Liraglutide modulates adhesion molecules and enhances cell properties in three-dimensional cultures of olfactory ensheathing cells.

Cell transplantation using olfactory ensheathing cells (OECs) is a promising approach for nerve repair but there are numerous limitations with their delivery method. Three-dimensional (3D) cell culture systems potentially offer a powerful approach for cell production and delivery options. To further optimise the use of OECs, strategies to promote cell viability and maintain cell behaviours in 3D cultures become important. We previously demonstrated an anti-diabetic drug, liraglutide, could modulate OEC migration and re-model extracellular matrix in two-dimensional (2D) cultures. In the present study, we further investigated its beneficial effects in our 3D culture system using primary OECs. OECs treated with liraglutide at 100 nM showed improved cell viability and had modulated expression of N-cadherin and ß1-integrin (two important cell adhesion molecules). When formed into 3D spheroids, the pre-treated OECs generated spheroids with an increased volume and a decreased cell density compared to control spheroids. OECs that subsequently migrated out of the liraglutide pre-treated spheroids had higher capacity for migration with increased duration and length, which was attributed to a reduction in the pauses during the migration. Moreover, OECs that migrated out from liraglutide spheroids had a more bipolar morphology consistent with higher migratory capacity. In summary, liraglutide improved the viability of OECs, modulated cell adhesion molecules, and resulted in stable 3D cell constructs which conferred enhanced migratory capacity on the OECs. Overall, liraglutide may potentially improve the therapeutic use of OECs for neural repair by enhancing the generation of stable 3D constructs and increasing the migratory behaviour of OECs.

Liraglutide modulates olfactory ensheathing cell migration with activation of ERK and alteration of the extracellular matrix.

Transplantation of olfactory ensheathing cells (OECs) is a promising approach for repairing the injured nervous system that has been extensively trialed for nervous system repair. However, the method still needs improvement and optimization. One avenue of improving outcomes is to stimulate OEC migration into the injury site. Liraglutide is a glucagon-like peptide-1 receptor agonist used for management of diabetes and obesity. It has been shown to be neuroprotective and to promote cell migration, but whether it can stimulate glial cells remains unknown. In the current study, we investigated the effects of liraglutide on OEC migration and explored the involved mechanisms. We showed that liraglutide at low concentration (100 nM) overall promoted OEC migration over time. Liraglutide modulated the migratory behavior of OECs by reducing time in arrest, and promoted random rather than straight migration. Liraglutide also induced a morphological change of primary OECs towards a bipolar shape consistent with improved migration. We found that liraglutide activated extracellular signal-regulated kinase (ERK), which has key roles in cell migration; the timing of ERK activation correlated with stimulation of migration. Furthermore, liraglutide also modulated the extracellular matrix by upregulating laminin-1 and down-regulating collagen IV. In summary, we found that liraglutide can stimulate OEC migration and re-model the extracellular matrix to better promote cell migration, and possibly also to become more conducive for axonal regeneration. Thus, liraglutide may improve OEC transplantation outcomes.

Neuroinflammatory Processes, A1 Astrocyte Activation and Protein Aggregation in the Retina of Alzheimer's Disease Patients, Possible Biomarkers for Early Diagnosis.

Alzheimer's disease (AD), a primary cause of dementia in the aging population, is characterized by extracellular amyloid-beta peptides aggregation, intracellular deposits of hyperphosphorylated tau, neurodegeneration and glial activation in the brain. It is commonly thought that the lack of early diagnostic criteria is among the main causes of pharmacological therapy and clinical trials failure; therefore, the actual challenge is to define new biomarkers and non-invasive technologies to measure neuropathological changes in vivo at pre-symptomatic stages. Recent evidences obtained from human samples and mouse models indicate the possibility to detect protein aggregates and other pathological features in the retina, paving the road for non-invasive rapid detection of AD biomarkers. Here, we report the presence of amyloid beta plaques, tau tangles, neurodegeneration and detrimental astrocyte and microglia activation according to a disease associated microglia phenotype (DAM). Thus, we propose the human retina as a useful site for the detection of cellular and molecular changes associated with Alzheimer's disease.