Uterine-specific SIRT1 deficiency confers premature uterine aging and impairs invasion and spacing of blastocyst and stromal cell decidualization in mice
Notice bibliographique
Résumé
Abstract A distinct age-related alteration in the uterine environment has recently been identified as a prevalent cause of the reproductive decline in older female mice. However, the molecular mechanisms that underlie age-associated uterine adaptability to pregnancy are not known. Sirtuin 1 (SIRT1), a multifunctional NAD + -dependent deacetylase that regulates cell viability, senescence and inflammation during aging, is reduced in aged decidua. Thus, we hypothesize that SIRT1 plays a critical role in uterine adaptability to pregnancy and that uterine-specific ablation of Sirt1 gene accelerates premature uterine aging. Female mice with uterine ablation of Sirt1 gene using progesterone receptor Cre ( Pgr Cre ) exhibit subfertility and signs of premature uterine aging. These Sirt1 -deficient mothers showed decreases in litter size from their 1 st pregnancy and became sterile (25.1±2.5 weeks of age) after giving birth to the 3 rd litter. We report that uterine-specific Sirt1 deficiency impairs invasion and spacing of blastocysts, and stromal cell decidualization, leading to abnormal placentation. We found that these problems traced back to the very early stages of hormonal priming of the uterus. During the window of receptivity, Sirt1 deficiency compromises uterine epithelial-stromal crosstalk, whereby estrogen (E2), progesterone (P4) and Indian hedgehog (IHH) signaling pathways are dysregulated, hampering stromal cell priming for decidualization. Uterine transcriptomic analyses also link these causes to perturbations of histone proteins and epigenetic modifiers, as well as adrenomedullin signaling, hyaluronic acid metabolism, and cell senescence. Strikingly, our results also identified genes with significant overlaps with the transcriptome of uteri from aged mice and transcriptomes related to master regulators of decidualization (e.g., Foxo1, Wnt4, Sox17, Bmp2, Egfr and Nr2f2 ). Our results also implicate accelerated deposition of aging-related fibrillar type I and III collagens in Sirt1 -deficient uteri. Collectively, SIRT1 is an indispensable age-related regulator of invasion and spacing of blastocysts, as well as decidualization of stromal cells. Author Summary Advanced maternal age (i.e., ≥35 years old) is considered a significant risk factor for birth defects, including fetal growth restriction, stillbirth, preterm birth, and preeclampsia. Lifestyle factors such as tobacco smoke, alcohol usage and other environmental toxins are facilitators of premature reproductive aging. Thus, understanding the precise mechanisms by which female reproductive organs age is a prerequisite for ultimately developing counteracting therapies. Much attention has been focused on ovarian function and oocyte quality, but we provide evidence that severe placentation defects are a major cause of age-related reproductive decline, which results from an impaired decidual response by uterine stromal cells. This problem is due to a blunted progesterone (P4) responsiveness of the aging uterus, via its cognate receptor, PGR. In the present study, the uterine SIRT1 gene was deleted to advance understanding of the genetics of premature uterine aging in a mouse model of blunted PGR actions that is similar to physiological aging. Our results have informed as to molecular changes in response to blunting PGR actions in aging uteri that are unrelated to oocyte quality, and provide new insights into strategies for developing counteracting measures for pregnancy in females at an advanced reproductive age.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,001 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».