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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,3,18]]},"abstract":"<jats:p>\n                    Recurrent implantation failure (RIF) is a devastating condition that leaves many undergoing fertility treatment childless. The human endometrium is receptive to a blastocyst for a brief period, the window of implantation. Critical knowledge underpinning biological processes leading to RIF, essential for effective treatment, is lacking. We employed spatial transcriptomics to define region- and cell-type-specific differences in endometrial gene expression in luteinizing hormone timed biopsies between women with RIF (n = 8) and fertile controls (FC) (n = 8). Differentially expressed genes (DEGs) were identified when comparing endometrial regions between FC and RIF (685 luminal epithelium, 293 glandular epithelium, 419 subluminal stroma, 264 functionalis stroma, 1,125 subluminal stromal CD45\n                    <jats:sup>+<\/jats:sup>\n                    leukocytes, and 1,049 functionalis stromal CD56\n                    <jats:sup>+<\/jats:sup>\n                    leukocytes). Only 57 DEGs were common to all subregions and cell types, which highlights that multiple DEGs are lost when the endometrium is examined as a single entity. When RIF-specific DEGs were leveraged against knowledge from mouse genetic models, genes associated with aberrant embryo implantation phenotypes were observed, mostly in immune cell populations. Dysregulated pathways in specific endometrial regions included the \u201cWNT signaling pathway,\u201d altered in the functionalis and subluminal stroma. \u201cResponse to estradiol\u201d and \u201covulation cycle\u201d pathways were dysregulated in the subluminal stroma. In silico drug screening identified potential compounds that can reverse the RIF gene expression profile (e.g., raloxifene, bisoprolol). Our findings, in a well-characterized cohort, highly endorse consideration of each endometrial region and cell type as separate entities. Ignoring individual regions and composite cell populations will overlook important aberrations, forego potential treatment targets, and lead to research waste pursuing clinically irrelevant treatment options.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2421254122","type":"journal-article","created":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T15:06:16Z","timestamp":1741619176000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":17,"title":["Cell type and region-specific transcriptional changes in the endometrium of women with RIF identify potential treatment targets"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3633-1592","authenticated-orcid":false,"given":"Nicola","family":"Tempest","sequence":"first","affiliation":[{"name":"Department of Women\u2019s and Children\u2019s Health, Centre for Women\u2019s Health Research, Institute of Life Course and Medical Sciences, University of Liverpool, Member of Liverpool Health Partners","place":["Liverpool, United Kingdom"]},{"name":"Liverpool Women\u2019s National Health Service Foundation Trust, Member of Liverpool Health Partners","place":["Liverpool, United Kingdom"]},{"name":"Hewitt Centre for Reproductive Medicine, Liverpool Women\u2019s National Health Service Foundation Trust","place":["Liverpool, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie","family":"Soul","sequence":"additional","affiliation":[{"name":"Institute of Systems, Molecular and Integrative Biology, University of Liverpool","place":["Liverpool, United Kingdom"]},{"name":"Computational Biology Facility, Liverpool Shared Research Facilities, University of Liverpool","place":["Liverpool, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Hill","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s and Children\u2019s Health, Centre for Women\u2019s Health Research, Institute of Life Course and Medical Sciences, University of Liverpool, Member of Liverpool Health Partners","place":["Liverpool, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7737-5941","authenticated-orcid":false,"given":"Eva","family":"Caama\u00f1o Gutierrez","sequence":"additional","affiliation":[{"name":"Institute of Systems, Molecular and Integrative Biology, University of Liverpool","place":["Liverpool, United Kingdom"]},{"name":"Computational Biology Facility, Liverpool Shared Research Facilities, University of Liverpool","place":["Liverpool, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0270-0150","authenticated-orcid":false,"given":"Dharani K.","family":"Hapangama","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s and Children\u2019s Health, Centre for Women\u2019s Health Research, Institute of Life Course and Medical Sciences, University of Liverpool, Member of Liverpool Health Partners","place":["Liverpool, United Kingdom"]},{"name":"Liverpool Women\u2019s National Health Service Foundation Trust, Member of Liverpool Health Partners","place":["Liverpool, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,3,10]]},"reference":[{"key":"e_1_3_4_1_2","unstructured":"HFEA Fertility Treatment 2021: Preliminary Trends and Figures (2023). https:\/\/www.hfea.gov.uk\/about-us\/publications\/research-and-data\/fertility-treatment-2021-preliminary-trends-and-figures\/. 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