TTNPB Promotes Human Pluripotent Stem Cell-To-Neural Stem Cell Transition Via Modulation Of Chromatin Accessibility And The S-(5'-Adenosyl)-L-Homocysteine/Choline Metabolic Network

The study demonstrates that the combination of TTNPB, a retinoic acid receptor agonist, and CHIR99021, a GSK3β inhibitor, in a chemically defined medium effectively induces advanced neural stem cells (ANSCs) from human pluripotent stem cells (PSCs). This process enhances chromatin accessibility at neuroectoderm-specific regulatory elements and reduces it at pluripotency loci. Metabolomic analysis reveals a unique metabolic state in ANSCs, characterized by elevated choline and other metabolites, which can induce neuroectodermal marker expression. ANSCs successfully engrafted into depressed rat hippocampi, improving depression-like behaviors. This research introduces a novel strategy using TTNPB for epigenetic and metabolic modulation to drive neural differentiation.