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Single-cell atlas of patient-derived trophoblast organoids (TO) in on-going pregnancies.

ABSTRACT: Trophoblast organoids (TOs) hold great promise for elucidating human placental development and function. By deriving TOs in on-going pregnancies using chorionic villus sampling (CVS), we established a platform to study trophoblast differentiation and function in early pregnancy, including pregnancies with different fetal genetic abnormalities. We addressed cellular heterogeneity of CVS-derived TOs by providing a single-cell transcriptomic atlas and show that CVS-TOs recapitulate key aspects of the human placenta, including syncytial fusion and hormone synthesis. This study demonstrates the utility of trophoblast organoids for investigating genetic defects in the placenta and describes an experimental platform for future personalized placental medicine approaches, including genotype-phenotype mapping.

ORGANISM(S): Homo sapiens

PROVIDER: GSE211429 | GEO | 2022/10/01

REPOSITORIES: GEO

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Project description:Pre-existing and gestationally-developed diabetes mellitus during pregnancy have been linked to impaired metabolic function in the villous trophoblast layer of the placenta. These metabolic impairments have been thought to mediate an increased risk of early life metabolic disease development in the exposed offspring. Previous research using the BeWo trophoblast cell line has suggested that independently, hyperglycemia is an important modulator of placental metabolic function in diabetic pregnancies. However, the direct impacts of hyperglycemia on specific aspects of placental metabolic function known to be impaired in diabetic pregnancies including nutrient storage and mitochondrial respiration, are largely unknown. The current study, therefore, utilized functional readouts of metabolic enzyme activity and endpoint readouts of nutrient storage in conjunction with multi-omics analysis (transcriptomics and metabolomics) in BeWo trophoblasts cultured under hyperglycemia conditions (25 mM glucose) for 72 hours to further characterize the impacts of elevated glucose levels on placental metabolic function. While metabolic enzyme activities and mitochondrial oxidative respiratory function were not altered following 72 hours of hyperglycemia, increased triglyceride and glycogen nutrient stores were observed in the high-glucose exposed BeWo trophoblasts. We speculated that the increased nutrient stores serve to modulate intracellular glucose levels and may reduce the amount of glucose available for oxidation and subsequently protect trophoblast cells from mitochondrial damage during acute high glucose exposures. Additionally, hyperglycemic-culture conditions in BeWo trophoblasts were associated with an altered transcriptomic profile highlighted by altered mRNA expression of metabolic enzymes as well as with an altered metabolome profile highlighted by an intracellular accumulation of lactate, malonate, and riboflavin. Overall, the results demonstrate that exposure to excess glucose modulates placental metabolism and nutrient storage and highlights that increased glucose abundance is an important independent regulator of placental function in diabetic pregnancies.

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Single-cell atlas of patient-derived trophoblast organoids (TO) in on-going pregnancies.

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