Hippo signaling disruption and Akt stimulation of ovarian follicles for infertility treatment

被引：662

作者：

Kawamura, Kazuhiro ^{[1
,3
]}

Cheng, Yuan ^{[4
]}

Suzuki, Nao ^{[1
]}

Deguchi, Masashi ^{[4
]}

Sato, Yorino ^{[1
,4
]}

Takae, Seido ^{[1
,4
]}

Ho, Chi-hong ^{[4
]}

Kawamura, Nanami ^{[2
,3
]}

Tamura, Midori ^{[1
]}

Hashimoto, Shu ^{[5
]}

Sugishita, Yodo ^{[1
]}

Morimoto, Yoshiharu ^{[5
]}

Hosoi, Yoshihiko ^{[6
]}

Yoshioka, Nobuhito ^{[1
]}

Ishizuka, Bunpei ^{[2
]}

Hsueh, Aaron J. ^{[4
]}

机构：

[1] St Marianna Univ, Sch Med, Dept Obstet & Gynecol, Kawasaki, Kanagawa 2168511, Japan

[2] St Marianna Univ, Sch Med, Dept Adv Reprod Med, Kawasaki, Kanagawa 2168511, Japan

[3] Akita Univ, Grad Sch Med, Dept Obstet & Gynecol, Akita 0108543, Japan

[4] Stanford Univ, Sch Med, Dept Obstet & Gynecol, Program Reprod & Stem Cell Biol, Stanford, CA 94305 USA

[5] IVF Namba Clin, Osaka 5500015, Japan

[6] Kinki Univ, Grad Sch Biol Oriented Sci & Technol, Wakayama 6496493, Japan

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2013年 / 110卷 / 43期

基金：

美国国家卫生研究院;

关键词：

ovary; aging; YAP; CCN2; PTEN; TISSUE-GROWTH; F-ACTIN; PATHWAY; PTEN; SIZE; PROLIFERATION; REGENERATION; ACTIVATION; FAILURE; MARKERS;

D O I：

10.1073/pnas.1312830110

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Primary ovarian insufficiency (POI) and polycystic ovarian syndrome are ovarian diseases causing infertility. Although there is no effective treatment for POI, therapies for polycystic ovarian syndrome include ovarian wedge resection or laser drilling to induce follicle growth. Underlying mechanisms for these disruptive procedures are unclear. Here, we explored the role of the conserved Hippo signaling pathway that serves to maintain optimal size across organs and species. We found that fragmentation of murine ovaries promoted actin polymerization and disrupted ovarian Hippo signaling, leading to increased expression of downstream growth factors, promotion of follicle growth, and the generation of mature oocytes. In addition to elucidating mechanisms underlying follicle growth elicited by ovarian damage, we further demonstrated additive follicle growth when ovarian fragmentation was combined with Akt stimulator treatments. We then extended results to treatment of infertility in POI patients via disruption of Hippo signaling by fragmenting ovaries followed by Akt stimulator treatment and autografting. We successfully promoted follicle growth, retrieved mature oocytes, and performed in vitro fertilization. Following embryo transfer, a healthy baby was delivered. The ovarian fragmentation-in vitro activation approach is not only valuable for treating infertility of POI patients but could also be useful for middle-aged infertile women, cancer patients undergoing sterilizing treatments, and other conditions of diminished ovarian reserve.

引用

页码：17474 / 17479

页数：6