Human mesenchymal stem cells (hMSCs) self-renew and possess multi-lineage differentiation potential, including the neural lineages (neurons, astrocytes, and oligodendrocytes). Cell lineage differentiation potential is often influenced by the localised microenvironment or niche, in which the extracellular matrix (ECM) is a major component. Proteoglycans (PGs) are major constituents of the neural ECM and are characteristically comprised of a core protein to which a series of glycosaminoglycan (GAG) side chains attach at specific sites. Recent findings by our group have identified specific PGs as potential novel markers of human neural stem cell (hNSC) lineage specification by demonstrating their role in hNSC maintenance and lineage commitment. In addition, our group has identified a potential role for HSPG core proteins, syndecans and glypicans, in hMSC neural lineage differentiation. hMSC populations (n = 3) were differentiated under neural lineage culture conditions through direct terminal differentiation and terminal differentiation via intermediate sphere formation. RNA and protein was collected throughout differentiation at days 7, 14, and 28 during basal lineage differentiation conditions along with cultures augmented for stimulation (heparin) and inhibition (sodium chlorate) of PGs and GAG side chains respectively. Gene expression analysis showed distinct differences in PG expressions between neural specific culture conditions, stages of differentiation, and between untreated, heparin and chlorate-treated cultures. Overall, the data strongly suggest PGs, particularly the syndecans and glypicans may be key players in hMSC neurogenesis and we aim to examine these PGs in further detail. A deeper understanding of the complex and dynamic processes mediating hMSC neurogenesis will likely enable advances in stem cell therapy for application to the understanding and repair of neurological disorders.