Modeling human embryo implantation in vitro

Matteo A Molè¹, Sarah Elderkin², Irene Zorzan², Christopher Penfold³, Nicole Horsley⁴, Alexandra Pokhilko⁵, Max Polanek⁶, Andrea Palomar⁷, Molika Sinha⁸, Yang Wang², Alicia Quiñonero⁹, Charalampos Androulidakis¹⁰, Richard Acton², Kathryn Balmanno¹¹, Anneliese Jarman¹², Jhanavi Srinivasan², Adam Bendall², Sara Morales-Álvarez⁹, Roberto Yagüe-Serrano⁹, Katie Heywood¹³, Stephen Harbottle¹³, Mina Vasilic¹⁴, Suzanne Cawood¹⁴, Srividya Seshadri¹⁴, Paul Serhal¹⁴, Lauren Weavers¹⁵, Ippokratis Sarris¹⁵, Anastasia Mania¹⁵, Rachel Gibbons¹⁵, Lucy Laurier¹⁵, Immaculada Sánchez-Ribas¹⁶, Amparo Mercader¹⁷, Pilar Alamá¹⁷, Anthony Hoa Bui¹⁸, Graham J Burton¹⁹, Tereza Cindrova-Davies¹⁹, Ridma C Fernando²⁰, Afshan McCarthy²¹, Lusine Aghajanova¹⁸, Liesl Nel-Themaat¹⁸, Ruth B Lathi¹⁸, Simon J Cook¹¹, Kathy K Niakan²², Alexander R Dunn²³, Francisco Domínguez²⁴, Peter J Rugg-Gunn²⁵

Affiliations

¹ Epigenetics Programme, Babraham Institute, Cambridge, UK; Division of Reproductive, Stem Cell and Perinatal Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA; Dunlevie Maternal Fetal Medicine Center for Discovery, Innovation and Impact, Stanford University School of Medicine, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA. Electronic address: mmole@stanford.edu.
² Epigenetics Programme, Babraham Institute, Cambridge, UK.
³ Epigenetics Programme, Babraham Institute, Cambridge, UK; Loke Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK; Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
⁴ Division of Reproductive, Stem Cell and Perinatal Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA.
⁵ Epigenetics Programme, Babraham Institute, Cambridge, UK; Bioinformatics Group, Babraham Institute, Cambridge, UK.
⁶ Division of Reproductive, Stem Cell and Perinatal Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA; Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
⁷ Epigenetics Programme, Babraham Institute, Cambridge, UK; Instituto de Investigación Sanitaria La Fe, Valencia, Spain; IVIRMA Global Research Alliance, IVI Foundation, Valencia, Spain.
⁸ Division of Reproductive, Stem Cell and Perinatal Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA.
⁹ Instituto de Investigación Sanitaria La Fe, Valencia, Spain; IVIRMA Global Research Alliance, IVI Foundation, Valencia, Spain.
¹⁰ Department of Chemical Engineering, Stanford University, Stanford, CA, USA; Prometheus Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium; Skeletal Biology and Engineering Research, KU Leuven, Leuven, Belgium.
¹¹ Signalling Programme, Babraham Institute, Cambridge, UK.
¹² Babraham Institute Imaging Facility, Cambridge, UK.
¹³ Cambridge IVF, Cambridge, UK.
¹⁴ Centre for Reproductive and Genetic Health, London, UK.
¹⁵ King's Fertility, The Fetal Medicine Research Institute, London, UK.
¹⁶ IVIRMA Global Research Alliance, IVI Foundation, Valencia, Spain; IVIRMA Global Research Alliance, IVIRMA, Barcelona, Spain.
¹⁷ IVIRMA Global Research Alliance, IVI Foundation, Valencia, Spain; IVIRMA Global Research Alliance, IVIRMA, Valencia, Spain.
¹⁸ Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA.
¹⁹ Loke Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
²⁰ Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
²¹ Human Embryo and Stem Cell Laboratory, Francis Crick Institute, London, UK.
²² Epigenetics Programme, Babraham Institute, Cambridge, UK; Loke Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK; Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK; Human Embryo and Stem Cell Laboratory, Francis Crick Institute, London, UK.
²³ Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
²⁴ Division of Reproductive, Stem Cell and Perinatal Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA; Instituto de Investigación Sanitaria La Fe, Valencia, Spain; IVIRMA Global Research Alliance, IVI Foundation, Valencia, Spain. Electronic address: francisco.dominguez@ivirma.com.
²⁵ Epigenetics Programme, Babraham Institute, Cambridge, UK; Loke Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK; Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Electronic address: peter.rugg-gunn@babraham.ac.uk.

PMID: 41443191
DOI: 10.1016/j.cell.2025.10.027

Free article

Modeling human embryo implantation in vitro

Matteo A Molè et al. Cell. 2026.

Free article

. 2026 Jan 8;189(1):87-105.e28.

doi: 10.1016/j.cell.2025.10.027. Epub 2025 Dec 23.

Authors

Affiliations

¹ Epigenetics Programme, Babraham Institute, Cambridge, UK; Division of Reproductive, Stem Cell and Perinatal Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA; Dunlevie Maternal Fetal Medicine Center for Discovery, Innovation and Impact, Stanford University School of Medicine, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA. Electronic address: mmole@stanford.edu.
² Epigenetics Programme, Babraham Institute, Cambridge, UK.
³ Epigenetics Programme, Babraham Institute, Cambridge, UK; Loke Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK; Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
⁴ Division of Reproductive, Stem Cell and Perinatal Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA.
⁵ Epigenetics Programme, Babraham Institute, Cambridge, UK; Bioinformatics Group, Babraham Institute, Cambridge, UK.
⁶ Division of Reproductive, Stem Cell and Perinatal Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA; Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
⁷ Epigenetics Programme, Babraham Institute, Cambridge, UK; Instituto de Investigación Sanitaria La Fe, Valencia, Spain; IVIRMA Global Research Alliance, IVI Foundation, Valencia, Spain.
⁸ Division of Reproductive, Stem Cell and Perinatal Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA.
⁹ Instituto de Investigación Sanitaria La Fe, Valencia, Spain; IVIRMA Global Research Alliance, IVI Foundation, Valencia, Spain.
¹⁰ Department of Chemical Engineering, Stanford University, Stanford, CA, USA; Prometheus Division of Skeletal Tissue Engineering, KU Leuven, Leuven, Belgium; Skeletal Biology and Engineering Research, KU Leuven, Leuven, Belgium.
¹¹ Signalling Programme, Babraham Institute, Cambridge, UK.
¹² Babraham Institute Imaging Facility, Cambridge, UK.
¹³ Cambridge IVF, Cambridge, UK.
¹⁴ Centre for Reproductive and Genetic Health, London, UK.
¹⁵ King's Fertility, The Fetal Medicine Research Institute, London, UK.
¹⁶ IVIRMA Global Research Alliance, IVI Foundation, Valencia, Spain; IVIRMA Global Research Alliance, IVIRMA, Barcelona, Spain.
¹⁷ IVIRMA Global Research Alliance, IVI Foundation, Valencia, Spain; IVIRMA Global Research Alliance, IVIRMA, Valencia, Spain.
¹⁸ Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA.
¹⁹ Loke Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK.
²⁰ Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland.
²¹ Human Embryo and Stem Cell Laboratory, Francis Crick Institute, London, UK.
²² Epigenetics Programme, Babraham Institute, Cambridge, UK; Loke Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK; Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK; Human Embryo and Stem Cell Laboratory, Francis Crick Institute, London, UK.
²³ Department of Chemical Engineering, Stanford University, Stanford, CA, USA.
²⁴ Division of Reproductive, Stem Cell and Perinatal Biology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA; Instituto de Investigación Sanitaria La Fe, Valencia, Spain; IVIRMA Global Research Alliance, IVI Foundation, Valencia, Spain. Electronic address: francisco.dominguez@ivirma.com.
²⁵ Epigenetics Programme, Babraham Institute, Cambridge, UK; Loke Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK; Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK. Electronic address: peter.rugg-gunn@babraham.ac.uk.

PMID: 41443191
DOI: 10.1016/j.cell.2025.10.027

Abstract

Implantation of a human embryo into the endometrium is a crucial event in gestation, as it marks the initiation of a pregnancy and is prone to high failure rates. We have limited understanding of these stages because of the inaccessibility of implanting embryos and the lack of suitable model systems. Here, we establish an in vitro model that recapitulates the luminal, glandular, and stromal compartments of the superficial layer of receptive human endometrium. Human embryos and blastoids implant into the endometrial model, achieving post-implantation hallmarks including advanced trophoblast structures that underlie early events in placental development. Single-cell RNA sequencing of the embryo-endometrial interface at day 14 uncovers predicted molecular interactions between conceptus and endometrium. Disrupting signaling interactions between extravillous trophoblast and endometrial stromal cells caused defects in trophoblast outgrowth, demonstrating the importance of crosstalk processes to sustain embryogenesis. This platform opens the opportunity to investigate early stages of human embryo implantation.

Keywords: development; embryo; embryogenesis; endometrium; human; implantation; in vitro model; placenta; reproduction; trophoblast.

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Conflict of interest statement

Declaration of interests Babraham Institute filed a patent application describing the endometrial scaffold (WO2024184624A1; PCT/GB2024/050559). M.A.M. and P.J.R.-G. are inventors on this patent.

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Modeling human embryo implantation in vitro

Affiliations

Modeling human embryo implantation in vitro

Authors

Affiliations

Abstract

Conflict of interest statement

MeSH terms

LinkOut - more resources

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