title: New strategy for in vitro activation of primordial follicles with mTOR and PI3K stimulators.
abstract: It had been known for decades that primordial follicles in mammalian ovaries are assembled with definite numbers and represent the ovarian reserve throughout the reproductive life. Intra-oocyte PI3K/mTOR pathways have been indicated to play a central role on the activation of primordial follicles. Genetic modified mouse models with chronic activation of PI3K/mTOR signals in primordial oocytes showed premature activation of all primordial follicles and eventually their exhaustion. On the other hand, this may suggest that, unlike chronic activation of PI3K/mTOR, its acute activation in infertility would activate primordial follicles, permitting fertility during the treatment. Previously, PI3K stimulators were reported as a temporary measure to accelerate primordial follicle activation and follicular development in both mouse and human, and were applied in the treatment of infertility in premature ovarian failure (POF) patients. To address whether mTOR stimulators could play similar role in the process, we transiently treated neonatal and aged mouse ovaries with mTOR stimulators-phosphatidic acid (PA) and propranolol. Our results demonstrated the stimulators increased activation of primordial follicles and the production of progeny. Human ovarian cortex cubes were also treated with mTOR or/and PI3K stimulators in vitro. When they were used separately, both of them showed similar promotive effects on primordial follicles. Surprisingly, after joint-treatment with the 2 kinds of stimulators together, synergistic effects on follicular development were observed. Based on increased efficiency of follicular activation in humans, here we propose in vitro transient treatment with mTOR and PI3K stimulators as an optimized protocol for the application in different clinical conditions with limited follicle reserve.
authors.affiliation: a State Key Laboratory of Reproductive Medicine ; Nanjing Medical University ; Nanjing , China.
authors.forename: Xinhui
authors.initials: X
authors.lastname: Sun
authors.forename: Yiping
authors.initials: Y
authors.lastname: Su
authors.forename: Yuanlin
authors.initials: Y
authors.lastname: He
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Wenwen
authors.initials: W
authors.lastname: Liu
authors.forename: Huilin
authors.initials: H
authors.lastname: Zhang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Hou
authors.forename: Jiayin
authors.initials: J
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Li
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D000831:Animals, Newborn; D047108:Embryonic Development / Q000187:drug effects; D005260:Female; D005307:Fertilization in Vitro; D005455:Fluorescent Antibody Technique; D006801:Humans; D008810:Mice, Inbred C57BL; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D006080:Ovarian Follicle / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D010712:Phosphatidic Acids / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011433:Propranolol / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D010712:Phosphatidic Acids; D019869:Phosphatidylinositol 3-Kinases; D011433:Propranolol; D058570:TOR Serine-Threonine Kinases
keywords: PA, phosphatidic acid; POF, premature ovarian failure; PRO, propranolol.; PTEN, Phosphatase and Tensin Homolog deleted on chromosome 10; TSC1, tuberous sclerosis complex 1 or hamartin; TSC2, tuberous sclerosis complex 2 or tuberin; fertility preservation; follicular activation; mTOR, mammalian target of rapamycin; ovary; premature ovarian failure; primordial follicle