ADIPOSE TISSUE-TARGETED STEM CELL TRANSPLANTATION FOR INSULIN RESISTANCE-RELATED CNS DEFICITS

Compelling evidence indicates that Type 2 Diabetes (T2D) and Alzheimer’s Disease (AD) may possibly share a common pathological origin, but the underlying mechanisms remain poorly understood. T2D is a known risk factor for AD and insulin resistance (hallmark of T2D) has been extensively documented in AD patients. Notably, insulin is important for learning and memory due to its role in LTP and LTD modulation. Adipose tissue (AT) dysfunction is a risk factor for T2D, in fact elevated levels of free fatty acids are prodromal to insulin resistance and have been reported in AD brains, as well. In this study, I used a mouse model (AtENPP1Tg mouse) that recapitulates typical characteristics of human metabolic syndrome and insulin resistance, when nourished with a high-fat diet, but also shows hippocampal dysfunction and memory deficits, hence offering a unique chance to explore which mechanistic pathways connect diabetes with AD. In last decades, stem cell therapy has recently developed as potential therapeutic strategy for diabetes. Previous studies showed that a systemic administration of mesenchymal stem cells (MSC) improves peripheral insulin sensitivity and blood glucose levels as well as restores insulin signaling cascade. Interestingly, the pool of MSC in AT of diabetic patients is significantly reduced, with consequent decreased adipocytes’ turnover. As a result, the adipocytes cannot be replaced, thus becoming immature, the fat cannot be stored anymore, consequently ectopic fat deposition occurs. A major limitation of a systemic stem cell transplantation is the scattered cell distribution throughout the body and the circulation (with high risk of vessel occlusions) which reduced presence in target organ. Here, I propose a novel approach aimed to deliver, directly into AT, via subcutaneous injection, human umbilical cord-derived Wharton’s Jelly (WJ) MSCs. The overall aim was to restore diabetes-related CNS alterations through the correction of peripheral insulin sensitivity. The results show improvement of blood glucose levels and LTP response in hippocampus in transgenic transplanted mice compared to not–transplanted ones. It is conceivable that the replenishment of MSCs within the AT may restore insulin signaling both in periphery and CNS, thus reestablishing both peripheral and CNS insulin sensitivity with a mechanism, likely mediated by MSC-released factors and supposedly delivered to CNS from the periphery. Further studies are needed to elucidate the potential protective mechanism provided by MSCs.