Generation of Regionally Specified Neural Progenitors and Functional Neurons from Human Embryonic Stem Cells under Defined Conditions

TLDR

The study develops a method to generate regionally specified neural progenitors and neurons from human embryonic stem cells for modeling human neural fate and regenerative therapies. The method employs a small‑molecule activator of canonical WNT signaling to rapidly and dose‑dependently induce progenitors spanning forebrain to hindbrain fates. Ten days after differentiation, the progenitors transplanted into adult rat striatum formed neuron‑rich, tumor‑free grafts that preserved regional identity, and ventral midbrain‑patterned cells produced authentic dopaminergic neurons that released dopamine and restored motor function in a Parkinson’s disease model.

Abstract

To model human neural-cell-fate specification and to provide cells for regenerative therapies, we have developed a method to generate human neural progenitors and neurons from human embryonic stem cells, which recapitulates human fetal brain development. Through the addition of a small molecule that activates canonical WNT signaling, we induced rapid and efficient dose-dependent specification of regionally defined neural progenitors ranging from telencephalic forebrain to posterior hindbrain fates. Ten days after initiation of differentiation, the progenitors could be transplanted to the adult rat striatum, where they formed neuron-rich and tumor-free grafts with maintained regional specification. Cells patterned toward a ventral midbrain (VM) identity generated a high proportion of authentic dopaminergic neurons after transplantation. The dopamine neurons showed morphology, projection pattern, and protein expression identical to that of human fetal VM cells grafted in parallel. VM-patterned but not forebrain-patterned neurons released dopamine and reversed motor deficits in an animal model of Parkinson@s disease.