Prodyot K. Chatterjee

Cellular senescence leads to stable cell cycle arrest and an inflammatory senescence-associated secretory phenotype that varies with stressor and cell type. To mitigate these effects and improve health, senotherapeutics (e.g., senolytics and senomorphics) have been developed. Senescent-like endometrial stromal cells (eSCs) lining the uterus of patients with endometriosis and infertility are proposed to impair decidualization, a differentiation process required for uterine receptivity in humans. Quercetin, a natural flavonoid senolytic, dramatically improves decidualization and reduces endometriosis in rodent models. However, little is known about the comparative effects of various senotherapeutics on eSCs. Using menstrual effluent-derived eSCs, we evaluated the effects of flavonoid and non-flavonoid compounds on eSC functions associated with endometriosis, aiming to identify optimal senotherapeutics for future clinical trials. Among flavonoids tested, all senolytics (quercetin, fisetin, and luteolin) and kaempferol, a senomorphic, significantly improved decidualization without cytotoxicity. Although non-flavonoids exhibited notable cytotoxicity, dasatinib, but neither ABT-737 nor navitoclax, enhanced decidualization. Flavonoid senotherapeutics and dasatinib significantly inhibited eSC migration. Mechanistic studies revealed that all flavonoids and dasatinib suppressed AKT phosphorylation and upregulated p53 expression. Notably, only quercetin and fisetin reduced ERK1/2 phosphorylation. Furthermore, flavonoid-senolytics and dasatinib consistently eliminated senescent eSCs. These findings support future studies to assess the therapeutic potential of in vivo supplementation with flavonoid senolytics on eSC function using menstrual effluent.

Hereditary hemorrhagic telangiectasia (HHT) is a potentially life-threatening genetic vascular disorder caused by loss-of-function mutations in the genes encoding activin receptor-like kinase 1 (ALK1), endoglin, Smad4, and bone morphogenetic protein 9 (BMP9). Injections of mouse neonates with BMP9/10 blocking antibodies lead to HHT-like vascular defects in the postnatal retinal angiogenesis model. Mothers and newborns share the same immunity through the transfer of maternal antibodies during breastfeeding. Here, we investigated whether the transmammary delivery route could improve the ease and consistency of administering anti-BMP9/10 antibodies in the postnatal retinal angiogenesis model. We found that anti-BMP9/10 antibodies, when intraperitoneally injected into lactating dams, are efficiently transferred into the circulation of breastfed neonatal pups. Strikingly, pups receiving anti-BMP9/10 antibodies via breastfeeding displayed consistent and robust vascular pathology in the retina, which included hypervascularization and defects in arteriovenous specification, as well as the presence of multiple and massive arteriovenous malformations. Furthermore, RNA-Seq analyses of neonatal retinas identified an increase in the key pro-angiogenic factor, angiopoietin-2, as the most significant change in gene expression triggered by the transmammary delivery of anti-BMP9/10 antibodies. Transmammary-delivered BMP9/10 immunoblocking in the mouse neonatal retina is therefore a practical, noninvasive, reliable, and robust model of HHT vascular pathology.

Maternal obesity may program the fetus and increase the susceptibility of the offspring to adult diseases. Metformin crosses the placenta and has been associated with decreased inflammation and reversal of fatty liver in obese leptin-deficient mice. We investigated the effects of metformin on maternal and fetal lipid metabolism and hepatic inflammation using a rat model of diet-induced obesity during pregnancy. Female Wistar rats (6–7 weeks old) were fed normal or high calorie diets for 5 weeks. After mating with normal-diet fed males, half of the high calorie-fed dams received metformin (300 mg/kg, daily); dams (8 per group) continued diets through gestational day 19. Maternal and fetal livers and fetal brains were analyzed for fatty acids and for fatty acid metabolism-related gene expression. Data were analyzed by ANOVA followed by Dunnett’s post hoc testing. When compared to control-lean maternal livers, obesogenic-diet-exposed maternal livers showed significantly higher saturated fatty acids (14:0 and 16:0) and monounsaturated fatty acids (16:1n7 and 18:1n9) and lower polyunsaturated (18:2n6 and 20:4n6 [arachidonic acid]) and anti-inflammatory n3 polyunsaturated fatty acids (18:3n3 and 22:6n3 [docosahexaenoic acid]) (p < 0.05). Metformin did not affect diet-induced changes in maternal livers. Fetal livers exposed to the high calorie diet showed significantly increased saturated fatty acids (18:0) and monounsaturated fatty acids (18:1n9 and 18:1n7) and decreased polyunsaturated fatty acids (18:2n6, 20:4n6 and 22:6n3) and anti-inflammatory n3 polyunsaturated fatty acids, along with increased gene expression of fatty acid metabolism markers (Fasn, D5d, D6d, Scd1, Lxrα). Metformin significantly attenuated diet-induced inflammation and 18:1n9 and 22:6n3 in fetal livers, as well as n3 fatty acids (p < 0.05). Prenatal obesogenic diet exposure significantly increased fetal liver IFNγ levels (p < 0.05), which was reversed by maternal metformin treatment (p < 0.05). Consumption of a high calorie diet significantly affected maternal and fetal fatty acid metabolism. It reduced anti-inflammatory polyunsaturated fatty acids in maternal and fetal livers, altered gene expression of fatty acid metabolism markers, and induced inflammation in the fetal livers. Prenatal metformin attenuated some diet-induced fatty acid changes and inflammation in the fetal livers without affecting maternal livers, suggesting that maternal metformin may impact fetal/neonatal fatty acid/lipid metabolism.