Palabras clave
Desarrollo folicular in vitro
Cultivo in vitro
Cómo citar
Resumen
Pregunta de estudio: ¿Es posible la restauración de la fertilidad mediante el desarrollo folicular in vitro de folículos primordiales (FPs) contenidos en corteza ovárica criopreservada, en pacientes con contraindicaciones para el autotrasplante de tejido ovárico? Respuesta resumida: La técnica de desarrollo folicular in vitro a partir de tejido ovárico criopreservado se presenta como una estrategia prometedora, todavía en estado experimental, para este tipo de pacientes. Aunque todavía enfrenta desafíos, como la baja tasa de viabilidad folicular y la pobre eficiencia de la técnica, su potencial para generar ovocitos maduros ha sido demostrado, siendo necesario optimizar las condiciones de cultivo. Lo que se sabe: Los tratamientos antineoplásicos en niñas prepuberales y mujeres de edad fértil causan daño gonadal, generando una disminución en la fertilidad. La criopreservación y el autotrasplante de tejido ovárico son la única opción de preservación de la fertilidad disponible en niñas prepuberales y pacientes que no pueden retrasar el inicio del tratamiento. Sin embargo, en algunos tipos de cáncer hematológicos como leucemia y linfoma de Burkitt, existe la posibilidad de reintroducir células malignas ocultas en el tejido ovárico trasplantado. Esta clase de pacientes podrían beneficiarse con la técnica de desarrollo folicular in vitro de folículos. Esta técnica, todavía en estado experimental, consiste en el crecimiento in vitro de folículos primordiales (FP) contenidos en la corteza ovárica, hasta alcanzar folículos maduros con ovocitos en estadio de metafase II (MII). Diseño del estudio: El artículo presenta una revisión narrativa que recopila información sobre la foliculogénesis, las vías de señalización involucradas, diversos sistemas de cultivo in vitro, estrategias de optimización de la activación folicular in vitro, y direcciones futuras de investigación para mejorar la técnica. Resultados: Si bien ya se ha demostrado que la técnica es factible en tejido humano, todavía existen limitaciones como la baja viabilidad folicular y la pobre eficiencia de la técnica. Todavía se necesitan nuevos estudios para optimizar las condiciones de cultivo y mejorar la tasa de éxito de esta técnica. Con una optimización y un perfeccionamiento continuo, el desarrollo folicular in vitro podría eventualmente ofrecer una valiosa opción de restauración de la fertilidad en el entorno clínico. Limitaciones del estudio: Aunque la técnica de desarrollo folicular in vitro muestra potencial, todavía presenta desafíos como la activación no controlada de folículos, la eficiencia limitada, y la falta de evaluación a largo plazo en la estabilidad genética ovocitaria y descendencia futura.
Citas
J. Donnez, M.-M. Dolmans, Fertility Preservation in Women. N Engl J Med 377, 1657– 1665 (2017).
K. Schmidt, E. Larsen, C. Andersen, A. Andersen, Risk of ovarian failure and fertility preserving methods in girls and adolescents with a malignant disease: Fertility preserving methods in girls with cancer. BJOG: An International Journal of Obstetrics & Gynaecology 117, 163–174 (2010).
L. A. Kondapalli, et al., Quality of life in female cancer survivors: is it related to ovarian reserve? Qual Life Res 23, 585–592 (2014).
N. Spears, et al., Ovarian damage from chemotherapy and current approaches to its protection. Human Reproduction Update 25, 673–693 (2019).
K. D. Dinas, Impact of Breast Cancer Treatment on Fertility. Adv Exp Med Biol 1252, 175–179 (2020).
M.-M. Dolmans, et al., EUropean REcommendations for female FERtility preservation (EU-REFER): A joint collaboration between oncologists and fertility special ists. Crit Rev Oncol Hematol 138, 233–240 (2019).
W. H. B. Wallace, T. W. Kelsey, R. A. Anderson, Fertility preservation in pre-pubertal girls with cancer: the role of ovarian tissue cryopreservation. Fertility and Sterility 105, 6–12 (2016).
D. Shai, et al., Ovaries of patients recently treated with alkylating agent chemotherapy indicate the presence of acute follicle activation, elucidating its role among other proposed mechanisms of follicle loss. Fertility and Sterility 115, 1239–1249 (2021).
M.-M. Dolmans, V. Luyckx, J. Donnez, C. Y. Andersen, T. Greve, Risk of transferring malignant cells with transplanted frozen- thawed ovarian tissue. Fertility and Sterility 99, 1514–1522 (2013).
R. Abir, et al., Ovarian minimal residual disease in chronic myeloid leukaemia. Reprod Biomed Online 28, 255–260 (2014).
A. Gougeon, Dynamics of follicular growth in the human: a model from preliminary results. Hum Reprod 1, 81–87 (1986).
L. Li, X. Shi, Y. Shi, Z. Wang, The Signaling Pathways Involved in Ovarian Follicle Development. Front Physiol 12, 730196 (2021).
K. Oktay, D. Briggs, R. G. Gosden, Ontogeny of Follicle-Stimulating Hormone Receptor Gene Expression in Isolated Human Ovarian Follicles 1. The Journal of Clinical Endocrinology & Metabolism 82, 3748–3751 (1997).
H. Kishi, Y. Kitahara, F. Imai, K. Nakao, H. Suwa, Expression of the gonadotropin receptors during follicular development. Reprod Med Biol 17, 11–19 (2018).
B. D. Manning, L. C. Cantley, AKT/PKB signaling: navigating downstream. Cell 129, 1261–1274 (2007).
D. H. Castrillon, L. Miao, R. Kollipara, J. W. Horner, R. A. DePinho, Suppression of Ovarian Follicle Activation in Mice by the Transcription Factor Foxo3a. Science 301, 215–218 (2003).
D. Adhikari, et al., Tsc/mTORC1 signaling in oocytes governs the quiescence and activation of primordial follicles. Hum Mol Genet 19, 397–410 (2010).
M. McLaughlin, H. L. Kinnell, R. A. Anderson, E. E. Telfer, Inhibition of phosphatase and tensin homologue (PTEN) in human ovary in vitro results in increased activation of primordial follicles but compromises development of growing follicles. Molecular Human Reproduction 20, 736–744 (2014).
C. Terren, M. Nisolle, C. Munaut, Pharmacological inhibition of the PI3K/PTEN/Akt and mTOR signalling pathways limits follicle activation induced by ovarian cryopreservation and in vitro culture. J Ovarian Res 14, 95 (2021).
R. Masciangelo, et al., Role of the PI3K and Hippo pathways in follicle activation after grafting of human ovarian tissue. J Assist Reprod Genet 37, 101–108 (2020).
E. H. Ernst, et al., Dormancy and activation of human oocytes from primordial and primary follicles: molecular clues to oocyte regulation. Human Reproduction 32, 1684– 1700 (2017).
D. Pan, Hippo signaling in organ size control. Genes Dev. 21, 886–897 (2007).
A. J. W. Hsueh, K. Kawamura, Y. Cheng, B. C. J. M. Fauser, Intraovarian Control of Early Folliculogenesis. Endocrine Reviews 36, 1–24 (2015).
Y. Cheng, et al., Actin polymerization‐enhancing drugs promote ovarian follicle growth mediated by the Hippo signaling effector YAP. FASEB j. 29, 2423–2430 (2015).
C. De Roo, S. Lierman, K. Tilleman, P. De Sutter, In-vitro fragmentation of ovarian tissue activates primordial follicles through the Hippo pathway. Hum Reprod Open 2020, hoaa048 (2020).
R. B. Gilchrist, M. Lane, J. G. Thompson, Oocyte-secreted factors: regulators of cumu lus cell function and oocyte quality. Human Reproduction Update 14, 159–177 (2008).
T. S. Hussein, J. G. Thompson, R. B. Gilchrist, Oocyte-secreted factors enhance oocyte developmental competence. Developmental Biology 296, 514–521 (2006).
J. Dong, et al., Growth differentiation factor- 9 is required during early ovarian folliculogenesis. Nature 383, 531–535 (1996).
C. Yan, et al., Synergistic Roles of Bone Morphogenetic Protein 15 and Growth Differentiation Factor 9 in Ovarian Function. Molecular Endocrinology 15, 854–866 (2001).
A. Kedem, et al., Growth Differentiating Factor 9 (GDF9) and Bone Morphogenetic Protein 15 both Activate Development of Human Primordial Follicles in vitro , with Seemingly More Beneficial Effects of GDF9.The Journal of Clinical Endocrinology & Metabolism 96, E1246–E1254 (2011).
C. Weenen, et al., Anti-Müllerian hormone expression pattern in the human ovary: potential implications for initial and cyclic follicle recruitment. Mol Hum Reprod 10, 77–83 (2004).
M.-C. Meinsohn, et al., Single-cell sequencing reveals suppressive transcriptional programs regulated by MIS/AMH in neonatal ovaries. Proc Natl Acad Sci U S A 118, e2100920118 (2021).
A. L. Durlinger, et al., Control of primordial follicle recruitment by anti-Müllerian hormone in the mouse ovary. Endocrinology 140, 5789–5796 (1999).
I. B. Carlsson, et al., Anti-Müllerian hormone inhibits initiation of growth of human primordial ovarian follicles in vitro. Hum Reprod 21, 2223–2227 (2006).
J. J. Eppig, Development in vitro of mouse oocytes from primordial follicles. Biology of Reproduction 54, 197–207 (1996).
C. A. Amorim, A. Van Langendonckt, A. David, M.-M. Dolmans, J. Donnez, Survival of human pre-antral follicles after cryopreservation of ovarian tissue, follicular isolation and in vitro culture in a calcium alginate matrix. Hum Reprod 24, 92–99 (2009).
R. Abir, Pilot study of isolated early human follicles cultured in collagen gels for 24 hours. Human Reproduction 14, 1299–1301 (1999).
L. Hosseini, et al., Platelet-rich plasma promotes the development of isolated human primordial and primary follicles to the preantral stage. Reprod Biomed Online 35, 343–350 (2017).
S. Xiao, et al., In vitro follicle growth supports human oocyte meiotic maturation. Sci Rep 5, 17323 (2015).
E. E. Telfer, M. McLaughlin, C. Ding, K. J. Thong, A two-step serum-free culture system supports development of human oocytes from primordial follicles in the presence of activin. Human Reproduction 23, 1151–1158 (2008).
M. Xu, et al., In vitro grown human ovarian follicles from cancer patients support oocyte growth. Hum Reprod 24, 2531–2540 (2009).
T. Wang, et al., Basic fibroblast growth factor promotes the development of human ovarian early follicles during growth in vitro. Hum Reprod 29, 568–576 (2014).
X. Xia, et al., Mesenchymal Stem Cells Facilitate In Vitro Development of Human Preantral Follicle. Reprod. Sci. 22, 1367–1376 (2015).
M.-C. Chiti, et al., Ovarian extracellular matrix- based hydrogel for human ovarian follicle survival in vivo: A pilot work. J Biomed Mater Res B Appl Biomater 110, 1012–1022 (2022).
C. Subiran Adrados, et al., Human platelet lysate improves the growth and survival of cultured human pre-antral follicles. Reprod Biomed Online 47, 103256 (2023).
L. J. Green, A. Shikanov, In vitro culture methods of preantral follicles. Theriogenology 86, 229–238 (2016).
H. Yin, S. G. Kristensen, H. Jiang, A. Rasmussen, C. Y. Andersen, Survival and growth of isolated pre-antral follicles from human ovarian medulla tissue during long-term 3D culture. Hum Reprod 31, 1531–1539 (2016).
M. McLaughlin, D. F. Albertini, W. H. B. Wallace, R. A. Anderson, E. E. Telfer, Metaphase II oocytes from human unilaminar follicles grown in a multi-step culture system. Mol Hum Reprod 24, 135–142 (2018).
A. Camboni, et al., Alginate beads as a tool to handle, cryopreserve and culture isolated human primordial/primary follicles. Cryobiology 67, 64–69 (2013).
M. M. Laronda, et al., Alginate encapsulation supports the growth and differentiation of human primordial follicles within ovarian cortical tissue. J Assist Reprod Genet 31, 1013–1028 (2014).
R. Abir, et al., Mechanical isolation and in vitro growth of preantral and small antral human follicles. Fertil Steril 68, 682–688 (1997).
O. Hovatta, R. Silye, R. Abir, T. Krausz, R. M. Winston, Extracellular matrix improves survival of both stored and fresh human primordial and primary ovarian follicles in long-term culture. Hum Reprod 12, 1032–1036 (1997).
J. G. Hreinsson, et al., Growth Differentiation Factor-9 Promotes the Growth, Development, and Survival of Human Ovarian Follicles in Organ Culture. The Journal of Clinical Endocrinology & Metabolism 87, 316–321 (2002).
J. E. Scott, I. B. Carlsson, B. D. Bavister, O. Hovatta, Human ovarian tissue cultures: extracellular matrix composition, coating density and tissue dimensions. Reprod Biomed Online 9, 287–293 (2004).
G. Lerer-Serfaty, et al., Attempted application of bioengineered/biosynthetic supporting matrices with phosphatidylinositol-trisphosphate- enhancing substances to organ culture of human primordial follicles. J Assist Reprod Genet 30, 1279–1288 (2013).
M. McLaughlin, et al., mTOR kinase inhibition results in oocyte loss characterized by empty follicles in human ovarian cortical strips cultured in vitro. Fertility and Sterility 96, 1154-1159.e1 (2011).
F. Khosravi, et al., In vitro development of human primordial follicles to preantral stage after vitrification. J Assist Reprod Genet 30, 1397–1406 (2013).
E. Asadi, et al., Ovarian tissue culture in the presence of VEGF and fetuin stimulates follicle growth and steroidogenesis. J Endocrinol 232, 205–219 (2017).
J. Grosbois, I. Demeestere, Dynamics of PI3K and Hippo signaling pathways during in vitro human follicle activation. Human Reproduction 33, 1705–1714 (2018).
F. Vitale, et al., Importance of oxygen tension in human ovarian tissue in vitro culture. Human Reproduction 38, 1538–1546 (2023).
C. Hossay, et al., Follicle outcomes in human ovarian tissue: effect of freezing, culture, and grafting. Fertility and Sterility 119, 135–145 (2023).
D. Tagler, et al., Promoting extracellular matrix remodeling via ascorbic acid enhances the survival of primary ovarian follicles encapsulated in alginate hydrogels. Biotechnol Bioeng 111, 1417–1429 (2014).
D. Bhartiya, H. Patel, An overview of FSHFSHR biology and explaining the existing conundrums. J Ovarian Res 14, 144 (2021).
G. Nagamatsu, S. Shimamoto, N. Hamazaki, Y. Nishimura, K. Hayashi, Mechanical stress accompanied with nuclear rotation is involved in the dormant state of mouse oocytes. Sci Adv 5, eaav9960 (2019).
E. Novella-Maestre, S. Herraiz, B. Rodríguez- Iglesias, C. Díaz-García, A. Pellicer, Short-Term PTEN Inhibition Improves In Vitro Activation of Primordial Follicles, Preserves Follicular Viability, and Restores AMH Levels in Cryopreserved Ovarian Tissue From Cancer Patients. PLoS One 10, e0127786 (2015).
J. Li, et al., Activation of dormant ovarian follicles to generate mature eggs. Proc. Natl. Acad. Sci. U.S.A. 107, 10280–10284 (2010).
W. H. Shen, et al., Essential Role for Nuclear PTEN in Maintaining Chromosomal Integrity. Cell 128, 157–170 (2007).
K. Jagarlamudi, et al., Oocyte-Specific Deletion of Pten in Mice Reveals a Stage-Specific Function of PTEN/PI3K Signaling in Oocytes in Controlling Follicular Activation. PLoS ONE 4, e6186 (2009).
M. Maidarti, Y. L. Clarkson, M. McLaughlin, R. A. Anderson, E. E. Telfer, Inhibition of PTEN activates bovine non-growing follicles in vitro but increases DNA damage and reduces DNA repair response. Human Reproduction 34, 297–307 (2019).
I. B. Carlsson, et al., Anti-Müllerian hormone inhibits initiation of growth of human primordial ovarian follicles in vitro. Hum Reprod 21, 2223–2227 (2006).
G. P. Redding, J. E. Bronlund, A. L. Hart, Mathematical modelling of oxygen transport-limited follicle growth. Reproduction 133, 1095–1106 (2007).
S. Shimamoto, et al., Hypoxia induces the dormant state in oocytes through expression of Foxo3. Proc. Natl. Acad. Sci. U.S.A. 116, 12321–12326 (2019).
J. B. Nagashima, R. El Assal, N. Songsasen, U. Demirci, Evaluation of an ovary-on-achip in large mammalian models: Species specificity and influence of follicle isolation status. J Tissue Eng Regen Med 12, e1926–e1935 (2018).
S. Önen, et al., A pumpless monolayer microfluidic device based on mesenchymal stem cell-conditioned medium promotes neonatal mouse in vitro spermatogenesis. Stem Cell Res Ther 14, 127 (2023).
S. Sharma, B. Venzac, T. Burgers, S. Le Gac, S. Schlatt, Microfluidics in male reproduction: is ex vivo culture of primate testis tissue a future strategy for ART or toxicology research? Molecular Human Reproduction 26, 179–192 (2020).
M. Hosseini, et al., Improvement of in situ Follicular Activation and Early Development in Cryopreserved Human Ovarian Cortical Tissue by Co-Culturing with Mesenchymal Stem Cells. Cells Tissues Organs 208, 48–58 (2019).
V. Smolinská, M. Boháč, Ľ. Danišovič, Current status of the applications of conditioned media derived from mesenchymal stem cells for regenerative medicine. Physiol Res 72, S233–S245 (2023).