Advancing human health in the decade ahead: pregnancy as a key window for discovery
2020; Elsevier BV; Volume: 223; Issue: 3 Linguagem: Inglês
10.1016/j.ajog.2020.06.031
ISSN1097-6868
AutoresYoel Sadovsky, Sam Mesiano, Graham J. Burton, Michelle Lampl, Jeffrey C. Murray, Rachel M. Freathy, Anita Mahadevan‐Jansen, Ashley Moffett, Nathan D. Price, Paul H. Wise, Derek E. Wildman, Ralph Snyderman, Nigel Paneth, John A. Capra, Marcelo A. Nóbrega, Yaacov Barak, Louis J. Muglia,
Tópico(s)Global Maternal and Child Health
ResumoRecent revolutionary advances at the intersection of medicine, omics, data sciences, computing, epidemiology, and related technologies inspire us to ponder their impact on health. Their potential impact is particularly germane to the biology of pregnancy and perinatal medicine, where limited improvement in health outcomes for women and children has remained a global challenge. We assembled a group of experts to establish a Pregnancy Think Tank to discuss a broad spectrum of major gestational disorders and adverse pregnancy outcomes that affect maternal-infant lifelong health and should serve as targets for leveraging the many recent advances. This report reflects avenues for future effects that hold great potential in 3 major areas: developmental genomics, including the application of methodologies designed to bridge genotypes, physiology, and diseases, addressing vexing questions in early human development; gestational physiology, from immune tolerance to growth and the timing of parturition; and personalized and population medicine, focusing on amalgamating health record data and deep phenotypes to create broad knowledge that can be integrated into healthcare systems and drive discovery to address pregnancy-related disease and promote general health. We propose a series of questions reflecting development, systems biology, diseases, clinical approaches and tools, and population health, and a call for scientific action. Clearly, transdisciplinary science must advance and accelerate to address adverse pregnancy outcomes. Disciplines not traditionally involved in the reproductive sciences, such as computer science, engineering, mathematics, and pharmacology, should be engaged at the study design phase to optimize the information gathered and to identify and further evaluate potentially actionable therapeutic targets. Information sources should include noninvasive personalized sensors and monitors, alongside instructive "liquid biopsies" for noninvasive pregnancy assessment. Future research should also address the diversity of human cohorts in terms of geography, racial and ethnic distributions, and social and health disparities. Modern technologies, for both data-gathering and data-analyzing, make this possible at a scale that was previously unachievable. Finally, the psychosocial and economic environment in which pregnancy takes place must be considered to promote the health and wellness of communities worldwide. Recent revolutionary advances at the intersection of medicine, omics, data sciences, computing, epidemiology, and related technologies inspire us to ponder their impact on health. Their potential impact is particularly germane to the biology of pregnancy and perinatal medicine, where limited improvement in health outcomes for women and children has remained a global challenge. We assembled a group of experts to establish a Pregnancy Think Tank to discuss a broad spectrum of major gestational disorders and adverse pregnancy outcomes that affect maternal-infant lifelong health and should serve as targets for leveraging the many recent advances. This report reflects avenues for future effects that hold great potential in 3 major areas: developmental genomics, including the application of methodologies designed to bridge genotypes, physiology, and diseases, addressing vexing questions in early human development; gestational physiology, from immune tolerance to growth and the timing of parturition; and personalized and population medicine, focusing on amalgamating health record data and deep phenotypes to create broad knowledge that can be integrated into healthcare systems and drive discovery to address pregnancy-related disease and promote general health. We propose a series of questions reflecting development, systems biology, diseases, clinical approaches and tools, and population health, and a call for scientific action. Clearly, transdisciplinary science must advance and accelerate to address adverse pregnancy outcomes. Disciplines not traditionally involved in the reproductive sciences, such as computer science, engineering, mathematics, and pharmacology, should be engaged at the study design phase to optimize the information gathered and to identify and further evaluate potentially actionable therapeutic targets. Information sources should include noninvasive personalized sensors and monitors, alongside instructive "liquid biopsies" for noninvasive pregnancy assessment. Future research should also address the diversity of human cohorts in terms of geography, racial and ethnic distributions, and social and health disparities. Modern technologies, for both data-gathering and data-analyzing, make this possible at a scale that was previously unachievable. Finally, the psychosocial and economic environment in which pregnancy takes place must be considered to promote the health and wellness of communities worldwide. Major adverse pregnancy-specific complications—preterm birth, preeclampsia, fetal growth restriction, and stillbirth—remain leading causes of maternal, fetal, and neonatal morbidity and mortality and are associated with increased disease risk across the lifespan.1Lane-Cordova A.D. Khan S.S. Grobman W.A. Greenland P. Shah S.J. Long-term cardiovascular risks associated With adverse pregnancy outcomes: JACC review topic of the week.J Am Coll Cardiol. 2019; 73: 2106-2116Crossref PubMed Scopus (151) Google Scholar Despite growing attention, much greater progress is needed in revealing mechanisms and pathogenic pathways, advancing clinical diagnostic and therapeutic tools, and designing preventive strategies to push the field forward into the 22nd century. Modern technologies such as next-generation sequencing, artificial intelligence, machine learning, electronic medical records, and noninvasive imaging, data capture and biochemistries, and contemporary conceptual approaches now position this field to accelerate efforts in understanding and optimizing pregnancy, reaping the associated benefits for lifelong health.Glossary of termsAltricial: born in an immature state requiring prolonged careArtificial intelligence: the computation ability to process data, to learn from data analysis, and to apply and adapt to that learning to attain goalsEpigenetic: external modifications to DNA or RNA that lead to changes in gene expression without change to the nucleic acid sequence itselfGenome-wide association study (GWAS): a method commonly used in genetics to identify associations between common genetic variations occurring in populations with specific disease or traitsGenomics: the study of the structure, function, and evolution of genomesGene-regulatory elements: genome components that modulate transcriptional and posttranscriptional activity of genes. Examples include promoters and enhancers that are cis-acting DNA sequences, most often in noncoding regions of DNA that regulate transcription.Hemotrophic: the transfer of blood-borne materials between the maternal and fetal circulations for nutrition of the fetusHistotrophic: the use of extracellular material derived from the endometrium and the uterine glands that accumulates in the space between the maternal and fetal tissues for nutritionMachine learning: the use of computational algorithms and statistical models that perform analyses without specific instructionsMechanisms: the fundamental processes responsible for a specified action, phenotype, trait, or other natural phenomenonMetabolome: the composition of the entire set of metabolites present within an organism or one of its compartmentsMicrobiome: microorganisms and their genes that populate a specific environmentOrganoid: three-dimensional tissue constructs that are derived from stem cells in vitro that mimic the corresponding in vivo organPersonalized medicine: healthcare individualized by a person's unique genetic, environmental, and social characteristicsPhenome: the set of all phenotypes expressed by a biological compartment such as a cell, tissue, organ, or organismPopulation medicine: clinical contributors to health that includes the important function of nonmedical stakeholders (education, social, business) to have a wider influencePrecocial: born in an advanced state capable of early survival with little supportProteome: the composition of the entire set of proteins present within an organism or one of its compartmentsTranscription factor: proteins that activate or repress genes by binding to DNATranscriptome: the composition of the entire set of RNA transcripts present within an organism or one of its compartmentsViviparous: giving rise to live birth from inside the body of the parent Altricial: born in an immature state requiring prolonged care Artificial intelligence: the computation ability to process data, to learn from data analysis, and to apply and adapt to that learning to attain goals Epigenetic: external modifications to DNA or RNA that lead to changes in gene expression without change to the nucleic acid sequence itself Genome-wide association study (GWAS): a method commonly used in genetics to identify associations between common genetic variations occurring in populations with specific disease or traits Genomics: the study of the structure, function, and evolution of genomes Gene-regulatory elements: genome components that modulate transcriptional and posttranscriptional activity of genes. Examples include promoters and enhancers that are cis-acting DNA sequences, most often in noncoding regions of DNA that regulate transcription. Hemotrophic: the transfer of blood-borne materials between the maternal and fetal circulations for nutrition of the fetus Histotrophic: the use of extracellular material derived from the endometrium and the uterine glands that accumulates in the space between the maternal and fetal tissues for nutrition Machine learning: the use of computational algorithms and statistical models that perform analyses without specific instructions Mechanisms: the fundamental processes responsible for a specified action, phenotype, trait, or other natural phenomenon Metabolome: the composition of the entire set of metabolites present within an organism or one of its compartments Microbiome: microorganisms and their genes that populate a specific environment Organoid: three-dimensional tissue constructs that are derived from stem cells in vitro that mimic the corresponding in vivo organ Personalized medicine: healthcare individualized by a person's unique genetic, environmental, and social characteristics Phenome: the set of all phenotypes expressed by a biological compartment such as a cell, tissue, organ, or organism Population medicine: clinical contributors to health that includes the important function of nonmedical stakeholders (education, social, business) to have a wider influence Precocial: born in an advanced state capable of early survival with little support Proteome: the composition of the entire set of proteins present within an organism or one of its compartments Transcription factor: proteins that activate or repress genes by binding to DNA Transcriptome: the composition of the entire set of RNA transcripts present within an organism or one of its compartments Viviparous: giving rise to live birth from inside the body of the parent To better explore and propose potential avenues to capitalize on new concepts and technologies, the Burroughs Wellcome Fund (BWF) supported a Pregnancy Think Tank meeting on November 19 to 20, 2019, in Research Triangle Park, North Carolina (See Box for description of BWF). BoxAbout the Burroughs Wellcome FundThe Burroughs Wellcome Fund (BWF) was established in the United States in 1955 on the legacy of Silas Burroughs and Henry Wellcome, two American-born colleagues who founded the Burroughs Wellcome Co. in London in the 1880s. The pharmaceutical company flourished through the 20th Century establishing entities around the globe.The Fund was the philanthropic arm of the North American branch of the pharmaceutical company. By the time of its creation, the corporation was run by the Wellcome Trust, a nonprofit entity created by the corporate shares of the global companies. In 1993, the Burroughs Wellcome Fund was the beneficiary of a $400 million gift from the Wellcome Trust. This endowment allowed BWF to become a completely independent foundation, with no direct ties to its founding company.The Reproductive Sciences have been a long-standing focus of BWF as being a critical yet underfunded, undervalued area of research. BWF history in this domain includes support for American Association of Obstetricians and Gynecologists Foundation (1997-2003), the Reproductive Scientist Development Program (1998 – present with the NIH), Frontiers in Reproduction, Marine Biological Laboratories Summer Course (1998 – present), and the Preterm Birth Research Consortium and the Preterm Birth Initiative (2007 – 2020) to initially support meetings and then fund discovery grants around preterm birth. This Think-Tank was the evolution of these initiatives to determine productive paths for the future discovery.BWF remains an independent private foundation whose mission is to advance the medical sciences by supporting research and other scientific and educational activities. BWF focus is on early stage biomedical scientists, particularly physician scientists, along with areas of investigation that are undervalued or underfunded by other organizations.George Hitchings, Ph.D., a Nobel laureate who spent most of his career with Burroughs Wellcome Co., served as BWF's president from 1974 until 1990, and his vision promoted the Fund's belief in the critical link of basic research and clinical applications in medicine. BWF is governed by a Board of Directors consisting of accomplished scientists and administrators, with many distinguished advisory committee members for its competitive award programs. These include HHMI Investigators, National Academies Members, and Nobel Laureates.For more information on the history of the Burroughs Wellcome Fund please see: https://www.bwfund.org/history. Open table in a new tab The Think Tank meeting centered on generating novel ideas and stimulating new research opportunities for bolstering knowledge in the area of pregnancy and mechanisms underlying pregnancy complications. We were motivated by the joint biennial meetings that were convened by the BWF and the March of Dimes, starting in 2008 under the title "Preventing Prematurity: Establishing a Network for Innovation and Discovery,"2Muglia L.J. Katz M. The enigma of spontaneous preterm birth.N Engl J Med. 2010; 362: 529-535Crossref PubMed Scopus (544) Google Scholar and by recent initiatives such as the Magee-Womens Research Institute Summit. Considering the effect of those meetings on recent advances in basic, translational, clinical, and epidemiologic research and the advances that have emerged overall, the outlook for the field has expanded beyond the vision of BWF's earlier Preterm Birth focus to include broader gestational conditions and their effect on lifelong maternal and infant health. BoxAbout the Burroughs Wellcome FundThe Burroughs Wellcome Fund (BWF) was established in the United States in 1955 on the legacy of Silas Burroughs and Henry Wellcome, two American-born colleagues who founded the Burroughs Wellcome Co. in London in the 1880s. The pharmaceutical company flourished through the 20th Century establishing entities around the globe.The Fund was the philanthropic arm of the North American branch of the pharmaceutical company. By the time of its creation, the corporation was run by the Wellcome Trust, a nonprofit entity created by the corporate shares of the global companies. In 1993, the Burroughs Wellcome Fund was the beneficiary of a $400 million gift from the Wellcome Trust. This endowment allowed BWF to become a completely independent foundation, with no direct ties to its founding company.The Reproductive Sciences have been a long-standing focus of BWF as being a critical yet underfunded, undervalued area of research. BWF history in this domain includes support for American Association of Obstetricians and Gynecologists Foundation (1997-2003), the Reproductive Scientist Development Program (1998 – present with the NIH), Frontiers in Reproduction, Marine Biological Laboratories Summer Course (1998 – present), and the Preterm Birth Research Consortium and the Preterm Birth Initiative (2007 – 2020) to initially support meetings and then fund discovery grants around preterm birth. This Think-Tank was the evolution of these initiatives to determine productive paths for the future discovery.BWF remains an independent private foundation whose mission is to advance the medical sciences by supporting research and other scientific and educational activities. BWF focus is on early stage biomedical scientists, particularly physician scientists, along with areas of investigation that are undervalued or underfunded by other organizations.George Hitchings, Ph.D., a Nobel laureate who spent most of his career with Burroughs Wellcome Co., served as BWF's president from 1974 until 1990, and his vision promoted the Fund's belief in the critical link of basic research and clinical applications in medicine. BWF is governed by a Board of Directors consisting of accomplished scientists and administrators, with many distinguished advisory committee members for its competitive award programs. These include HHMI Investigators, National Academies Members, and Nobel Laureates.For more information on the history of the Burroughs Wellcome Fund please see: https://www.bwfund.org/history. Open table in a new tab Our event aimed to assess how convening experts from divergent biomedical disciplines, with many scientists from outside the field of pregnancy research, might foster productive and convergent thinking and generate novel ideas to stimulate innovative research projects. Together, 30 participants from the United States, Canada, and United Kingdom encompassed biological disciplines (Table 1). Our event was also designed to reshape the BWF strategy to accelerate discovery, encouraging proposals that incorporate new tools, analytic approaches, and scientific disciplines. This summary encapsulates the ideas and discussions organized by broad categories that span the contributions by experts in the fields (Table 1) and illuminate advances in ideas, technology, and talent to have the greatest potential: developmental genomics, physiology, and personalized and population medicine. We generated suggested questions and a call for scientific action, delineating next-generation challenges and opportunities in the science underlying pregnancy and human early development.Table 1Disciplines representedAnatomyImmunologyBioengineeringMachine learning and artificial intelligenceChronobiologyMicrobiome and microbiologyDevelopmental biologyObstetricsDrug and device developmentPathologyEndocrinologyPediatricsEpidemiologyPersonalized medicineEvolutionary biologyPharmacologyGenomicsPopulation geneticsGlobal healthSystems biologyHealth policyVascular biologyImaging sciencesSadovsky. Pregnancy as a key window for discovery. Am J Obstet Gynecol 2020. Open table in a new tab Sadovsky. Pregnancy as a key window for discovery. Am J Obstet Gynecol 2020. The field of developmental genomics applies state-of-the-art methodologies that strive to assist in bridging genotypes, physiology, and disease specifically to developmental processes from embryogenesis to parturition biology. From identification of genetic variants through sequencing or genome-wide association studies (GWAS) to defining nucleotide changes and investigating their downstream proteomic, metabolomic, and physiological consequences that may play an etiologic role in phenotypic consequences during pregnancy, numerous interrelated steps are logically aligned to chart the molecular maps underlying diseases3Zhang G. Srivastava A. Bacelis J. Juodakis J. Jacobsson B. Muglia L.J. Genetic studies of gestational duration and preterm birth.Best Pract Res Clin Obstet Gynaecol. 2018; 52: 33-47Crossref PubMed Scopus (36) Google Scholar (Figure 1). Pregnancy phenotypes are shaped by the maternal, fetal, and placental genomes and epigenomes, and therefore, the genomic studies of these phenotypes would benefit from an integrative approach in mother-infant pairs. Furthermore, these maps are not two-dimensional, but include regulatory elements that form three-dimensional DNA loop configurations to influence more than 1 proximal or distal gene.4Sakabe N.J. Nobrega M.A. Beyond the ENCODE project: using genomics and epigenomics strategies to study enhancer evolution.Philos Trans R Soc Lond B Biol Sci. 2013; 368: 20130022Crossref PubMed Scopus (13) Google Scholar Notably, gene-regulatory elements comprise modular arrays of binding sites for transcription factors whose expression is context and time specific, changing across interacting maternal-fetal tissues and during gestational ages. These are further modified by environment-, diet-, or disease-induced epigenetic changes whose characterization and transmission are increasingly well understood.5Agarwal P. Morriseau T.S. Kereliuk S.M. Doucette C.A. Wicklow B.A. Dolinsky V.W. Maternal obesity, diabetes during pregnancy and epigenetic mechanisms that influence the developmental origins of cardiometabolic disease in the offspring.Crit Rev Clin Lab Sci. 2018; 55: 71-101Crossref PubMed Scopus (130) Google Scholar,6Yeung H.Y. Dendrou C.A. Pregnancy immunogenetics and genomics: implications for pregnancy-related complications and autoimmune disease.Annu Rev Genomics Hum Genet. 2019; 20: 73-97Crossref PubMed Scopus (13) Google Scholar Generalizing these genomic processes across populations and ethnic groups can be accomplished with large databases and biospecimen banks with machine learning tools to probe them, guided, wherever possible, by biological reasoning and hypothesis formulation. To date, for most DNA sequence variants identified, relatively little mechanistic and actionable data have emerged. As associations now exist for preterm birth and birthweight, these should drive functional studies to translate the findings to improvements in clinical care.3Zhang G. Srivastava A. Bacelis J. Juodakis J. Jacobsson B. Muglia L.J. Genetic studies of gestational duration and preterm birth.Best Pract Res Clin Obstet Gynaecol. 2018; 52: 33-47Crossref PubMed Scopus (36) Google Scholar,7Yaghootkar H. Freathy R.M. Genetic origins of low birth weight.Curr Opin Clin Nutr Metab Care. 2012; 15: 258-264Crossref PubMed Scopus (32) Google Scholar These functional studies should first indicate conclusive evidence for the actual genes responsible for the association because the nearest gene is not always the one relevant for the phenotype being investigated.8Claussnitzer M. Dankel S.N. Kim K.H. et al.FTO obesity variant circuitry and adipocyte browning in humans.N Engl J Med. 2015; 373: 895-907Crossref PubMed Scopus (916) Google Scholar Subsequent investigations to determine the mechanism of action of the causal polymorphism can be performed in vitro, in cell lines, and now in vivo using gene-editing technologies. These approaches determine when and how during pregnancy the variants modulate pregnancy outcomes. By viewing the genesis of pregnancy through an evolutionary biology lens, significant insights have been gained, for example, into the signals required to maintain the long gestations that many mammals display. One recent elegant study by Griffith9Griffith O.W. Chavan A.R. Protopapas S. Maziarz J. Romero R. Wagner G.P. Embryo implantation evolved from an ancestral inflammatory attachment reaction.Proc Natl Acad Sci U S A. 2017; 114: E6566-E6575Crossref PubMed Scopus (154) Google Scholar and colleagues found that by studying marsupial pregnancy the implantation reaction of eutherians (formerly "placentals") derives from the attachment reaction in ancestral therian mammals (encompasses both eutherians and marsupials). In marsupials such as the opossum, this event leads to prompt parturition. The ability to shift from the inflammatory attachment reaction to a prolonged noninflammatory period in gestation is a central innovation in eutherian mammals that allowed an extended period of intimate placentation. Although inferences based on evolutionary biology are powerful in mapping regulatory elements and traits at the organism-level, the rapid evolutionary changes in relevant organs, such as the placenta,10Zhang J. Simonti C.N. Capra J.A. Genome-wide maps of distal gene regulatory enhancers active in the human placenta.PLoS One. 2018; 13e0209611Crossref Scopus (8) Google Scholar may benefit from system-specific and well-thought-out machine learning approaches to link genomes to phenomes. Although the genomic roots of maternal-fetal tolerance and exchange are ancient, dating back to reptiles, fish, and velvet worms, at term only a small fraction of genes represent the core placental transcriptome that is conserved across mammalian or marsupial species.11Gundling Jr., W.E. Wildman D.E. A review of inter- and intraspecific variation in the eutherian placenta.Philos Trans R Soc Lond B Biol Sci. 2015; 370: 20140072Crossref PubMed Scopus (41) Google Scholar Moreover, eutherian and marsupial mammals have evolved imprinting (a way of generating monoallelic expression) as an additional mechanism to tune gene expression in a manner informed by parent of origin. It is possible that pharmacologically induced diseases in model organisms, such as the stimulation of preterm birth in mice, might not be as revealing as naturally arising variations in the timing of birth. In this instance, a mouse strain that evolved to spontaneously deliver its pups 3 days early might be more informative. This approach has been utilized in genetically inbred mouse strains to determine genetic contributors to gestational duration and also the coordination of gestational duration with rates of organ maturation.12Besnard V. Wert S.E. Ikegami M. et al.Maternal synchronization of gestational length and lung maturation.PLoS One. 2011; 6e26682Crossref Scopus (11) Google Scholar,13Murray S.A. Morgan J.L. Kane C. et al.Mouse gestation length is genetically determined.PLoS One. 2010; 5e12418Crossref Scopus (108) Google Scholar Importantly, the divergent strategies between species to optimize reproductive outcomes may in themselves prove informative for greater mechanistic insights into healthy and complicated pregnancies. These challenges are further amplified by the general paucity in knowledge of maternal-fetal biology. Better tools such as next-generation sequencing, single-cell omics, and high-resolution imaging could bridge the divide between commonly used mouse and other gestational models and human pregnancy. The advent of single-cell sequencing of human placental cells, other cells at the maternal-fetal interface, and cells in the placenta of other model organisms may shed light on shared processes that might otherwise seem disparate. For example, single-cell transcriptomics from first-trimester placentas, maternal blood, and decidual cells identified regulatory interactions that are critical for immune adaptation and for placentation and diseases during pregnancy.14Vento-Tormo R. Efremova M. Botting R.A. et al.Single-cell reconstruction of the early maternal-fetal interface in humans.Nature. 2018; 563: 347-353Crossref PubMed Scopus (1239) Google Scholar It is now clear that the origins of many healthy developmental processes or diseases begin in the preconception period and in early pregnancy. For example, abnormal placental function may be rooted in defects of the trophoblastic shell, which encases the embryo within the maternal milieu.15Burton G.J. Cindrova-Davies T. Turco M.Y. Review: histotrophic nutrition and the placental-endometrial dialogue during human early pregnancy.Placenta. 2020; Crossref PubMed Scopus (45) Google Scholar Research into cellular and organismal physiology has dramatically advanced in the past decade. GWAS and next-generation sequencing studies, single-cell omics, organoids, functional biochemical imaging, and other new technologies usher in ways to interrogate gestational physiology and major obstetrical syndromes.14Vento-Tormo R. Efremova M. Botting R.A. et al.Single-cell reconstruction of the early maternal-fetal interface in humans.Nature. 2018; 563: 347-353Crossref PubMed Scopus (1239) Google Scholar,16Turco M.Y. Gardner L. Kay R.G. et al.Trophoblast organoids as a model for maternal-fetal interactions during human placentation.Nature. 2018; 564: 263-267Crossref PubMed Scopus (389) Google Scholar, 17Brosens I.A. Robertson W.B. Dixon H.G. The role of the spiral arteries in the pathogenesis of pre-eclampsia.J Pathol. 1970; 101 (Pvi)PubMed Google Scholar, 18Fisher S.J. Why is placentation abnormal in preeclampsia?.Am J Obstet Gynecol. 2015; 213: S115-S122Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar, 19Zhang G. Feenstra B. Bacelis J. et al.Genetic associations with gestational duration and spontaneous preterm birth.N Engl J Med. 2017; 377: 1156-1167Crossref PubMed Scopus (245) Google Scholar During the critical phase of organogenesis across the first 8 to 10 weeks of human gestation, the endometrial glands supply secretions (commonly termed "uterine milk") that support the developing embryo and are involved in placental development during the first trimester of pregnancy and spiral artery remodeling. A recently introduced hormone-responsive endometrial organoid model may shed light on this early histotrophic support to the embryo.20Turco M.Y. Gardner L. Hughes J. et al.Long-term, hormone-responsive organoid cultures of human endometrium in a chemically defined med
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