Menstrual flow as a non-invasive source of endometrial organoids

Tereza Cindrova-Davies, Xiaohui Zhao, Kay Elder, Carolyn J. P. Jones, Ashley Moffett, Graham J. Burton & Margherita Y. Turco

Abstract

Assessment of the endometrium often necessitates a biopsy, which currently involves an invasive, transcervical procedure. Here, we present an alternative technique based on deriving organoids from menstrual flow. We demonstrate that organoids can be derived from gland fragments recovered from menstrual flow. To confirm they faithfully reflect the in vivo state we compared organoids derived from paired scratch biopsies and ensuing menstrual flow from patients undergoing in vitro fertilisation (IVF). We demonstrate that the two sets of organoids share the same transcriptome signature, derivation efficiency and proliferation rate. Furthermore, they respond similarly to sex steroids and early-pregnancy hormones, with changes in morphology, receptor expression, and production of ‘uterine milk’ proteins that mimic those during the late-secretory phase and early pregnancy. This technique has wide-ranging impact for non-invasive investigation and personalised approaches to treatment of common gynaecological conditions, such as endometriosis, and reproductive disorders, including failed implantation after IVF and recurrent miscarriage.

Our results demonstrate that menstrual flow contains viable endometrial gland progenitor cells, and can be used to derive physiologically relevant organoid cultures in a non-invasive manner. We confirmed that the transcriptome of the resultant organoids is identical to that of organoids generated from an endometrial biopsy taken earlier in the same cycle. Furthermore, the two sets of organoids respond in the same fashion to steroid and early pregnancy hormones. Together, our findings validate the use of menstrual flow as an easily obtainable and non-invasive alternative to endometrial biopsies for the derivation of endometrial organoids.

This technique has wide-ranging impact for non-invasive investigation and personalised approaches to treatment of common gynaecological conditions, such as endometriosis, and reproductive disorders, including failed implantation after IVF and recurrent miscarriage. Secretions from the endometrial glands play a key role in determining the receptivity of the endometrium and the implantation competence of the blastocyst, as well as stimulating the development of the placenta during the first months of pregnancy. Deficient functioning of the glands will therefore have profound impact on pregnancy success and outcome. Our technique will, for example, enable patients undergoing fertility treatments to have their endometrial function assessed non-invasively prior to initiating a treatment cycle, allowing the hormonal regime and timing of treatment to be tailored accordingly. This approach provides opportunities for personalised medicine in a similar fashion to that of kidney organoids derived from the urine of patients.