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Periodic Reporting for period 1 - HUTER (HUMAN UTERUS CELL ATLAS)

Período documentado: 2020-01-01 hasta 2020-12-31

The Human Uterus Cell Atlas (HUTER) project is creating a single-cell and spatial reference map of the human uterus. HUTER will provide unprecedented insight to transcriptomic, genomic and spatial changes of this key female organ across both the menstrual cycle and the lifespan.

Infertility affects at least 48 million couples globally (International Classification of Diseases, WHO 2018). Roughly 3% to 5% of cases are caused by uterine dysfunction, with uterine factor infertility occurring in as many as 1:500 reproductive-aged women. Infertility is both a medical issue and a socio-economic problem, due to its strong psychological effects on couples wishing to conceive and its negative effect on population replacement. Further, infertility is an increasing public health issue in Europe, the continent with the lowest total fertility rate. Optimal reproductive health is critical to effective economic growth and societal well-being.

Beyond conception, the uterus is crucial to health in other life stages. For example, pregnancy complications like preeclampsia are important contributors to maternal and infant mortality and morbidity. Uterine pathologies, which can be congenital or acquired, benign or malignant, also significantly impact women's health and/or quality of life. The most prevalent conditions are uterine fibroids, endometriosis and endometrial cancer. Such conditions exert an economic burden similar to that of chronic conditions like Crohn's disease and rheumatoid arthritis. Finally, endometrial cancer is the most common gynaecologic malignancy in Europe and the USA, with an estimated lifetime risk of 2,6%, and a median age at diagnosis of 61 years.

Hence, the HUTER project is motivated by the need to better understand the human uterus to more effectively address conditions that impact women´s health, reproductive outcomes and maternal and fetal mortality and morbidity, and, by extension, negatively impact population well-being.

HUTER will lay crucial foundations for innovating new diagnostic and prognostic tools for uterine dysfunctions. The main objectives are to:
- Ensure a tight coordination with the international Human Cell Atlas (HCA) initiative and legal and ethical compliance.
- Design and implement a biotechnological platform that will ensure HUTER project results are sustainable beyond the project. The platform enables data uploading and data query for raw data, analytical results, and spatial resolution images from our single-cell molecular characterisation, epigenomics and transcriptomics studies.
- Achieve molecular characterisation (transcriptomics, epigenomics, genomics and transcriptomics/protein spatial maps) at single-cell resolution in endometrium and myometrium, allowing the identification of cell types and states in those tissues across the lifespan for a healthy uterus.
To date, even with COVID restrictions affecting sample collection, 5 whole-uterus samples and 7 endometrial biopsies from healthy women at reproductive age have been collected and processed. Whole tissue from deceased donors and women that attended hysterectomy provided tissue and cellular samples from two different regions of endometrial epithelium and stroma as well as myometrium. Together with the collected endometrial biopsies, a total of 38 samples for single-cell RNA sequencing, sc-epigenomics, WGS, protein atlas and spatial transcriptomics have been collected. So far, 13 of those 38 samples have been sequenced and analysed at the single-cell level, while 18 samples are currently under analysis.

Generated data is allowing a better characterisation of uterine tissues and helping to better define uterine cell subpopulations and cell-to-cell interactions. This information is revealing how cells organize into uterine tissues and allow the regulation of important processes such the menstrual cycle or embryo implantation, and how deregulation of those processes could contribute to infertility and disease. Moreover, since different molecular characterisation approaches are being performed by different members of the HUTER consortium, joint analysis of the data will provide an unprecedent scientific tool to better understand the functioning of the human uterus in health and disease.
As foreseen on the call SC1-BHC-31-2019 challenge, each Pilot Action should demonstrate “the utility of an interdisciplinary technological/biological platform to generate and integrate standardised molecular, cellular, biochemical and other data sets, characterising single cells or their nuclear components, their interactions and/or spatial location in tissues from one human organ”. Therefore, HUTER will provide significant progress on the state of the art through single-cell uterine characterisation, providing useful resources for the scientific community. HUTER’s results could inform discovery of new treatments and diagnostic tools that improve women’s health and reproductive medicine, with attendant socio-economic benefits.

Single-cell (sc) characterisation through state-of-the-art methodologies such as sc-transcriptomics, sc-epigenomics, sc-whole-genome sequencing and high-resolution transcriptomics spatial maps and protein atlases of both endometrial and myometrial tissues will provide unprecedented information about healthy uterine physiology, and allow molecular characterisation of uterine cell populations, cell-to-cell interactions and regulatory pathways involved in the menstrual cycle and various life stages. Importantly, obtained data will be shared with the scientific community and uploaded to the Human Cell Atlas (HCA) public database, serving as a reference that enables future studies to characterise relevant uterine pathological conditions.

HUTER will also perform a pilot study of severe preeclampsia (sPE), one of the most prevalent pregnancy complications worldwide. Sc-RNA sequencing data generated from endometrial biopsies from patients with sPE will provide key evidence to define sPE pathology and unmask the molecular pathways underpinning this clinically important condition.

Thus, HUTER results will yield a comprehensive understanding of the uterine molecular dynamics involved in healthy physiology and in sPE and, moreover, will provide the first time single-cell molecular characterisation of the myometrium tissue. Given increasing infertility issues and the parallel increase in fertility treatments, the HUTER project will achieve even more important impacts: beyond the obvious biomedical and health aspects, infertility entails a wide socio-economic and public health problem.

An added benefit is the development of the HUTER platform that will allow researchers to gather massive data, perform high-throughput analysis of sc-sequencing data, save and share clinical and experimental metadata, share results among partners, view advanced microscopy images, transform format-closed imaging files to an open medical standard format (DICOM), and visualise and downloading gathered data, among other functionalities related to HUTER management. The expected integrated tools will facilitate and catalyse discovery from our datasets as well as being easily adaptable to other potential uses cases after project completion.

In summary, HUTER results will be a valuable and useful resource for the scientific community to define the cellular basis of health and disease and to support women’s clinical care.
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