Multi-omic analyses of hiPSC-derived astrocytes during differentiation

Astrocytes are essential players in brain development and functions, being particularly relevant as regulators of energy metabolism, ionic homeostasis, and synaptic transmission. They are also the major source of L-serine (L-Ser) in the brain, which is synthesized from the glycolytic intermediate 3-phosphoglycerate through the phosphorylated pathway (PP), which comprises 3- phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT) and phosphoserine phosphatase (PSP). L-Ser is the precursor of the two main co-agonists of the N-methyl-D-aspartate receptors, glycine and D-serine. Remarkably, astrocytes also contribute to neurodegenerative disorders by various mechanisms, including metabolic alterations. We generated human mature astrocytes from pluripotent stem cells (hiPSC) to get a picture of the changes that occur during astrocytes differentiation and here we report the metabolic rewiring occurring during differentiation. We have recently reported that the levels of the enzymes of the PP are increased in Alzheimer’s disease brains. Following this observation, we overexpressed PHGDH, PSAT or PSP in the hiPSC-derived astrocyte model and significant metabolic alterations were apparent. These results provide a valuable model for developing potential novel approaches to address brain diseases, especially those related to serine metabolism alterations. By exploiting the potential of hiPSCs, we studied the cellular processes timely involved in the differentiation program. The molecular understanding of astrocyte differentiation from NSCs is an important aspect to consider for modulating astrocyte physiology in human pathologies and for developing potential therapeutic strategies. By overexpressing the enzymes of the PP pathway, we demonstrated that this model is a valuable tool for developing potential novel approaches to address brain diseases, especially those related to serine metabolism alterations.