The scientific interests of the maternal-embryonic cross-talk group focus on understanding the existing mechanisms of communication between the mother and the embryo and elucidating how the mother genetically modifies the preimplantation embryo. The group’s research was the first to demonstrate the transmission of genetic information from the mother to the preimplantation embryo, demonstrating that the mother can modify the embryo at the transcriptional and/or epigenetic level regardless of the genetic background (PMID: 26395145). They also studied the effect of microRNAs secreted by endometrial cells on the embryo (PMID: 31665361, 29390102) and used endometrial biopsies to enable the discovery of a transcriptomic signature of human endometrial receptivity.
Maternal fetal crosstalk group’s scientific interests focus on understanding the communication mechanisms between the mother and the embryo and elucidating how the mother genetically modifies the preimplantation embryo. Their research was the first to demonstrate the transmission of genetic information from the mother to the preimplantation embryo, showing that the mother can modify the embryo transcriptomically and/or epigenetically regardless of genetic background (PMID: 26395145). They also studied the effect of microRNAs secreted by endometrial cells on the embryo (PMID: 31665361, 29390102) and used endometrial biopsies to enable the discovery of a transcriptomic signature of human endometrial receptivity.
In the 1990s, Professor David J. Barker identified a link between fetal/infant growth with cardiovascular diseases and modified adult disease models by including environmental programming during fetal/infant life. Intercellular communication is essential to allow multicellular and unicellular organisms to interact with their environment and for hosts to communicate with other cells. We investigated how the mother communicates with the preimplantation embryo before implantation and discovered that the maternal endometrium modifies the transcriptomics of the embryo under healthy and pathological conditions.
Our laboratory demonstrated that endometrial cells secrete particular molecules and extracellular vesicles into the endometrial fluid and that the embryo can capture these secreted factors before implantation to initiate pregnancy. We focus on further understanding this crucial dialogue between the embryo and the mother as the basis of creating a new preconception care concept.
Progenitor cells of endometrial regeneration
Endometrial tissue undergoes complete remodeling throughout each menstrual cycle, which involves reconstructing several differentiated tissue types: vascular tissue, stromal tissue, and the luminal and glandular epithelium. In the human endometrium, the stem cell niche has been identified in the basal layer, specifically in the endothelium of the spiral arterioles. Our group demonstrated the presence of immature cells; however, the coexistence of immature populations, the common origin of several lineages, cannot be ruled out.
Our research group analyzes gene expression in different menstrual cycle phases to identify progenitor cells responsible for endometrial regeneration throughout the distinct cell layers. We have identified candidate populations that could harbor cells that can regenerate the endometrial epithelium and stroma; we are currently validating their stem cell capacity using advanced three-dimensional cell culture models.
Study of endometrial receptivity
Endometrial receptivity is a postovulatory process of endometrial remodeling to prepare for pregnancy, including all the morphological and molecular modifications known as plasma membrane transformation. Menstruation is a resetting process that occurs across the reproductive lifespan – from menarche to menopause – to prepare the uterine cavity for synchrony of the blastocyst’s arrival during the endometrial receptivity window of implantation (WOI). This allows the blastocyst to adhere and triggers the completion of decidualization of stromal compartments that control trophoblast invasion and subsequent placentation.
Prior research in our laboratory enabled the discovery of a transcriptomic signature of human endometrial receptivity. This finding has been clinically validated in more than 20 scientific peer-reviewed articles in cases of repeated implantation failure. We now focus on deep endometrial characterization using single-cell analysis to provide unprecedented insights into the transcriptomic, genomic, and spatial alterations in this critical female organ throughout the menstrual cycle and across the patient’s lifespan.
Felipe Vilella, a Ph.D. in molecular biology, is the consolidated group leader of the Maternal Fetal Crosstalk Laboratory at INCLIVA/Carlos Simon Foundation. He performed two post-doctoral positions, one in the Clinical Science Centre of the MRC in London (UK) and the other in the Centro de Investigaciones Principe Felipe in Valencia (Spain). He was a visiting researcher for five years at Stanford University (USA) and two years at Harvard University (USA).
His main scientific interest focuses on understanding the communication mechanisms occurring between the mother and the embryo and elucidating how the mother can genetically modify the preimplantation embryo.
His research was the first to demonstrate the transmission of genetic information from the mother to the preimplantation embryo, demonstrating that the mother can modify the embryo transcriptomically and/or epigenetically, regardless of its genetic background (PMID: 26395145). He studied the effect of microRNAs and mitochondrial DNA secreted by endometrial cells on the embryo (PMID: 31665361; PMID: 29390102). He also focuses on understanding the implantation process, elucidating how endometrial cells communicate with each other at the single-cell level (PMID: 32929266).
He has published 44 papers in peer-reviewed journals with an accumulated impact factor of 399.35. His papers have been cited 2,267 times with an average of 56.68 citations/paper. He has an H-Index of 24, has published 12 book chapters, and has directed 6 Ph.D. theses. He has participated in over 16 international projects, being an independent principal investigator in 11. He has participated as an invited speaker at over 80 international conferences.
- Endometrial Liquid Biopsy Provides a miRNA Roadmap of the Secretory Phase of the Human Endometrium. Grasso A, Navarro R, Balaguer N, Moreno I, Alama P, Jimenez J, Simón C, Vilella F. J Clin Endocrinol Metab. 2020 Mar 1;105(3):dgz146. https://doi.org/10.1210/clinem/dgz146.
- MicroRNA-30d deficiency during preconception affects endometrial receptivity by decreasing implantation rates and impairing fetal growth. Balaguer N, Moreno I, Herrero M, Gonzalez-Monfort M, Vilella F, Simon C. Am J Obstet Gynecol. 2019 Jul;221(1):46.e1-46.e16. https://doi.org/10.1016/j.ajog.2019.02.047
- The role of extracellular vesicles in intercellular communication in human reproduction. Gonzalez-Fernandez J, Moncayo-Arlandi J, Ochando A, Simon C, Vilella F. The role of extracellular vesicles in intercellular communication in human reproduction. Clin Sci (Lond). 2023 Feb 14;137(3):281-301. https://doi.org/10.1042/CS20220793.
- Extracellular vesicles in human reproduction in health and disease. Simon C, Greening DW, Bolumar D, Balaguer N, Salamonsen LA, Vilella F. Endocr Rev 2018; 1;39(3):292-332. https://doi.org/10.1210/er.2017-00229
- Hsa-miR-30d, secreted by the human endometrium, is taken up by the pre-implantation embryo and might modify its transcriptome. Vilella F, Moreno-Moya JM, Balaguer N, Grasso A, Herrero M, Martinez S, Marcilla A, Simon C. Development 2015 15; 142(18):3210-21. https://doi.org/10.1242/dev.124289
Progenitor cells of endometrial regeneration
- Leucine-rich repeat-containing G-protein-coupled receptor 5-positive cells in the endometrial stem cell niche. Cervello I, Gil-Sanchis C, Santamaria X, Faus A, Vallve-Juanico J, Diaz-Gimeno P, Genolet O, Pellicer A, Simon C. FERTIL STERIL. 2017 Feb;107(2):510-519. https://doi.org/10.1016/j.fertnstert.2016.10.021
- Bone marrow-derived cells from male donors do not contribute to the endometrial side population of the recipient. Cervello I, Gil-Sanchis C, Mas A, Faus A, Sanz J, Moscardo F, Higueras G, Sanz MA, Pellicer A, Simon C. PLoS One. 2012;7(1):e30260. https://doi.org/10.1371/journal.pone.0030260
- Reconstruction of endometrium from human endometrial side population cell lines. Cervello I, Mas A, Gil-Sanchis C, Peris L, Faus A, Saunders PT, Critchley HO, Simon C. PLoS One. 2011;6(6):e21221. https://doi.org/10.1371/journal.pone.0021221
- Human endometrial side population cells exhibit genotypic, phenotypic and functional features of somatic stem cells. Cervello I, Gil-Sanchis C, Mas A, Delgado-Rosas F, Martinez-Conejero JA, Galan A, Martinez-Romero A, Martinez S, Navarro I, Ferro J, Horcajadas JA, Esteban FJ, O’Connor JE, Pellicer A, Simon C. PLoS One. 2010 Jun 24;5(6):e10964. https://doi.org/10.1371/journal.pone.0010964
Study of endometrial receptivity
- A 5-year multicentre randomized controlled trial comparing personalized, frozen and fresh blastocyst transfer in IVF. Simon C, Gomez C, Cabanillas S, Vladimirov I, Castillon G, Giles J, Boynukalin K, Findikli N, Bahçeci M, Ortega I, Vidal C, Funabiki M, Izquierdo A, Lopez L, Portela S, Frantz N, Kulmann M, Taguchi S, Labarta E, Colucci F, Mackens S, Santamaria X, Muñoz E, Barrera S, Garcia-Velasco JA, Fernandez M, Ferrando M, Ruiz M, Mol BW, Valbuena D. ERA-RCT Study Consortium Group. Reprod Biomed Online. 2020 Sep;41(3):402-415. https://doi.org/10.1016/j.rbmo.2020.06.002. Epub 2020 Jun 15.
- Meta-signature of human endometrial receptivity: a meta-analysis and validation study of transcriptomic biomarkers. Altmäe S, Koel M, Võsa U, Adler P, Suhorutšenko M, Laisk-Podar T, Kukushkina V, Saare M, Velthut-Meikas A, Krjutškov K, Aghajanova L, Lalitkumar PG, Gemzell-Danielsson K, Giudice L, Simon C, Salumets A. Sci Rep. 2017 Aug 30;7(1):10077. https://doi.org/10.1038/s41598-017-10098-3. PMID: 28855728; PMCID: PMC5577343.
- The endometrial receptivity array for diagnosis and personalized embryo transfer as a treatment for patients with repeated implantation failure. Ruiz-Alonso M, Blesa D, Diaz-Gimeno P, Gomez E, Fernandez-Sanchez M, Carranza F, Carrera J, Vilella F, Pellicer A, Simon C. FERTIL STERIL. 2013 Sep;100(3):818-24. https://doi.org/10.1016/j.fertnstert.2013.05.004. Epub 2013 Jun 4. PMID: 23756099.
- The accuracy and reproducibility of the endometrial receptivity array is superior to histology as a diagnostic method for endometrial receptivity. Diaz-Gimeno P, Ruiz-Alonso M, Blesa D, Bosch N, Martinez-Conejero JA, Alama P, Garrido N, Pellicer A, Simon C. FERTIL STERIL. 2013 Feb;99(2):508-17. https://doi.org/10.1016/j.fertnstert.2012.09.046. Epub 2012 Oct 23. PMID: 23102856.
- A genomic diagnostic tool for human endometrial receptivity based on the transcriptomic signature. Diaz-Gimeno P, Horcajadas JA, Martinez-Conejero JA, Esteban FJ, Alama P, Pellicer A, Simon C. FERTIL STERIL. 2011 Jan;95(1):50-60, 60.e1-15. https://doi.org/10.1016/j.fertnstert.2010.04.063. Epub 2010 Jul 8. PMID: 20619403.