Secrets of menstrual cycle and early pregnancy

University of Cambridge scientists succeed in growing miniature functioning models of uterine lining in culture. These organoids, as they are called, could provide new insights into early stages of pregnancy and conditions like endometriosis — a painful overgrowth of the uterine lining affecting almost two million women in the UK alone.

The mucosal lining of the uterus is called the endometrium. Over the course of a menstrual cycle it changes, becoming thicker and rich with blood vessels in preparation for pregnancy. If the woman does not conceive, the uterus sheds this tissue which causes a woman's period.

A team from the Centre for Trophoblast Research at Cambridge Universiy, United Kingdom, grew the organoids in culture from cells derived from endometrial tissue. To maintain the organoids in culture for several months, they reproduced the genetic signature of the endometrium — meaning, that pattern of gene activity found only in the lining of the uterus. They then demonstrated how the organoids respond to female sex hormones and early pregnancy signals. These signals induce the secretion of what are collectively known as 'uterine milk'  — proteins nourishing the embryo during the first months of pregnancy.

Funded by the Medical Research Council, the Wellcome Trust and the Centre for Trophoblast Research, the findings of the study are published in the journal Nature Cell Biology.

"These organoids provide a major step forward in investigating the changes that occur during the menstrual cycle and events during early pregnancy when the placenta is established," says Dr Margherita Turco, the study's first author. "These events are impossible to capture in a woman, so until now we have had to rely on animal studies."

"Events in early pregnancy lay the foundations for a successful birth. There's increasing evidence that complications of pregnancy, such as restricted growth of the fetus, stillbirth and pre-eclampsia — which appear later in pregnancy — have their origins around the time of implantation, when the placenta begins to develop."

Graham Burton PhD, Professor, Director, Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, and joint senior author of the study with Ashley Moffett PhD, Department of Pathology, University of Cambridge, Cambridge, United Kingdom.

Professor Burton and colleagues believe that using endometrial organoids will allow them to investigate in detail how a conceptus communicates with a mother's glands. Identify factors being released by the embryo, allows the possibility to test the effects of such factors on maternal tissue.

Research in mice and sheep has shown factors secreted by endometrial glands are critical for enabling a fertilized egg ('conceptus') to implant into the uterine wall. There is also strong evidence a conceptus sends signals to endometrial glands that stimulate placental development.

Therefore, a conceptus stimulates its own development through a chemical 'dialogue' with it's mother. If it fails to send these signals, pregnancy can terminate or a fetus suffer growth restriction.

Burton's team will be collaborating with the Bourn Hall Clinic, Cambridgeshire, UK. Their intent is to investigate whether parts of this circuitry are impaired or deficient in women having difficulty in conceiving, and if so to devise potential new treatments.

The technique also enables researchers to grow organoids from endometrial cancer cells. As a proof-of-principle, this will allow them to model and understand diseases of the endometrium, including cancer of the uterus and endometriosis.

Abstract
In humans, the endometrium, the uterine mucosal lining, undergoes dynamic changes throughout the menstrual cycle and pregnancy. Despite the importance of the endometrium as the site of implantation and nutritional support for the conceptus, there are no long-term culture systems that recapitulate endometrial function in vitro. We adapted conditions used to establish human adult stem-cell-derived organoid cultures to generate three-dimensional cultures of normal and decidualized human endometrium. These organoids expand long-term, are genetically stable and differentiate following treatment with reproductive hormones. Single cells from both endometrium and decidua can generate a fully functional organoid. Transcript analysis confirmed great similarity between organoids and the primary tissue of origin. On exposure to pregnancy signals, endometrial organoids develop characteristics of early pregnancy. We also derived organoids from malignant endometrium, and so provide a foundation to study common diseases, such as endometriosis and endometrial cancer, as well as the physiology of early gestation.

Search terms: Disease model Homeostasis Organogenesis Stem-cell differentiation

Reference
Turco, MY et al. Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined medium. Nature Cell Biology; 10 April 2017; DOI: 10.1038/ncb3516
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Apr 20, 2017   Fetal Timeline   Maternal Timeline   News   News Archive   

Uterine 'organoids' responded to female sex hormones and early pregnancy signals prodcing secretions known as 'uterine milk'  — proteins that nourish the embryo during the first months of pregnancy..
Image Credit: Uterine tissue, public domain, color enhanced by MouseWorks.