Olfactory ensheathing cells (OECs) represent an interesting candidate for cell therapy and could be obtained from olfactory mucosa (OM-OECs) or olfactory bulbs (OB-OECs). Recent reports suggest that, depending on their origin, OECs display different functional properties. We show here the complementary and additive effects of co-transplanting OM-OECs and OB-OECs after lesion of a peripheral nerve. For this, a selective motor denervation of the laryngeal muscles was performed by a section/anastomosis of the recurrent laryngeal nerve (RLN). Two months after surgery, recovery of the laryngeal movements and synkinesis phenonema were analyzed by videolaryngoscopy. To complete these assessments, measure of latency and potential duration were determined by electrophysiological recordings and myelinated nerve fiber profiles were defined based on toluidine blue staining. To explain some of the mechanisms involved, tracking of GFP positive OECs was performed. It appears that transplantation of OM-OECs or OB-OECs displayed opposite abilities to improve functional recovery. Indeed, OM-OECs increased recuperation of laryngeal muscles activities without appropriate functional recovery. In contrast, OB-OECs induced some functional recovery by enhancing axonal regrowth. Importantly, co-transplantation of OM-OECs and OB-OECs supported a major functional recovery, with reduction of synkinesis phenomena. This study is the first which clearly demonstrates the complementary and additive properties of OECs obtained from olfactory mucosa and olfactory bulb to improve functional recovery after transplantation in a nerve lesion model.
OBJECTIVES
Endothelial dysfunction during ischaemia-reperfusion (IR) is a major cause of primary graft dysfunction during lung transplantation. The routine use of cardiopulmonary bypass (CPB) during lung transplantation remains controversial. However, the contribution of CPB to pulmonary endothelial dysfunction remains unclear. The objective was to investigate the impact of CPB on endothelial dysfunction in a lung IR rat model.
METHODS
Rats were allocated to 4 groups: (i) Sham, (ii) IR, (iii) CPB and (iv) IR-CPB. The primary outcome was the study of pulmonary vascular reactivity by wire myograph. We also assessed glycocalyx degradation by enzyme-linked immunosorbent assay and electron microscopy and both systemic and pulmonary inflammation by enzyme-linked immunosorbent assay and immunohistochemistry. Rats were exposed to 45 min of CPB and IR. We used a CPB model allowing femoro-femoral support with left pulmonary hilum ischaemia for IR.
RESULTS
Pulmonary endothelium-dependent relaxation to acetylcholine was markedly reduced in the IR-CPB group (10.7 ± 9.1%) compared to the IR group (50.5 ± 5.2%, P < 0.001), the CPB group (54.1 ± 4.7%, P < 0.001) and the sham group (80.8 ± 6.7%, P < 0.001), suggesting that the association of pulmonary IR and CPB increases endothelial dysfunction. In IR-CPB, IR and CPB groups, vasorelaxation was completely abolished when inhibiting nitric oxide synthase, suggesting that this relaxation process was mainly mediated by nitric oxide. We observed higher syndecan-1 plasma levels in the IR-CPB group in comparison with the other groups, reflecting an increased degradation of glycocalyx. We also observed higher systemic inflammation in the IR-CPB group as shown by the increased plasma levels of IL-1β, IL-10.
CONCLUSIONS
CPB significantly increased the IR-mediated effects on pulmonary endothelial dysfunction. Therefore, the use of CPB during lung transplantation could be deleterious, by increasing endothelial dysfunction.
In human neonates, immature GABAergic interneurons are markedly affected by an excitotoxic insult. While in adults the interest of cell transplantation has been demonstrated in several neurological disorders, few data are available regarding the immature brain. The low survival rate constitutes a strong limitation in the capacity of transplanted neurons to integrate the host tissue. Because i) autophagy is an adaptive process to energetic/nutrient deprivation essential for cell survival and ii) literature describes cross-talks between autophagy and apoptosis, we hypothesized that regulation of autophagy would represent an original strategy to favor long-term survival of GABAergic precursors grafted in the immature neocortex. Morphological, neurochemical, and functional data showed that in control conditions, few grafted Gad67-GFP precursors survived. The first hours following transplantation were a critical period with intense apoptosis. Experiments performed on E15.5 ganglionic eminences revealed that Gad67-GFP precursors were highly sensitive to autophagy. Rapamycin and 3-MA impacted on LC3 cleavage, LC3II translocation, and autophagosome formation. Quantification of Bax, mitochondrial integrity, caspase-3 cleavage, and caspase-3 immunolocalization and activity showed that 3-MA induced a significant decrease of Gad67-GFP precursor apoptosis. In vivo, 3-MA induced, within the first 24 h, a diffuse LC3 pattern of grafted Gad67-GFP precursors, an increase of precursors with neurites, a reduction of the density of caspase-3 immunoreactive cells. A twofold increase in the survival rate occurred 15 days after the graft. Surviving neurons were localized in the cortical layers II-IV, which were still immature when the transplantation was done. Altogether, these data indicate that inhibition of autophagy represents an original strategy to allow GABAergic interneurons to overpass the first critical hours following transplantation and to increase their long-term survival in mice neonates.
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