Irene Cervelló Alcaraz, PhD | Carlos Simón MD, PhDPhD Student:
Aymara Mas Perucho | Claudia Gil SanchisLab Technician:
Endometrial Stem Cells
The human endometrium is a highly proliferative tissue suffering several changes during each menstrual cycle and growing from 0.5 to 7-8 mm during all the reproductive life of women (occurring 400 times in total throughout the reproductive life). The aim of these structural, functional and morphological changes is to ensure the proper implantation of the embryo. Due to this high regenerative ability of the endometrium the hypothesis of the presence of somatic stem cells (SSCs) was postulated years ago. The SSCs, as occurs in other organs and tissues, would be responsible for maintaining the appropriate homeostasis and functioning of the endometrium. Along this research work at the Fundación IVI we have achieved to identify, localize, characterize and isolate the stem cell population for the understanding of the endometrial physiology and associated pathologies. The identification of SSCs in this tissue offers a promising therapeutic tool. Throughout the different studies published, they concluded that there are two populations of endometrial stem cells that are actively involved in the regeneration of the endometrium. An endogenous population (SSCs tissue specific) located in an exclusive niche corresponding to the basal layer of the endometrium. And moreover, an endogenous population derived from the bone marrow and with the capacity to migrate under certain stimuli and to repopulate the endometrial tissue. Currently our research is focused on two key aspects: (1) An accurate study based on the identification and verification of specific SSCs markers described in the human endometrium in the last ten years (W5C5, ICAM and Side Population) both with in vitro and in vivo experiments; and (2) to investigate cell therapies using stem cells derived from bone marrow as well as their secreted paracrine factors to regenerate the endometrium in pathologies like Asherman's syndrome and endometrial atrophy.
Tisular Bioengineering to create a Uterus
The bioengineering science is currently one of the most promising fields of the regenerative medicine (RM). The cell therapy (also included in RM) is based uniquely on the use of several types of cells in order to repair damaged tissues and organs, in contrast the bioengineering has been established on the use of scaffolds or supports capable to carry out three-dimensional structures similar to those that they found in living beings. The main objective of this project is to apply the bioengineering advances to the reproductive medicine. To this end, we have proposed and we are starting working on the development of bioengineered uteri (rabbit and pig) based both on decellularized scaffolds and artificial designed supports. Also, we are developing bioreactors to establish appropriate and standards conditions for both decellularization-recellularization and maintenance situations. The maintenance of these organs and tissues is also a key aspect in the development of this research work.
A: Dynamics of the human menstrual cycle showing the locations of SSCs.
B: Decellularization of the left horn of pig uteri using bioengineering techniques.
- Santamaría X, Cabanillas S, Cervelló I, Arbona C, Raga F, Ferro J, Palmero J, Remohí J, Pellicer J, Simón C.
Autologous cell therapy with CD133+ bone marrow-derived stem cells in refractory Asherman’s syndrome and endometrial atrophy: a pilot cohort study. Human Reproduction. 2015 IN PRESS.
- Cervelló I, Gil-Sanchis C, Santamaría X, Cabanillas S, Díaz A, Faus A, Pellicer A, Simón C.
Human CD133 (+) bone marrow-derived stem cells promote endometrial proliferation in a murine model of Asherman syndrome. Fertil Steril. 2015 Sep ,15.
- Cervelló I, Santamaría X, Miyazaki K, Maruyama T, Simón C.
Cell Therapy and Tissue Engineering from and toward the Uterus. Semin Reprod Med. 2015 Sep; 33(5):366-72.
- Gil-Sanchis C, Cervelló I, Khurana S, Faus A, Verfaillie C, Simón C.
Contribution of different bone marrow-derived cell types in endometrial regeneration using an irradiated murine model. Fertil Steril. 2015 Jun; 103(6):1596-605.
- Mas A, Cervelló I, Fernández-Álvarez A, Faus A, Díaz A, Burgués O, Casado M, Simón C.
Overexpression of the truncated form of High Mobility Group A proteins (HMGA2) in human myometrial cells induces leiomyoma-like tissue formation. Mol Hum Reprod. 2015 Apr; 21(4):330-8.
- Mas A, Cervelló I, Gil-Sanchis C, Simón C.
Current understanding of somatic stem cells in leiomyoma formation. Fertil Steril. 2014 Sep;102(3):613-20.
- Belmar-Lopez C, Mendoza G, Oberg D, Burnet J, Simon C, Cervelló I, Iglesias M, Ramirez JC, Lopez-Larrubia P, Quintanilla M, Martin-Duque P.
Tissue-derived mesenchymal stromal cells used as vehicles for anti-tumor therapy exert different in vivo effects on migration capacity and tumor growth. BMC Med. 2013 May.
- Gil-Sanchis C, Cervelló I, Mas A, Faus A, Pellicer A, Simón C.
Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) as a putative human endometrial stem cell marker. Molecular Human Reproduction. 2013 Jul.
- Cervelló I, Mas A, Gil-Sanchis C, Simón C.
Somatic stem cells in the human endometrium. Semin Reprod Med. 2013 Jan;31(1):69-76.
CONTRIBUTIONS TO BOOKS:
- Cervelló I, Medrano JV, Simón C.
Translating Regenerative Medicine to the Clinic.
Volume II in the Translational Medicine Series. Capítulo: Regenerative Medicine and Tissue Engineering in Reproductive Medicine: Future Clinical Applications in Human Infertility. Año y Editorial: 2015- Elsevier, Inc. Biomedical Research.
- Gargett CE, Cervelló I, Nguyen HTP, Simón C.
Stem Cells in Reproductive Medicine. Basic Science and Therapeutic Potential.
Third Edition. Capítulo. Part 4 Chapter 11 Adult stem cells in the human endometrium. Año y Editorial. Simon C. Pellicer A, Reijo Pera R.2013. ISBN 978-1-107-03447-1s.
Tipo de participación: Póster- Human Bone Marrow-Derived Stem Cells improve endometrial regeneration in a murine experimental Asherman´s Syndrome model. SRI, Society for Reproductive Investigation. 62nd Annual Scientific Meeting. San Francisco, USA-Marzo 2015.
Tipo de participación: Ponencia invitada- Bioengineering the Human Uterus. 6th International IVI Congress. Reproductive Medicine and Beyond. Alicante, España-Abril 2015.
Tipo de participación: Ponencia invitada- Regeneración endometrial con células madre. I Foro de debate sobre receptividad endometrial e implantación (Angelini y Ediciones Mayo). Alcalá de Henares, Madrid, España-Octubre 2015.
Tipo de participación: Ponencia invitada- Endometrial reconstruction from stem cells 16th World Congress of Gynecological Endocrinology (ISGE). Florencia, Italia. Marzo 2014.
Tipo de participación: Póster- Gene Expression Profile of the Lgr5 Cell Population in the Human Endometrium. Society for Gynecologic Investigation 61st Annual Scientific Meeting.Florencia, Italy Marzo 2014.
Tipo de participación: Ponencia invitada- Caracterización de las células madre neoplásicas en el cáncer de endometrio. Implicaciones patogénicas, pronosticas y terapéuticas. Día Mundial del Cáncer. “Gent per Gent rindiendo cuentas. Tres años de investigación en oncología. Real Academia de Medicina de la Cominudad Valenciana. Fundación Gent per Gent de la Comunitat Valenciana. Junta Provincial Asociada de la AECC en Valencia. Valencia (España), Febrero 2013.
Tipo de participación: Ponencia invitada- Endometrial regeneration and its clinical translation. Extreme Infertility. American Hospital Conferences. Estambul (Turquía), Enero 2013.
Autores: Carlos Simón, Xavier Santamaría, Irene Cervelló, Antonio Pellicer. Título: Stem cell therapy in endometrial pathologies. Núm: 62/013,121. (2014).