Cells that make up the lining of the uterus play an important role in allowing embryo implantation and subsequent fetal development.

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Bringing the womb to birth

24 Jan 2020

A*STAR scientists have identified stem cells required for successful embryo implantation during pregnancy.

Despite the availability of fertility drugs and procedures such as in vitro fertilization, a successful pregnancy still depends on the proper development and maintenance of the uterus. Should abnormalities occur in the uterine lining, a woman may still experience difficulty conceiving a child.

“The glands and epithelial cells that line the inner surface of the uterus are essential for embryo implantation in the adult female. However, their neonatal source was unknown,” said Nick Barker, a Research Director at A*STAR’s Institute of Medical Biology (IMB). His team, collaborating with colleagues in Singapore and Japan, therefore decided to perform a series of cell-tracking experiments in mice to identify the cells that eventually make up the uterine lining.

The researchers noted that the uterine lining of prepubertal female mice contained stem cells expressing the protein Lgr5. Using female mouse embryos genetically engineered so that the cells fluoresced whenever Lgr5 is expressed, Barker’s team showed that Lgr5-containing stem cells already exist in female mouse embryos.

The expression of Lgr5 in the reproductive tract of female mice increased dramatically in the first two weeks after birth, before gradually declining to low levels post-puberty. Importantly, the Lgr5-expressing cells eventually generate the epithelial lining of not just the uterus, but also that of the ovaries and upper vagina.

These findings were further confirmed by harvesting Lgr5-expressing uterine cells from two-week old mice and establishing a 3D culture system that mimics the structure and function of the female reproductive tract. Collectively, the results show that Lgr5-expressing cells are indispensable for the normal development of the female reproductive tract.

“Our ex vivo organoid cultures revealed that Lgr5-expressing cells initially function as stem cells for both the uterine epithelia and the uterine glands, but then later function exclusively as gland stem cells as the uterus matures. These glands secrete key hormones later in adulthood that are essential for successful embryo implantation during pregnancy,” Barker explained.

Additionally, the team discovered that uterine cells which do not express Lgr5 secrete molecules called Wnt ligands to regulate the development and organization of Lgr5-expressing cells. The Wnt signaling pathway is known to control cell proliferation and regeneration, so Barker and colleagues are interested in exploring how the dysregulation of Wnt signaling could contribute to cancer formation in the female reproductive tract.

“Understanding the cause of uterine disorders in adults, including cancer, where stem cells have a role, could lead to development of novel therapeutics for those conditions,” Barker concluded.

The A*STAR-affiliated researchers contributing to this research are from the Institute of Medical Biology (IMB) and the Skin Research Institute of Singapore (SRIS).

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Seishima, R., Leung, C., Yada, S., Murad, K. B. A., Tan, L. T. et al. Neonatal Wnt-dependent Lgr5 positive stem cells are essential for uterine gland development. Nature Communications 10, 5378 (2019) | article

About the Researcher

Nick Barker

Research Director

Institute of Medical Biology
Nick Barker obtained his PhD from Reading University, UK in 1996. Together with Professor Hans Clevers, he identified dysregulated Wnt signaling as the initiating event in colon cancer. In 2001, he joined Semaia Pharmaceuticals to develop colon cancer therapeutics, then returned to Hans Clevers’ group as a Senior Staff Scientist in 2006, where he identified Lgr5 as a marker of various adult stem cell populations and intestinal Lgr5 stem cells as being the cell-of-origin of colon cancer. Moving to Singapore in 2010, he joined A*STAR’s Institute of Medical Biology (IMB) as a Senior Principal Investigator and now holds the position of Research Director. His research focuses on Lgr5 gastric stem cells in self-renewal and cancer. In 2017, he received the NRF Investigatorship and was recognized as a Web of Science Highly Cited Researcher. He is also an Adjunct Professor at Nanyang Technological University, Singapore, and a Research Professor at Kanazawa University, Japan.

This article was made for A*STAR Research by Wildtype Media Group