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Investigating maternal-fetal interface in the context of obesity using trophoblast organoids
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A incidência de obesidade aumentou exponencialmente na última década, tendo sido considerada pela Organização Mundial de Saúde como epidemia. Mulheres grávidas com obesidade são mais susceptíveis a complicações na gravidez, frequentemente resultado de problemas no desenvolvimento da placenta. Contudo, o processo molecular subjacente aos efeitos da obesidade no desenvolvimento da placenta permanece elusivo. O nosso objetivo é investigar as adaptações da placenta na obesidade materna, focando-nos na forma como a obesidade afeta o transcriptoma placentário e o ambiente celular. Empregámos metodologias inovadoras, incluindo a sequenciação de RNA de núcleo-único e organoides 3D derivados de trofoblastos de placenta-termo humana (tborgs), de forma a modelar adaptações placentárias em condições obesogénicas. Os nossos resultados sugerem que alterações nas proporções de sinciciotrofoblastos e células imunes da placenta, são possivelmente resultado da obesidade materna. Através de um sistema de co-cultura microfluídica, simulámos o ambiente intrauterino em condições obesogénicas e encontrámos alterações na expressão genética, incluindo o aumento da expressão de KISS1, FLT1 e GDF15, e indicações de perturbações na diferenciação dos trofoblastos extravilosos e inflamação crónica. Tborgs de placentas com IMC (índice de massa corporal) elevado não reproduzem totalmente padrões de expressão referentes ao doador, porém foram identificados genes diferencialmente expressos relacionados com problemas derivados da obesidade. Esta investigação realça a necessidade de um maior refinamento dos modelos in vitro para melhor compreender a interface materno-fetal em condições de obesidade materna.
Obesity has increased exponentially over the last decade to be considered by the World Health Organization as an epidemic. Pregnant women with obesity are more susceptible to pregnancy complications, many of them arising from issues in placental development. However, the molecular process underlying the effects of obesity on placental development remains elusive. Here we aim to investigate placental adaptations in maternal obesity, focusing on how obesity affects the placental transcriptome and cellular environment. We employed innovative methodologies, including single-nuclei RNA sequencing and 3D human-derived trophoblast organoids (tborgs) from term placenta to model placental adaptations in obesogenic conditions. Our findings suggest that alterations in the proportions of syncytiotrophoblasts and immune cells are a possible result of maternal obesity. Through a microfluidic coculture system, we simulated the intrauterine environment under obesogenic conditions and found gene expression alterations, including increased KISS1, FLT1 and GDF15 expression, and indications for disruption of extravillous trophoblast differentiation and chronic inflammation. While tborgs from high BMI (body mass index) placentas did not fully replicate donor signature, differentially expressed genes linked to obesity-related complications were identified. This research highlights the need for further refinement of in vitro models to better understand the maternal-fetal interface under conditions of maternal obesity.
Obesity has increased exponentially over the last decade to be considered by the World Health Organization as an epidemic. Pregnant women with obesity are more susceptible to pregnancy complications, many of them arising from issues in placental development. However, the molecular process underlying the effects of obesity on placental development remains elusive. Here we aim to investigate placental adaptations in maternal obesity, focusing on how obesity affects the placental transcriptome and cellular environment. We employed innovative methodologies, including single-nuclei RNA sequencing and 3D human-derived trophoblast organoids (tborgs) from term placenta to model placental adaptations in obesogenic conditions. Our findings suggest that alterations in the proportions of syncytiotrophoblasts and immune cells are a possible result of maternal obesity. Through a microfluidic coculture system, we simulated the intrauterine environment under obesogenic conditions and found gene expression alterations, including increased KISS1, FLT1 and GDF15 expression, and indications for disruption of extravillous trophoblast differentiation and chronic inflammation. While tborgs from high BMI (body mass index) placentas did not fully replicate donor signature, differentially expressed genes linked to obesity-related complications were identified. This research highlights the need for further refinement of in vitro models to better understand the maternal-fetal interface under conditions of maternal obesity.
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maternal obesity microfluidics placenta trophoblast organoids