Phosphoinositide 3-Kinase (PI3K) Subunit p110δ Is Essential for Trophoblast Cell Differentiation and Placental Development in Mouse

Hu, Xiwen; Li, Jiangchao; Zhang, Qianqian; Zheng, Lianfang; Wang, Guang; Zhang, Xiaohan; Zhang, Jingli; Gu, Qing; Ye, Yuxiang; Guo, Sun‐Wei; Yang, Xuesong; Wang, Lijing

doi:10.1038/srep28201

Cited by 8 publications

(5 citation statements)

References 81 publications

(101 reference statements)

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“…In keeping with this notion, we found reduced expression of transcription factors that mediate blood vessel development in PHF placentae. Heme oxygenase (HO, encoded by Hmox1 ) facilitates blood vessel development through regulating matrix metalloproteinases MMP14 and MMP2 [ 33 ]. Paternal obesity reduced transcript levels of Hmox1 in male and female placentae at E14.5 ( P Diet = 0.0203), but not at E18.5 ( Supplemental Table S6 ).…”

Section: Resultsmentioning

confidence: 99%

Paternal obesity induces placental hypoxia and sex-specific impairments in placental vascularization and offspring metabolism

Jazwiec

Patterson

Ribeiro

et al. 2022

Biology of Reproduction

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Paternal obesity predisposes offspring to metabolic dysfunction, but the underlying mechanisms remain unclear. We investigated whether this metabolic dysfunction is associated with changes in placental vascular development and is fueled by endoplasmic reticulum (ER) stress-mediated changes in fetal hepatic development. We also determined whether paternal obesity indirectly affects the in utero environment by disrupting maternal metabolic adaptations to pregnancy. Male mice fed a standard chow or high fat diet (60%kcal fat) for 8–10 weeks were time-mated with female mice to generate pregnancies and offspring. Glucose tolerance was evaluated in dams at mid-gestation (embryonic day (E) 14.5) and late gestation (E18.5). Hypoxia, angiogenesis, endocrine function, macronutrient transport, and ER stress markers were evaluated in E14.5 and E18.5 placentae and/or fetal livers. Maternal glucose tolerance was assessed at E14.5 and E18.5. Metabolic parameters were assessed in offspring at ~60 days of age. Paternal obesity did not alter maternal glucose tolerance but induced placental hypoxia and altered placental angiogenic markers, with the most pronounced effects in female placentae. Paternal obesity increased ER stress-related protein levels (ATF6 and PERK) in the fetal liver and altered hepatic expression of gluconeogenic factors at E18.5. Offspring of obese fathers were glucose intolerant and had impaired whole-body energy metabolism, with more pronounced effects in female offspring. Metabolic deficits in offspring due to paternal obesity may be mediated by sex-specific changes in placental vessel structure and integrity that contribute to placental hypoxia and may lead to poor fetal oxygenation and impairments in fetal metabolic signaling pathways in the liver.

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Section: Resultsmentioning

confidence: 99%

Paternal obesity induces placental hypoxia and sex-specific impairments in placental vascularization and offspring metabolism

Jazwiec

Patterson

Ribeiro

et al. 2022

Biology of Reproduction

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“…Given that blocking p110α stabilizes the stem cell state, defective differentiation could account for the reduced labyrinthine compartment in fetuses heterozygous for inactive p110α . Hu et al showed that p110δ mutants have smaller litter sizes . However, it is not clear if this effect is due to placental defects, and if the placental defects observed are intrinsic to the trophoblast compartment or instead caused by reduced leukocyte function in the maternal decidua.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Phosphoinositide-3-Kinase Signaling Promotes the Stem Cell State of Trophoblast

et al. 2019

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Trophoblast stem cells (TSCs) are a heterogeneous cell population despite the presence of fibroblast growth factor (FGF) and transforming growth factor β (TGFB) as key growth factors in standard culture conditions. To understand what other signaling cascades control the stem cell state of mouse TSCs, we performed a kinase inhibitor screen and identified several novel pathways that cause TSC differentiation. Surprisingly, inhibition of phosphoinositide-3-kinase (PI3K) signaling increased the mRNA and protein expression of stem cell markers instead, and resulted in a tighter epithelial colony morphology and fewer differentiated cells. PI3K inhibition could not substitute for FGF or TGFB and did not affect phosphorylation of extracellular signal-regulated kinase, and thus acts independently of these pathways. Upon removal of PI3K inhibition, TSC transcription factor levels reverted to normal TSC levels, indicating that murine TSCs can reversibly switch between these two states. In summary, PI3K inhibition reduces the heterogeneity and seemingly heightens the stem cell state of TSCs as indicated by the simultaneous upregulation of multiple key marker genes and cell morphology. STEM CELLS 2019;37:1307-1318 SIGNIFICANCE STATEMENTTrophoblast stem cells (TSCs) are crucial to the development of a healthy placenta. However, not much is known about the signaling pathways that sustain their self-renewal and drive differentiation. This study uses a kinase inhibitor screen to identify novel pathways that regulate TSCs. Specifically, the authors identified that inhibition of phosphoinositide-3-kinase (PI3K) signaling increases the expression of stem cell markers in these cells. This is in contrast to other cell types, where PI3K inhibition leads to differentiation and apoptosis. The data suggest that just like embryonic stem cells, TSCs exhibit a dynamic stem cell state.

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“…Bowman space and GC tuft area were normalized to glomeruli length and glomeruli area, respectively. For placental histology, decidual, junctional zone, and labyrinth length and area were quantified for each section and normalized to respective placental length and areas (21, 24,45). Histological measurements for each animal tissue section were averaged and used for statistical analysis.…”

Section: Histologymentioning

confidence: 99%

Paternal deficiency of complement component C1q leads to a preeclampsia-like pregnancy in wild-type female mice and vascular adaptations postpartum

Sutton

Gemmel

Brands

et al. 2020

American Journal of Physiology-Regulatory, Integrative and Comp

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Preeclampsia is a spontaneously occurring, pregnancy-specific syndrome that is clinically diagnosed by new onset hypertension and proteinuria. Epidemiological evidence describes an association between a history of preeclampsia and increased risk for cardiovascular disease in later life; however, the mechanism(s) driving this relationship are unclear. Our study aims to leverage a novel preeclampsia-like mouse model, the C1q−/− model, to help elucidate the acute and persistent vascular changes during and following a preeclampsia-like pregnancy. Female C57BL/6J mice were mated to C1q−/− male mice to model a preeclampsia-like pregnancy (“PE-like”), and the maternal cardiovascular phenotype (blood pressure, renal function, systemic glycocalyx, and ex vivo vascular function) was assessed in late pregnancy and postpartum at 6 and 10 mo of age. Uncomplicated, normotensive pregnancies (female C57BL/6J bred to male C57BL/6J mice) served as age-matched controls. In pregnancy, PE-like dams exhibited increased systolic and diastolic pressure during mid- and late gestation, renal dysfunction, fetal growth restriction, and reduced placental efficiency. Ex vivo wire myography studies of mesenteric arteries revealed severe pregnancy-specific endothelial-dependent and -independent vascular dysfunction. At 3 and 7 mo postpartum (6 and 10 mo old, respectively), hypertension resolved in PE-like dams, whereas mild vascular dysfunction persisted at 3 mo postpartum. In conclusion, the female C57BL/6J-by-male C57BL/6J C1q−/− model recapitulates many aspects of the human preeclampsia syndrome in a low-risk, wild-type female mouse. The pregnancy-specific phenotype results in systemic maternal endothelial-dependent and -independent vascular dysfunction that persists postpartum.

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Phosphoinositide 3-Kinase (PI3K) Subunit p110δ Is Essential for Trophoblast Cell Differentiation and Placental Development in Mouse

Cited by 8 publications

References 81 publications

Paternal obesity induces placental hypoxia and sex-specific impairments in placental vascularization and offspring metabolism

Paternal obesity induces placental hypoxia and sex-specific impairments in placental vascularization and offspring metabolism

Inhibition of Phosphoinositide-3-Kinase Signaling Promotes the Stem Cell State of Trophoblast

Paternal deficiency of complement component C1q leads to a preeclampsia-like pregnancy in wild-type female mice and vascular adaptations postpartum

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