Human pluripotent stem cell (PSC)-derived mesenchymal stem cells (MSCs) show potent neurogenic capacity which is enhanced with cytoskeletal rearrangement

Mesenchymal stem cells (MSCs) are paraxial mesodermal progenitors with potent immunomodulatory properties. Reports also indicate that MSCs can undergo neural-like differentiation, offering hope for use in neurodegenerative diseases. However, ex vivo expansion of these rare somatic stem cells for clinical use leads to cellular senescence. A newer source of MSCs derived from human pluripotent stem cells (PSC) can offer the ‘best-of-both-worlds’ scenario, abrogating the concern of teratoma formation while preserving PSC proliferative capacity. PSC-derived MSCs (PSC-MSCs) also represent MSCs at the earliest developmental stage, and we found that these MSCs harbor stronger neuro-differentiation capacity than post-natal MSCs. PSC-MSCs express higher levels of neural stem cell (NSC)-related genes and transcription factors than adult bone marrow MSCs at baseline, and rapidly differentiate into neural-like cells when cultured in either standard neurogenic differentiation medium (NDM) or when the cytoskeletal modulator RhoA kinase (ROCK) is inhibited. Interestingly, when NDM is combined with ROCK inhibition, PSC-MSCs undergo further commitment, acquiring characteristics of post-mitotic neurons including nuclear condensation, extensive dendritic growth, and neuron-restricted marker expression including NeuN, β-III-tubulin and Doublecortin. Our data demonstrates that PSC-MSCs have potent capacity to undergo neural differentiation and also implicate the important role of the cytoskeleton in neural lineage commitment.