Dataset Information

Multi-omic analyses of hiPSC-derived astrocytes during differentiation

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Simona Nonnis

LAB HEAD: Elisa Maffioli

PROVIDER: PXD045073 | Pride | 2025-08-25

REPOSITORIES: Pride

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Publications

Modulating the serine metabolism in human differentiated astrocytes: an integrated multi omics approach.

Tripodi Farida F Maffioli Elisa E Sacchi Silvia S Rabattoni Valentina V Motta Zoraide Z Bearzi Claudia C Tedeschi Gabriella G Pollegioni Loredano L Coccetti Paola P

Frontiers in cellular neuroscience 20250721

<h4>Introduction</h4>Astrocytes are the major source of L-serine (L-Ser) in the brain: the glycolytic intermediate D-3-phosphoglycerate is converted into L-Ser through the phosphorylated pathway (PP) made up of three enzymes, phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase (PSAT) and phosphoserine phosphatase (PSP), recently proposed to generate a metabolic assembly named serinosome. In the central nervous system, L-Ser is used for a number of functions, including the synt ...[more]

PMID: 40761926

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Project description:Since bone metastatic breast cancer is an incurable disease, causing significant morbidity and mortality, understanding of the underlying molecular mechanisms would be highly valuable. Here, we describe in vitro and in vivo evidence for the importance of serine biosynthesis in the metastasis of breast cancer to bone. We first characterized the bone metastatic propensity of the MDA-MB-231(SA) cell line variant as compared to the parental MDA-MB-231 cells by radiographic and histological observations in the inoculated mice. Genome-wide gene expression profiling of this isogenic cell line pair revealed that all the three genes involved in the L-serine biosynthesis pathway, phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH) were upregulated in the highly metastatic variant. This pathway is the primary endogenous source for L-serine in mammalian tissues. Consistently, we observed that the proliferation of MDA-MB-231(SA) cells in serine-free conditions was dependent on PSAT1 expression. In addition, we observed that L-serine is essential for the formation of bone resorbing human osteoclasts and may thus contribute to the vicious cycle of osteolytic bone metastasis. High expression of PHGDH and PSAT1 in primary breast cancer was significantly associated with decreased relapse-free and overall survival of patients and malignant phenotypic features of breast cancer. In conclusion, high expression of serine biosynthesis genes in metastatic breast cancer cells and the stimulating effect of L-serine on osteoclastogenesis and cancer cell proliferation indicate a functionally critical role for serine biosynthesis in bone metastatic breast cancer and thereby an opportunity for targeted therapeutic interventions. Parental MDA-MB-231 cells and MDA-MB-231(SA) cells were cultured in cell culture flasks. RNA was isolated in order to compare the gene expression profiles of these cell variants. Total of two samples. No replicates.

Project description:D-3-Phosphoglycerate dehydrogenase (Phgdh; EC 1.1.1.95) is a necessary enzyme for de novo L-serine biosynthesis via the phosphorylated pathway. We demonstrated previously that Phgdh is expressed exclusively by neuroepithelium and radial glia in developing mouse brain and later mainly by astrocytes. Mutations in the human PHGDH gene cause serine deficiency disorders (SDD) associated with severe neurological symptoms such as congenital microcephaly, psychomotor retardation, and intractable seizures. We recently demonstrated that genetically engineered mice, in which the gene for Phgdh has been disrupted, have significantly decreased levels of serine and glycine, and exhibit malformation of brain such as microcephaly. The Phgdh null (KO) embryos exhibit lethal phenotype after gestational day 14, indicating that the phosphorylated pathway is essential for embryogenesis, especially for brain development. It is worth noting that the Phgdh knockout (KO) embryos primarily displayed microcephaly, which is the most conspicuous phenotype of patients with SDD. Thus, Phgdh KO mice are a useful animal model for studying the effect of diminished L-serine levels on development of the central nervous system and other organs. To better understand the mechanism underlying the molecular pathogenesis of SDD, we sought to examine whether gene expression is altered in the Phgdh KO mouse model. We identify genes that have altered expression in the head of the Phgdh KO embryos using the GeneChip array. Some of the genes identified by this method belong in functional categories that are relevant to the biochemical and morphological aberrations of the Phgdh deletion. Experiment Overall Design: Total RNA samples were prepared from head tissues from 2 embryos of Phgdh knockout and littermate wild-type controls. Experiment Overall Design: RNA of 4 biological replicates was hybridized to Affymetrix Mouse Genome 430 2.0 arrays. Five microgram total RNA was labelled according to the ENZO-protocol, fragmented and hybridized according to Affymetrix's protocols.

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