High Yields of Oligodendrocyte Lineage Cells from Human Embryonic Stem Cells at Physiological Oxygen Tensions for Evaluation of Translational Biology

We have established and efficient system to specify NG2/PDGF-Rα/OLIG2+ oligodendrocyte precursor cells (OPCs) from human embryonic stem cells (hESCs) at low, physiological (3%) oxygen levels. This was achieved via both forebrain and spinal cord origins, with up to 98% of cells expressing NG2. Developmental insights reveal a critical role for fibroblast growth factor 2 (FGF-2) in OLIG2 induction via ventral forebrain pathways. The OPCs mature in vitro to express O4 (46%) and subsequently become galactocerebroside (GALC), O1, and myelin basic protein-positive (MBP+) multibranching oligodendrocytes. These were cultured alongside hESC-derived neurons. The electrophysiological properties of human OPCs are similar to those of rat OPCs, with large voltage-gated sodium currents and the ability to fire action potentials. Exposure to a selective retinoid X receptor agonist increased the proportion of O4+ oligodendrocytes that express MBP from 5% to 30%. Thus, we have established a developmentally engineered system to investigate the biological properties of human OPCs and test the effects of putative remyelinating agents prior to clinical application. •Human OPCs and oligodendrocytes can be generated at physiological (3%) O2 tensions•hESC-derived OPCs can be specified via both spinal cord and ventral forebrain origins•Human OPCs have large voltage-gated sodium currents and can fire action potentials•RXR signaling is a relevant target for remyelinating therapies in humans Stacpoole and colleagues established a system to specify human oligodendrocyte precursor cells (OPCs) and multibranching oligodendrocytes from embryonic stem cells at physiological (3%) oxygen, from both forebrain and spinal cord. These human OPCs can fire action potentials and respond to retinoid X receptor agonists, demonstrating the usefulness of this developmentally engineered system as a translational resource.