Developmental and meiotic potential of oocytes derived from human ovarian germ line stem cells (OSCs) in vitro.

Lead Research Organisation: University of Edinburgh
Department Name: Sch of Biological Sciences

Abstract

For decades, scientists have believed that women were born with all the eggs they would ever have and that no new ones could ever be made. Recently a group of researchers in the USA isolated a primitive "stem" like cell from the ovaries of adult women. These cells were shown to be capable of forming what appeared to be new eggs (oocytes) when they were injected back into ovarian tissue. The implications of this are potentially enormous, but at the moment we know very little about what these cells may or may not be capable of. If we could make new eggs we could eventually help restore fertility in women who have become infertile for a variety of reasons, including chemotherapy, early menopause or just normal ageing. However, these findings have led to controversy and many questions remain as to whether these new eggs can develop normally. This project will determine whether these cells can be isolated from the ovaries of healthy women from a range of ages. Then using a system which we have developed where we can grow eggs outside the body (culture system), we will determine whether these cells can form new eggs and whether they are normal. The ultimate end point of this work would be to determine whether these cells were capable of forming eggs that could be fertilised and form embryos.

Technical Summary

Cells with germ line potential have been isolated and purified from adult mouse ovary and from human ovarian tissue obtained from adult women. These cells, termed oogonial stem cells (OSCs) have been characterised in mice and after in vivo transplantation they form functional oocytes that can be matured, fertilised and form embryos. The equivalent human cells that have been isolated have been much less fully characterised. Yet the ability to develop these cells into mature oocytes would have many potential applications in assisted reproduction and fertility preservation as well being of huge value as a model for the study of human oogenesis. This project aims to confirm the isolation of this cell population from ovaries of adult women of varying ages and to determine the developmental potential of oocytes derived from human OSCs. To test the developmental potential of human OSCs we will combine them with a multistep culture system recently developed in our lab that supports development of human oocytes from the most immature stage (primordial) to fully developed stages with some being capable of undergoing meiotic maturation to Metaphase II. Using this system our preliminary data show that OSCs form follicles when injected into human ovary tissue, with confirmation that they can undergo the initial stages of folliculogenesis. By combining these two technologies we will be able to explore robustly the full meiotic and developmental potential of these cells, and provide a basis for future studies exploring their therapeutic potential.

Planned Impact

This proposal is to study a newly identified cell type isolated from the ovaries of adult women that appears to have the potential to form new eggs (oocytes). This study will determine whether these newly formed oocytes are normal and viable. The beneficiaries of this proposal will be:
1) Researchers in Reproductive Sciences: Researchers will benefit from this work as it will provide a model to study the early processes of human egg development. It will provide tools to study processes such as meiosis which has previously been in accessible in humans.
2) Students and Scientists will benefit as this project will offer greater insight into a central tenet of mammalian female reproduction. These results could lead to new hypotheses to explain the process of ovarian ageing.
3) Fertility Preservation patients and practitioners would benefit if positive results are obtained. This work could lead to the process of isolating this stem cell population as a method for fertility preservation. This would affect a range of patient groups from cancer sufferers to those with Premature Ovarian Failure and genetic conditions such as Turners syndrome.
4) Assisted Reproductive Technologies; healthcare providers, clinical practitioners and patients. If the results of this project are positive then we will be in a position to develop methodologies for novel approaches to assisted reproduction. These could potentially a) negate the need for hormonal stimulation of the patient, b) avoid multiple surgical procedures to harvest the resultant eggs, c) implement a series of quality control measures to optimise egg selection for subsequent fertilisation and d) improve success rates particularly in older women, and most importantly provide options for women who have no options currently available. All these are highly desirable outcomes for improving the treatment and management of infertile women.
5) Commercial companies. Assisted reproduction is an area of high commercial interest. With any new potential therapies comes the development of a range of techniques to facilitate it. This work would impact on the development of techniques to isolate, store and culture these cells.

Publications

10 25 50
 
Description MRC Project Grant
Amount £750,000 (GBP)
Funding ID MR/R003246/1 
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2017 
End 08/2020
 
Description Non EU industry,Commerce and Public Funding award
Amount £467,433 (GBP)
Organisation OvaScience 
Sector Private
Country United States
Start 03/2016 
End 07/2017
 
Description Molecular origin of non-disjunction in human meiotic and early mitotic divisions 
Organisation University of Warwick
Country United Kingdom 
Sector Academic/University 
PI Contribution Prof Richard Anderson and I have formed a collaboration with Prof Adele Marston in Cell Biology UOE who is an expert in the process of Meiosis. We are contributing through generating in vitro grown human oocytes that can be tested for meiotic errors.
Collaborator Contribution Prof Adele Marston
Impact Wellcome TRust Collaborative grant application
Start Year 2017
 
Description Clinical Achievements of Reproductive Medicine: Karolinska Institute Postgraduate Course 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact Presented two lectures to a postgraduate course at Karolinska Institute in Stockholm organised by Dr Kenny Rodriguez Wallberg. Talks were directly related to MRC awards, one on in vitro growth of human oocytes and the other on germ line stem cells. This resulted in discussion and further invitations to fertility group meeting in Stockholm later in the year.
Year(s) Of Engagement Activity 2015
 
Description Contributer to a Radio Four Programme: Rewinding the menopause 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Professor Telfer, Professor Richard Anderson and Dr Marie McLaughlin participated in making a radio programme for Radio 4 with Dr Aarathi Prasad. Dr Prasad and BBC producers visited Telfer's laboratory and warched the ongoing work and conducted interviews. This led to increased interest in the work and approaches from other BBC programme makers as well as enquiries from members of the public.
Year(s) Of Engagement Activity 2016
URL http://www.bbc.co.uk/programmes/b0643vfl
 
Description Excemed Workshop for Clinicians and Embryologists (Helsinki) 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact This was a pre- ESHRE workshop to explore new research that would form the basis of next generation fertility treatments. Over 150 practitioners attended and the topic of Evelyn Telfer's presentation (germ line stem cells) sparked many questions and discussion afterwards. This has led to other invitations and interest in this area.
Year(s) Of Engagement Activity 2016
URL https://www.excemed.org/live-events/pre-eshre-advanced-course-embryology-ivf-today-it-possible-furth...
 
Description Guardian Article on ABVD work 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Our work on ABVD was presented at the ESHRE meeting in Helsinki 2016 and won the best oral presentation award. Hannah Devlin, the Science writer for the Guardian wrote an article describing the work.
Year(s) Of Engagement Activity 2016
URL https://www.theguardian.com/science/2016/oct/07/evidence-suggests-womens-ovaries-can-grow-new-eggs
 
Description Invited Speaker Korean Society for Fertility Preservation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact I was the only international invited speaker at the Korean Society for Fertility Preservation. My talk generated a great deal of discussion and opened up the potential for collaborative research.
Year(s) Of Engagement Activity 2015
 
Description Invited Speaker at Ovarian Club 2016 Paris 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited to speak on female germline stem cells and their potential clinical use. This presentation contributed to the ongoing debate surrounding female germline stem cells.
Year(s) Of Engagement Activity 2016
URL http://oc2016.cme-congresses.com/scientific-program.aspx
 
Description Keynote Speaker at OvaScience Symposium Baltimore. ASRM meeting 2015 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk to practitioners and investors on applications of germ line stem cell work.
Year(s) Of Engagement Activity 2015
 
Description Named one of Porter's Magazine's Incredible Women of 2018 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Named as one of Porter's magazine in recognition of work on in vitro growth of human oocytes.
Year(s) Of Engagement Activity 2018
URL https://www.ed.ac.uk/news/2018/fertility-pioneer-receives-international-award
 
Description Participation in BBC programme: The Insiders' guide to the menopause 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Telfer lab participated in making of a programme on the menopause commissioned by BBC. Kirsty Wark and the production team visited the laboratory and filmed Dr Maclaughlin at work and interviewed Professor Telfer. This programme was broadcast in February 2017. This led directly to discussion of our work and enquiries from the public, media and other sources.
Year(s) Of Engagement Activity 2016,2017
URL http://www.bbc.co.uk/programmes/b08fmspd
 
Description Podcast for Women in Science day 2015 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Undergraduate students
Results and Impact I was interviewed by the University of Edinburgh Biology Society students for a special podcast for Women in Science day. The podcast led to interest from undergraduates and postgraduates and also invitations to speak at some of their events.
Year(s) Of Engagement Activity 2015
URL http://www.biology.ed.ac.uk/polopoly/podcasts/BIOPOD_OCT_2015_ALD.mp3
 
Description Professor Telfer interviewed on Good Morning Scotland, Radio Scotland. Dec 6th 2016 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Interview on observation that ABVD leads to greater number of oocytes. This led to a number of women who had been treated with the drug contacting us and relating their experiences which fits with our research. It also led to Sky news and Kirsty Wark getting in touch about other programmes.
Year(s) Of Engagement Activity 2016
URL http://www.bbc.co.uk/programmes/b083cx8m#play
 
Description Radio Interview on Newstalk Radio Programme New Zealand: Professor Telfer 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Prof Telfer was invited to participate in an interview on New Zealand Radio on December 7th 2016 to discuss findings published in Human Reproduction relating to increased number of oocytes in young women treated with ABVD chemotherapy. This was broadcast in New Zealand and Australia and published online. This directly led to increased interest from Australia and New Zealand in our research and requests for further information.
Year(s) Of Engagement Activity 2016
URL http://www.newstalkzb.co.nz/on-air/early-edition/audio/professor-evelyn-telfer-cancer-drug-increasin...
 
Description Radio Interview on Today Programme with John Humphries 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Interview on the morning programme Today with John Humphries to discuss our published work on growing human oocytes in vitro
Year(s) Of Engagement Activity 2018
 
Description Sky News piece on Telfer group's research 6th December 2016 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Professor Telfer interviewed on Sky News and lab team filmed to highlight the finding of new oocytes being formed after treatment with chemotherapy agents. This has resulted in other media requests and interest from companies regarding collaborations.
Year(s) Of Engagement Activity 2016
URL http://news.sky.com/story/cancer-drugs-prompt-ovaries-to-produce-eggs-10685811
 
Description Talk to GRECOT ( French Study and Research Group about Ovarian and Testicular tissue Cryopreservation) Paris 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Invited to speak at Fertility Preservation Forum in Paris. mainly Clinicians and Scientists working on storing ovarian and testicular tissue. My presentation will deal with in vitro follicle development.
Year(s) Of Engagement Activity 2017
 
Description Teaching RCOG 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Type Of Presentation Keynote/Invited Speaker
Geographic Reach National
Primary Audience Health professionals
Results and Impact Group of obstetricians and other clinicians attended and asked questions. Some have asked to visit our lab.

Arranged lab visits
Year(s) Of Engagement Activity 2013