Sonia Herraiz1, Anna Buigues2, César Díaz-García3, Mónica Romeu4, Susana Martínez4, Inés Gómez-Seguí5, Carlos Simón6, Aaron J Hsueh7, Antonio Pellicer8. 1. IVI Foundation, Valencia, Spain; Reproductive Medicine Research Group, Valencia, Spain; Department of Pediatrics, Obstetrics, and Gynecology, School of Medicine, Valencia University, Valencia, Spain. Electronic address: sonia.herraiz@ivi.es. 2. IVI Foundation, Valencia, Spain; Department of Pediatrics, Obstetrics, and Gynecology, School of Medicine, Valencia University, Valencia, Spain. 3. Reproductive Medicine Research Group, Valencia, Spain; Department of Pediatrics, Obstetrics, and Gynecology, School of Medicine, Valencia University, Valencia, Spain; IVI London, London, United Kingdom. 4. Reproductive Medicine Research Group, Valencia, Spain. 5. Hematology Department, La Fe University Hospital, Valencia, Spain. 6. Department of Pediatrics, Obstetrics, and Gynecology, School of Medicine, Valencia University, Valencia, Spain; Instituto Universitario IVI/INCLIVA, Valencia, Spain; Igenomix, Paterna, Spain; Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California. 7. Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, California. 8. IVI Foundation, Valencia, Spain; Reproductive Medicine Research Group, Valencia, Spain.
Abstract
OBJECTIVE: To assess if infusion of human bone marrow-derived stem cells (BMDSCs) could promote follicle development in patients with impaired ovarian functions. DESIGN: Experimental design. SETTING: University research laboratories. ANIMAL(S): Immunodeficient NOD/SCID female mice. INTERVENTION(S): Human BMDSCs were injected into mice with chemotherapy-induced ovarian damage and into immunodeficient mice xenografted with human cortex from poor-responder patients (PRs). MAIN OUTCOME MEASURE(S): Follicle development, ovulation, and offspring. Apoptosis, proliferation, and vascularization were evaluated in mouse and human ovarian stroma. RESULT(S): Fertility rescue and spontaneous pregnancies were achieved in mice ovaries mimicking PRs and ovarian insufficiency, induced by chemotherapy, after BMDSC infusion. Furthermore, BMDSC treatment resulted in production of higher numbers of preovulatory follicles, metaphase II oocytes, 2-cell embryos, and healthy pups. Stem cells promoted ovarian vascularization and cell proliferation, along with reduced apoptosis. In xenografted human ovarian tissues from PRs, infusion of BMDSCs and their CD133+ fraction led to their engraftment close to follicles, resulting in promotion of follicular growth, increases in E2 secretion, and enhanced local vascularization. CONCLUSION(S): Our results raised the possibility that promoting ovarian angiogenesis by BMDSC infusion could be an alternative approach to improve follicular development in women with impaired ovarian function. CLINICAL TRIAL REGISTRATION NUMBER: NCT02240342.
OBJECTIVE: To assess if infusion of human bone marrow-derived stem cells (BMDSCs) could promote follicle development in patients with impaired ovarian functions. DESIGN: Experimental design. SETTING: University research laboratories. ANIMAL(S): Immunodeficient NOD/SCID female mice. INTERVENTION(S): Human BMDSCs were injected into mice with chemotherapy-induced ovarian damage and into immunodeficientmice xenografted with human cortex from poor-responder patients (PRs). MAIN OUTCOME MEASURE(S): Follicle development, ovulation, and offspring. Apoptosis, proliferation, and vascularization were evaluated in mouse and humanovarian stroma. RESULT(S): Fertility rescue and spontaneous pregnancies were achieved in mice ovaries mimicking PRs and ovarian insufficiency, induced by chemotherapy, after BMDSC infusion. Furthermore, BMDSC treatment resulted in production of higher numbers of preovulatory follicles, metaphase II oocytes, 2-cell embryos, and healthy pups. Stem cells promoted ovarian vascularization and cell proliferation, along with reduced apoptosis. In xenografted human ovarian tissues from PRs, infusion of BMDSCs and their CD133+ fraction led to their engraftment close to follicles, resulting in promotion of follicular growth, increases in E2 secretion, and enhanced local vascularization. CONCLUSION(S): Our results raised the possibility that promoting ovarian angiogenesis by BMDSC infusion could be an alternative approach to improve follicular development in women with impaired ovarian function. CLINICAL TRIAL REGISTRATION NUMBER: NCT02240342.