-SCs or phosphate buffered saline (PBS) during reperfusion. Neurological function was assessed by behavioral tests on Days 1, 4, 7, 14, and 28. In a satellite cohort, rat brains were harvested and infarct volume was measured with 2,3,5-triphenyltetrazolium chloride (TTC) staining on Days 1 and 7, and migration and survival of SKP-SCs in the brain were traced by monitoring green fluorescence at 6 and12 h on Day 0, and on Days 1, 4, 7, 14, and 28. Histopathology and immunofluorescence staining were used to analyze the morphology, survival and apoptosis of neurons. Additionally, in an in vitro SKP-SC co-culture model using fetal rat primary cortical neurons underwent oxygen glucose deprivation/reoxygenation (OGD/R), Western blot was used to detect the expression of apoptosis indicators including activated caspase-3, Bax, and Bcl-2. TUNEL staining was used to count apoptotic cells.Results: Intracarotid transplantation of SKP-SCs effectively migrated to the periinfarct area and survived for at least 4 weeks. Transplanted SKP-SCs inhibited neuronal apoptosis, reduced infarct volume, and improved neurological recovery in the MCAO rats. Moreover, in vitro data showed that SKP-SCs treatment inhibited OGD/R-induced neuronal apoptosis and promoted survival of the cultured primary cortical neurons.Conclusions: Intracarotid transplantation of SKP-SCs promoted functional recovery in the rat AIS model and possesses the potential to be further developed as a novel therapy to treat ischemic stroke in humans.
Highlights
Stroke is the leading cause of neurological disability in adults worldwide [1], with the majority of patients (∼87%) being ischemic in etiology due to the occlusion of cerebral artery or arteries [2]
Immunofluorescence staining confirmed that skin-derived precursors (SKP)-SCs were positive for Schwann cell lineage markers S100, glial fibrillary acidic protein (GFAP) and P75 (Figures 2A–C)
skin-derived precursor Schwann cells (SKP-SCs) were clearly detected in the ischemic region of the right cerebral hemisphere as early as 6 h after transplantation, some SKP-SCs remained in the blood vessels (Figure 3, 6 h)
Summary
Stroke is the leading cause of neurological disability in adults worldwide [1], with the majority of patients (∼87%) being ischemic in etiology due to the occlusion of cerebral artery or arteries [2]. Intravenous thrombolysis and endovascular treatment have been proven to be beneficial, hospital-sourced databases demonstrate that the thrombolytic rate of patients with acute ischemic stroke (AIS) is only between 3.4 and 9.1%, and treatment rate of endovascular therapy is even lower [2]. Many patients are just not eligible for these treatments due to key exclusion criteria (e.g., time after onset and partial vascular occlusion). Only about 13%-20% AIS patients meet the indications for endovascular mechanical thrombectomy. Among these patients, only
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