Collectively dementias describe more than 100 diseases characterised by the impairment of brain functions associated with the loss of neural cells and tissue. With the number of Australians suffering from dementia estimated to triple between 2010 and 2050, rising to approximately 900 000 sufferers, new and effective approaches to enable long-lasting therapeutic interventions are required. Human mesenchymal stem cells (hMSCs) are promising therapeutic candidates due to their relative ease of isolation, large capacity for self-renewal and ability to differentiate into multiple cell types including neural cells. In contrast, acquisition andin vitro expansion of human neural stem cells (NSCs) can be more difficult. One of two major families of proteoglycans the heparan sulfate proteoglycans (HSPGs) are ubiquitously expressed, key components of the extracellular matrix and are widely documented to play important roles in neural regulation. HSPGs have been shown to influence progression of Alzheimer’s disease (AD) through interactions with amyloid precursor protein. In addition MSCs introduced into an AD model resulted in rescue from cell death demonstrating the potential role of HSPGs and MSCs in the progression of dementia. In this study hMSCs were induced to form NSC-like hMSC spheres at an early in vitro growth phase. Following differentiation, cultures were examined using immunocytochemistry (ICC) and Q-PCR. Staining by ICC revealed expression of HS correlating with increased HS initiation and modification enzyme expression (Q-PCR). In addition, a significant changes in expression of HSPG core proteins (glypicans; GPC1 decrease, P=0.03; GPC4 increase, P=0.01) was observed in spheres. Neural and mesenchymal lineage markers also demonstrated significant changes in sphere cultures with increased neural marker expression (ENO2, NEFM, GALC) and decreased mesenchymal (ADIPOQ, ACTA2, COL1A1) markers. Our preliminary data demonstrating NSC-like hMSC spheres retain or increase their neural lineage potential establish their relevance for use in therapeutic applications for the treatment of dementias.