Exploring Heparan Sulfate Proteoglycans as Mediators of Human Mesenchymal Stem Cell Neurogenesis

Alzheimer’s disease (AD) and traumatic brain injury (TBI) are major public health issues worldwide, with over 38 million people living with AD and approximately 48 million people (27–69 million) experiencing TBI annually. Neurodegenerative conditions are characterised by the accumulation of neurotoxic amyloid beta (Aβ) and microtubule-associated protein Tau (Tau) with current treatments focused on managing symptoms rather than addressing the underlying cause. Heparan sulfate proteoglycans (HSPGs) are a diverse family of macromolecules that interact with various proteins and ligands and promote neurogenesis, a process where new neural cells are formed from stem cells. The syndecan (SDC) and glypican (GPC) HSPGs have been implicated in AD pathogenesis, acting as drivers of disease, as well as potential therapeutic targets. Human mesenchymal stem cells (hMSCs) provide an attractive therapeutic option for studying and potentially treating neurodegenerative diseases due to their relative ease of isolation and subsequent extensive in vitro expansive potential. Understanding how HSPGs regulate protein aggregation, a key feature of neurodegenerative disorders, is essential to unravelling the underlying disease processes of AD and TBI, as well as any link between these two neurological disorders. Further research may validate HSPG, specifically SDCs or GPCs, use as neurodegenerative disease targets, either via driving hMSC stem cell therapy or direct targeting. Graphical abstract: Heparan sulfate proteoglycans as regulators of human mesenchymal stem cell neurogenesis. Traumatic brain injury (TBI) and genetic factors increase Alzheimer’s disease (AD) risk (yellow). Potential AD treatment targets (green) include human mesenchymal stem cells (hMSCs). Manipulating pathway and growth factor interactions with heparan sulfate proteoglycans (HSPGs) could regulate hMSC neurogenesis, potentially offering functional neural stem cell transplants as AD treatments