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REPRODUCTIONFOCUS REVIEW
WOMEN IN REPRODUCTIVE SCIENCE Lessons from bioengineering the ovarian follicle: a personal perspective
Teresa K Woodruff Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA Correspondence should be addressed to T K Woodruff; Email: [email protected] This paper forms part of a focus section on Women in Reproductive Science. The guest editor for this section was Professor Marilyn Renfree, Ian Potter Chair of Zoology, School of BioSciences, The University of Melbourne, Victoria, Australia
Abstract
The ovarian follicle and its maturation captivated my imagination and inspired my scientific journey – what we know now about this remarkable structure is captured in this invited review. In the past decade, our knowledge of the ovarian follicle expanded dramatically as cross-disciplinary collaborations brought new perspectives to bear, ultimately leading to the development of extragonadal follicles as model systems with significant clinical implications. Follicle maturationin vitro in an ‘artificial’ ovary became possible by learning what the follicle is fundamentally and autonomously capable of – which turns out to be quite a lot. Progress in understanding and harnessing follicle biology has been aided by engineers and materials scientists who created hardware that enables tissue function for extended periods of time. The EVATAR system supports extracorporeal ovarian function in an engineered environment that mimics the endocrine environment of the reproductive tract. Finally, applying the tools of inorganic chemistry, we discovered that oocytes require zinc to mature over time – a truly new aspect of follicle biology with no antecedent other than the presence of zinc in sperm. Drawing on the tools and ideas from the fields of bioengineering, materials science and chemistry unlocked follicle biology in ways that we could not have known or even predicted. Similarly, how today’s basic science discoveries regarding ovarian follicle maturation are translated to improve the experience of tomorrow’s patients is yet to be determined. Reproduction (2019) 158 F113–F126
Introduction needing to be purified by each lab. The chemically laborious Maxim–Gilbert sequencing method was also Sitting proudly on my desk is a first edition of Regnier giving way to the enzymatically elegant Sanger dideoxy De Graaf’s treatise on the ovarian follicle (de Graaf sequencing method. Within 4 years of publishing the rat 1672), given to me by my great friend Najiba Lalou on inhibin sequence, graduate students like me, would no the occasion of my investiture as the Thomas J Watkins longer be cloning, sequencing, and publishing genetic Chair of Obstetrics and Gynecology at Northwestern data – those tasks would become the purview of The University (Box 1). As strange as it may sound, I have Human Genome Project. loved the ovarian follicle and its cyclical rhythm since A little over a decade passed in which I continued my first introduction to the structure in graduate school. my work on the inhibins and activins, their cyclical My PhD thesis advisor, Dr Kelly Mayo, had cloned a regulation in and release from the ovarian follicle, and gene expressed by the human ovarian follicle, the inhibin their function in the reproductive axis. I collaborated α-subunit (Mayo et al. 1986). My task was to clone the with Dr Tom Thompson to solve the crystal structure inhibin subunits from rats and sequence the associated of activin with its receptor and binding proteins, genes, and then determine their molecular regulation elucidating key functional domains and shedding during the reproductive cycle (Woodruff et al. 1987, light on how the inhibin and activin ligands may have 1988, 1989, 1991, D’Agostino et al. 1989, Woodruff & co-evolved (Thompson et al. 2003, 2005, Cook et al. Mayo 1990, Makanji et al. 2014b). At the time, cloning 2005, Lin et al. 2006, 2011, Lerch et al. 2007a,b, Zhu of genes was reaching a fever pitch, with reagents like et al. 2010). Having the right tools at the right time is restriction enzymes available for purchase rather than a critical part of the advancement of science, and a
© 2019 Society for Reproduction and Fertility https://doi.org/10.1530/REP -19-0190 ISSN 1470–1626 (paper) 1741–7899 (online) Online version via https://rep.bioscientifica.com Downloaded from Bioscientifica.com at 09/30/2021 03:49:35PM via free access
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Box 1 Teresa K Woodruff PhD is the Dean and Associate Provost for Graduate Education in The Graduate School at Northwestern University. She is also the Thomas J Watkins Professor of Obstetrics & Gynecology, the Vice Chair for Research and the Chief of the Division of Reproductive Science in Medicine in the Department of Obstetrics and Gynecology, Feinberg School of Medicine. She is the Professor of Molecular Biosciences in the Weinberg College of Arts and Sciences and Professor of Biomedical Engineering in the McCormick School of Engineering. She is the Director of the Center for Reproductive Science (CRS), Founder and Director of the Women’s Health Research Institute (WHRI) and Director of the Oncofertility Consortium. She is an internationally recognized expert in ovarian biology and, in 2006, coined the term ‘oncofertility’ to describe the merging of two fields: oncology and fertility. She now heads the Oncofertility Consortium, an interdisciplinary team of biomedical and social scientist experts from across the country. She has been active in education not only at the professional level but also with high school students. In 2011, she was awarded the Presidential Award for Excellence in Science Mentoring in an oval office ceremony by President Obama. Prof Woodruff holds more than 10 U.S. Patents, and was elected to the National Academy of (2017). Her honors include a Guggenheim Fellowship (2017), the Society for Endocrinology Transatlantic Medal (2017), a Leadership Award from the Endocrine Society (2017) and the Mentor of the Year Award from the Society for the Study of Reproduction (2018). She has two honorary degrees, including one from the University of Birmingham, College of Medical Studies, UK (2016) and one from Bates College (2011). She is an elected member of the National Academy of Medicine (2018), a fellow of the American Institute of Medical and Biological Engineering (2017) and the American Association for the Advancement of Science (AAAS; 2005). She is past-president of the Endocrine Society and championed the new NIH policy that mandates the use of females in fundamental research. She currently serves as Editor-in-Chief of Endocrinology. She is civically active and is an elected member of The Economic Club of Chicago, The Chicago Network, a member of the Adler Planetary of Chicago Board of Trustees, and previously served on the school board of the Chicago-based Young Women’s Leadership Charter School.
Some important articles Ma Y, Oliveira DFM, Woodruff TK & Uzzi B 2019 Women who win prizes get less money and prestige. Nature 565 287–288. (https://doi. org/10.1038/d41586-019-00091-3) Smith BM, Duncan FE, Ataman L, Smith K, Quinn GP, Chang RJ, Finlayson C, Orwig K, Valli-Pulaski H, Moravek MB et al. 2018 The National Physicians Cooperative: transforming fertility management in the cancer setting and beyond. Future Oncology 14 3059–3072. (https://doi. org/10.2217/fon-2018-0278) Laronda MM, Rutz AL, Xiao S, Whelan KA, Duncan FE, Roth EW, Woodruff TK & Shah RN 2017 A bioprosthetic ovary created using 3D printed microporous scaffolds restores ovarian function in sterilized mice. Nature Communications 8 15261. (https://doi.org/10.1038/ncomms15261) Xiao S, Coppeta JR, Rogers HB, Isenberg BC, Zhu J, Olalekan SA, McKinnon KE, Dokic D, Rashedi AS, Haisenleder DJ et al. 2017 A microfluidic culture model of the human reproductive tract and 28-day menstrual cycle. Nature Communications 8 14584. (https://doi.org/10.1038/ ncomms14584) Duncan FE, Que EL, Zhang N, Feinberg EC, O’Halloran TV & Woodruff TK 2016 The zinc spark is an inorganic signature of human egg activation. Scientific Reports 6 24737. (https://doi.org/10.1038/srep24737) Zhang N, Duncan FE, Que EL, O’Halloran TV & Woodruff TK 2016 The fertilization-induced zinc spark is a novel biomarker of mouse embryo quality and early development. Scientific Reports 6 22772. (https://doi.org/10.1038/srep22772) Xiao S, Zhang J, Romero MM, Smith KN, Shea LD & Woodruff TK 2015b In vitro follicle growth supports human oocyte meiotic maturation. Scientific Reports 5 17323. (https://doi.org/10.1038/srep17323) Zhu J, Mishra RK, Schiltz GE, Makanji Y, Scheidt KA, Mazar AP & Woodruff TK 2015 Virtual High-Throughput Screening To Identify Novel Activin Antagonists. Journal of Medicinal Chemistry 58 5637–5648. (https://doi.org/10.1021/acs.jmedchem.5b00753) Kim AM, Vogt S, O’Halloran TV & Woodruff TK 2010 Zinc availability regulates exit from meiosis in maturing mammalian oocytes. Nature Chemical Biology 6 674–681. (https://doi.org/10.1038/nchembio.419) Woodruff TK, D’Agostino J, Schwartz NB & Mayo KE 1988 Dynamic changes in inhibin messenger RNAs in rat ovarian follicles during the reproductive cycle. Science 239 1296–1299. (https://doi.org/10.1126/science.3125611) willingness to cross-disciplinary lines and be an early Ovarian follicle maturation is autonomous to adopter or even an inventor is a winning combination. the follicle Here I provide a bit of background on some of the essential tools that my lab has utilized or invented to The ovary can be seen as an artful box that holds learn more about the ovarian follicle and the ways in individual organs called follicles. Each follicle contains which follicles develop over reproductive time. These a single germ cell – the oocyte – and is responsible tools have been prismatic – they have allowed us to for production of the hormones necessary for oocyte peer through them as the light shines in, revealing maturation and for endocrine feedback to the higher multiple facets of follicle biology that feather out in a brain centers within the reproductive axis. Several labs, spectrum to advance our thinking. including my own, have developed various two- and
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Table 1 Summary of eIVFG progress across species, follicle type and time.
Reproductive Article Species Follicle class Material Results outcome Rios et al. (2018) Mouse Aggregates of 0.5% Alginate Survival of multiple follicle populations Development of primordial, primary, was confirmed via histology, with the embryos and and secondary notable development of the antral mice co-cultured follicles follicles. Collected oocytes (63%) exhibited polar body extrusion and were fertilized by intracytoplasmic sperm injection and standard in vitro fertilization procedures. Successfully fertilized oocytes developed to the pronucleus (14%), two-cell (36%), and four-cell (7%) stages. Jakus et al. Human, Cortical culture strips Tissue paper Ovarian tissue papers support mouse Development of (2017) primate ovarian follicle adhesion, viability and humans and health in vitro, as well as support, and primates maintain the viability and hormonal function of nonhuman primate and human follicle-containing, live ovarian cortical tissues ex vivo for 8 weeks postmortem. Laronda et al. Mouse In vitro: multilayer 3DP 10% gelatin 30° and 60° scaffolds provide corners Pups (2017) secondary (150– that surround follicles on multiple sides 180 μm); in vivo: while 90° scaffolds have an open primordial, primary porosity that limits follicle–scaffold and small secondary interaction. Follicle-seeded scaffolds co-cultured follicles become highly vascularized and ovarian function is fully restored when implanted in surgically sterilized mice. Moreover, pups are born through natural mating and thrive through maternal lactation. Kniazeva et al. Mouse Primordial and Fibrin vs fibrin/ Aggregated follicles encapsulated within Primordial (2015) primary co-cultured alginate vs fibin/ fibrin had enhanced survival and follicles follicles collagen ECM integration with the host tissue develop following transplantation relative to the into pups fibrin–alginate and fibrin–collagen composites. All mice transplanted with fibrin-encapsulated follicles resumed cycling and live births were achieved only for follicles transplanted within VEGF-loaded fibrin beads. Xiao et al. Human Multilayer secondary Two-step: 0.5% Follicles developed from the preantral to Progression (2015b) follicles co-cultured alginate until antral stage, and, for the first time, to MII follicles diameter reached produced meiotically competent 400–500 μm with metaphase II (MII) oocytes after in vitro antrum, then maturation (IVM). released from alginate and cultured in the low attachment plates Xiao et al. Mouse Multilayer secondary 0.25% alginate Our study demonstrates that size-specific Progression (2015a) co-cultured follicles follicle selection can be used as a to MII (150–180 μm in noninvasive marker to identify diameter) high-quality oocytes and improve reproductive outcomes during eIVFG. Skory et al. Mouse Multilayered 0.5% (w/v) alginate When grown in this system, 96% of Progression (2015) secondary mouse follicles ovulated in response to to MII co-cultured follicles hCG and released meiotically (180–210 µm in competent eggs. diameter) Ovulated follicles recapitulated transcriptional, morphologic and hormone synthesis patterns post- luteinizing hormone (LH/hCG). Laronda et al. Mouse Whole ovary prep Bovine de-cell strips Recellularized grafts initiated puberty in Progression (2015) ECM mice that had been ovariectomized. to puberty
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Table 1 Continued.
Reproductive Article Species Follicle class Material Results outcome Laronda et al. Human Primordial 0.5% or 2% rigidity Human primordial follicles do not Growing (2014) alginate for isolated survive isolation and short-term culture; follicles primordial follicles; Encapsulated in situ culture of ovarian 0.25, 0.5, 1 or 2% tissue supports the long-term survival of alginate for strips human primordial follicles. Smith et al. Mouse Mostly primordial Fibrin Primordial follicles were recruited into Growing (2014) (94%) the growing pool. follicles Makanji et al. Mouse Early secondary Oxygen alginate Enhanced survival and growth for Progression (2014a) (110 μm) follicles cultured at 2.5% compared to MII with 20% O2 (hypoxia-mediated glycolysis is essential for growth and survival of early secondary follicles). Tagler et al. Mouse Secondary Media 0.25% alginate The supplementation of ascorbic acid Progression (2014) (diameter: (50 μg/mL) significantly enhanced the to MII 90–100 μm) and survival of primary follicles (<80 μm) primary follicles cultured in alginate hydrogels, which (diameter: coincided with improved structural 60–80 μm) integrity. Follicles developed antral cavities and increased to diameters exceeding 250 μm. Consistent with improved structural integrity, the gene/ protein expression of ECM and cell adhesion molecules was significantly changed. Tagler et al. Mouse Late primary media 0.25% alginate Supplemented αMEM/F12-based medium Progression (2013) (average initial enables the survival and growth of to MII diameter of 80 µm) primary ovarian follicles encapsulated and early secondary in alginate hydrogels. (average initial diameter of 90 µm) follicles Skory et al. Mouse Multilayered 0.5% alginate COMP has potential utility as a marker of (2013) secondary follicles follicle maturation. (150–180 μm in diameter) Hornick et al. Mouse Primary 0.5% alginate Increased growth and survival with Progression (2013) multiple follicle culture → maintained to MII follicle integrity and resulted in the formation of antral stage follicles containing meiotically competent gametes. Our data suggest that the follicle unit is necessary to produce the secreted factors responsible for the supportive effects of multiple follicle culture, as neither denuded oocytes, nor oocyte-secreted factors, nor granulosa cells alone were sufficient to support early follicle growth in vitro. Therefore, there may be signaling from both the oocyte and the follicle that enhances growth but requires both components in a feedback mechanism. Hornick et al. Primate Primordial 2 vs. 0.5% alginate Follicle survival and morphology were Progression (2012) rigidity more optimal when follicles were to MII cultured in 2% alginate compared with 0.5% alginate. Tagler et al. Mouse Early secondary 0.25% alginate Co-culture with MEFs enabled the Progression (2012) (average diameter of survival and growth of early secondary to MII 90–100 μm) and (average diameter of 90–100 μm) and primary (average primary (average diameter of 70–80 μm) diameter of follicles. 70–80 μm) follicles (Continued)
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Table 1 Continued.
Reproductive Article Species Follicle class Material Results outcome Hirschfeld- Mouse Secondary follicles, Fibrinogen-alginate These results suggest that the original Progression Cytron et al. ranging in average (FA)-IPNs ECM physical environment of the follicle to MII (2011) diameter from 150 within the ovary can impact its function to 163 µm when isolated and cultured. Secondary follicles isolated from different cohorts and grown in vitro had indistinguishable growth trajectories. However, the follicles isolated from older and heavier mice and those in diestrus had altered hormone profiles. These follicles contained oocytes with reduced meiotic competence and produced oocytes with greater spindle defects. Parrish et al. Mouse Two-layered 0.25% alginate PCR of key developmental genes during (2011) co-cultured folliculogenesis. These studies establish secondary follicles the similarities and differences between (100–130 μm) and in vivo and in vitro cultured follicles, multilayered guiding the creation of environments secondary follicles that maximize follicle development and (150–180 μm) oocyte quality. Endocrine: Cyp19a1, Lhcgr, Fshr, Inhα, Inhβa; Growth: Igf1, Gdf9, Kit, Kitl, Tgfβr2, Bmp15; Oocyte: Vasa, Jag1, Mater, Nobox, Zp1, Zp2, Zp3, Figlα Shikanov et al. Mouse Secondary (130– ECM fibrinogen- This combination provides a dynamic (2011b) 150 mm) alginate (FA)-IPNs mechanical environment because both components contribute to matrix rigidity initially; however, proteases secreted by the growing follicle degrade fibrin in the matrix leaving only alginate to provide support. Shikanov et al. Mouse Immature secondary PEG-VS For tri-functional crosslinkers, the (2011a) follicles (140– hydrogels supported a 17-fold 150 μm in diameter) volumetric expansion of the tissue during culture, with expansion dependent on the ability of the follicle to rearrange its microenvironment, which is controlled through the sensitivity of the cross-linking peptide to the proteolytic activity of plasmin. Xu et al. (2011) Primate Preantral Fibrin–alginate– Follicles grown in the absence of FSH Progression matrigel ECM produced MII oocytes with normal to MII spindle structure. Jin et al. (2010a) Primate Tissue This study provides evidence that markers of early follicle growth and development are preserved after slow cryopreservation and thaw, with little effect on follicle morphology and function. Jin et al. (2010b) Mouse Tissue, secondary Tissue culture × 4 A strategy combining whole ovary culture Progression days, then isolation of early-stage follicles and subsequent to MII of secondary in alg FA hydrogel in vitro follicle culture or alg-fib ECM × 12 produced a high percentage of oocytes days competent for fertilization. Shikanov et al. Mouse Two-layered FA IPN ECM The rate of meiotically competent oocytes Progression (2009) secondary follicles produced by culture in FA IPN was to MII 82%, which was significantly greater than in alginate alone. This increase in oocyte quality is an important step in identifying 3D culture systems. Xu et al. (2009b) Human Secondary 0.5% alginate bead No significant differences between Progression or Matrigel ECM alginate and matrigel. Our data support to MII the notion that human follicle development can be achieved in vitro in a bio-engineered culture system. (Continued) https://rep.bioscientifica.com Reproduction (2019) 158 F113–F126
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Table 1 Continued.
Reproductive Article Species Follicle class Material Results outcome Xu et al. (2009c) Primate Secondary 0.5 and 0.25% Regardless of gonadotropin treatment, Progression rigidity alginate follicles produced estradiol, to MII androstenedione and progesterone by 14–30 days in vitro. Thus, an alginate hydrogel maintains the 3D structure of individual secondary macaque follicles, permits follicle growth and supports steroidogenesis for ≤30 days in vitro. Xu et al. (2009a) Mouse Two-layered Alginate Overall, the present study demonstrated secondary follicles that mouse preantral follicles, either (100–130 μm, type within ovarian tissues or individually 4) isolated, could be successfully cryopreserved by the slow-freezing method, as evidenced by post-thaw follicle development and steroidogenesis, oocyte maturation and molecular markers for oocyte and/or granulosa cells connection. West- Mouse Multilayered 0.5 or 1.5% rigidity Matrices with a shear modulus of less Farrell et al. secondary follicles than 250 Pa are regarded as permissive, (2009) (150–180 μm in as a large percentage of follicles diameter) cultured in these matrices survive and increase in diameter, develop an antrum, have a steroidogenic profile similar to that of follicles in vivo, and produce metaphase II stage oocytes. West et al. Mouse Two-layered 3% rigidity alginate; Concentration enhanced follicle growth, (2007) (100-130 μm) and 1.5% rigidity and coordinated differentiation of the multilayered alginate; 0.7% follicle cell types, as evidenced by (150-180 μm) rigidity alginate; antral cavity formation, theca cell 1.5% rigidity differentiation, oocyte maturation, and oxidized alginate; relative hormone production levels. 1.5% rigidity While a stiff environment favored high irradiated alginate progesterone and androgen secretion, decreasing alginate stiffness resulted in estrogen production, which exceeded progesterone and androgen accumulation. Xu et al. (2006a) Mouse Multilayered 1.5% (w/v) alginate Embryos derived from cultured oocytes secondary follicles fertilized in vitro and transferred to (150–180 mm, type pseudopregnant female mice were 5b) viable, and both male and female offspring were fertile. Xu et al. (2006b) Mouse Two-layered follicle 0.25, 0.5, 1, and 2% The present study showed that the growth rigidity alginate alginate scaffold consistency affects folliculogenesis and oocyte development in vitro and that the alginate culture system can and should be tailored to maximally support follicle growth depending on the size and stage of the follicles selected for culture. Kreeger et al. Mouse Two-layered RGD-alginate or Morphology of the follicle and provides (2006) secondary follicles alginate/ECM an environment that supports follicle (100–130 µm, oocyte protein blends development. The ECM components <63 µm) and signal the somatic cells of the follicle, multilayered affecting their growth and secondary follicles differentiation, and unexpectedly also (150–180 µm) affect the meiotic competence of the oocyte. These effects depend upon both the identity of the ECM components and the initial stage of the follicle, indicating that the ECM is a dynamic regulator of follicle development.
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Table 1 Continued.
Reproductive Article Species Follicle class Material Results outcome Kreeger et al. Mouse Two-layered 1.5% rigidity (w/v) Responsive when cultured in alginate- Progression (2005) secondary (100-130 alginate or collagen I matrices, exhibiting FSH to MII micron) and alginate-collagen I dose-dependent increases in follicle multilayered matrices composed growth, lactate production, and steroid secondary (150-180 of 1.5% (w/v) secretion. Multilayered secondary micron) alginate and 0.2 mg/ follicles were FSH dependent, with mL of collagen I follicle survival, growth, steroid ECM secretion, metabolism, and oocyte maturation all regulated by FSH. However, doses greater than 25 mIU/mL of FSH negatively impacted multilayered secondary follicle development (reduced follicle survival). The present results indicate that the hormonal and environmental needs of the follicular complex change during the maturation process. Pangas et al. Mouse COCs 1.9% (w/v) The architecture of the follicular complex Progression (2003) was maintained during the to MII encapsulation and the subsequent culture. The granulosa cells proliferated, and the oocytes also grew in volume and obtained the structural characteristics of mature oocytes including cortical granule formation, a well-developed zona pellucida with microvilli, normal mitochondria, and lattice-like structures in the cytoplasm. Oocytes retrieved and matured were able to resume meiosis, a necessary step for proper development. Thus, this system represents a new in vitro methodology for growth of individual granulosa cell–oocyte complexes. Kreeger et al. Mouse GRM02 and primary 2% alginate ECM Surfaces (0.02–0.2 ng/cm2) attached and (2003) granulosa cells modified with RGD spread, with morphologies specific to the peptide identity and density. Additionally, progesterone and estradiol secretion was a function of peptide density, with up to threefold increases compared to controls. These results indicate that the density and identity of adhesion peptides regulate granulosa cell function. three-dimensional in vitro culture methods to grow development of a theca-like layer at a precise distance follicles outside the ovary. Biomaterials engineer Dr from the central egg; the development of an antral Lonnie Shea and I worked together to develop a variety cavity at the time of cumulus cell differentiation and of physical and biomaterials to support in vitro follicle follicle-stimulating hormone (FSH)-induced expression growth (Table 1 and Pangas et al. 2003, Kreeger et al. of the luteinizing hormone (LH) receptors necessary for 2005, 2006, Xu et al. 2006a,b, 2009a,b,c, 2011, 2013, ‘ovulation’ of the mature egg from the follicle following West et al. 2007, Shikanov et al. 2009, 2011a,b,c, West- human chorionic gonadotropin (hCG) induction. Farrell et al. 2009, Jin et al. 2010a,b, Hirshfeld-Cytron This has been accomplished across multiple species et al. 2011, Laronda et al. 2014, Makanji et al. 2014a, including the mouse, cat, dog, sheep, cow, nonhuman Smith et al. 2014, Tagler et al. 2014, Skory et al. 2015, Xiao primate and human (Fig. 1). Perhaps more profoundly, et al. 2015a,b). In particular, we used the algae-produced after ovulation, the surface of the follicle re-epithelizes material alginate to encapsulate follicles into beads that and the granulosa cells transform to display a luteal cell provide a simple structural support for long-term culture. phenotype and function (Skory et al. 2015). No prior This alginate-based encapsulated in vitro follicle growth system has been able to support the entire arc of follicle (eIVFG) culture system supports coordinated granulosa maturation from a follicular to luteal structure in vitro. cell proliferation and oocyte growth, the development Importantly, because of eIVFG, we know that hormones of mural and cumulus granulosa cell layers and are necessary to drive follicle maturation through each https://rep.bioscientifica.com Reproduction (2019) 158 F113–F126
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Figure 1 Human follicle maturation through encapsulated in vitro follicle growth (eIVFG) technologies. Human ovaries are populated with non-renewable pool of primordial follicles at birth. Chemotherapeutic treatments cause damage to the primordial egg resulting in sterility or infertility. Tissue biopsy from adolescent at risk for (A) low; (B) medium or (C) high sterilizing treatment retained ovarian follicles (REF) in their ovarian cortex. (D) Thin strips of tissue must be processed to isolate follicles for research or cryopreserve tissue samples for later fertility restoration. (E) At the time of ovarian tissue processing, follicles containing oocytes of different sizes and maturation levels can be collected and frozen for later use or the quality of the tissue assessed to determine whether the gametes are of sufficient quality to support the development of offspring (REF). (F) Human ovarian follicles have been isolated, growth through eIVFG and mature, MII eggs isolated (G). of these stages; to this dogma, we can now add the fact demonstrated the necessity for maintaining the follicle’s that ovarian follicles are themselves autonomous in their 3D architecture – the precise relationship of the somatic ability to respond to these signals, with no additional and germ cells – for the accurate development of each innervation, vasculature or circulating factors aside from cell compartment, including the oocyte. In addition gonadotropins needed to support follicle development to hormones and architecture, we have learned more and differentiation. This is an important observation that about the contribution of a third factor – the physical enables new thinking about the manipulation of follicles environment – to follicle fate determination. The for the purpose of contraceptive development, follicle primordial follicle pool and growing follicles are preservation technologies and new approaches to partitioned into regions of the ovary that have different human diseases like polycystic ovary syndrome (PCOS) physical properties. The cortex is relatively avascular and premature ovarian insufficiency (POI). We were and collagen rich with the medulla having more the first two to show that oocytes can mature entirelyin fibronectin and vascular investments Laronda( et al. vitro, giving rise to live birth in the mouse and to human 2015). The physical rigidity of the ovary changes with metaphase II (MII) eggs competent for fertilization (Fig. age and in cases of PCOS-related infertility. The aging 1). While critical to our understanding of the ability of ovary becomes more fibrotic with every ovulation cycle, oocytes to mature in vitro, more work is necessary to which likely contributes to the loss of fertility in the late determine the optimal conditions for supporting the 30s in ways yet to be fully described. Physicians have intertwined developmental processes of follicle growth described PCOS ovaries as more rigid; surgical wedge and oocyte maturation. resections or drilling were used therapeutically for many years to activate follicles and achieve short-term Hormones, architecture and environment – a resumption of cyclicity. Determining the actual physical properties of soft revised central dogma for follicle activation organs is a challenge for the entire field of biomedical Ovarian follicles require the gonadotropins to engineering, as tissue sizes and complexities are not yet drive growth and maturation. Our eIVFG cultures fully amenable to the tools we have today. To study ovary
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Table 2 Milestones in follicle maturation ex vivo. Shikanov et al. 2009, 2011a,b,c, West-Farrell et al. Biomaterial environment 2009, Jin et al. 2010a,b, Hirshfeld-Cytron et al. 2011, 1 Alginate Laronda et al. 2014, Makanji et al. 2014a, Smith et al. 2 Fibrin-alginate/interpenetrating 2014, Tagler et al. 2014, Skory et al. 2015, Xiao et al. networks (IPN) 2015a,b). Fundamentally, we learned that the physical 4 PEG/PEG-X environment informs follicle development and, along 6 7 Decellularized ovary paper with follicle architecture, is as important to follicle 8 3D printed collagen biology as the hormonal factors that have been known Animal environment for decades. Age, metabolic status, weight Species Mouse Follicles communicate with each other and likely Nonhuman primate between the ovaries in ways yet to be discovered Human Physical environment One of the most interesting studies we conducted Rigidity was the assessment of follicle growth when multiple ECM follicles are encapsulated together in a single bead. Media composition We learned that interfollicular factors support follicle Oxygen health and development (Tingen et al. 2011, Hornick Cellular environment et al. et al. et al. Stroma/theca 2012, 2013, Tagler 2012, Laronda Co-cultured follicles 2014). This was particularly important for the growth Co-cultured cells of small primary follicles that were only able to grow Cortical cultures autonomously when supplemented with factors Human enviroment produced by the surrounding stroma or supplemented Policy with factors from mouse embryonic fibroblast (MEF) Law cultures. Identifying these factors is an important next Religion Ethics step for the field. They may include peptide factors Follicle stage that are able to traffic between follicles, bioactive * Primordial lipids that can act through tissues rather than via the ** Primary bloodstream or miRNAs that modify or regulate RNAs *** Secondary that function in follicle health. **** Cultures to embryos or live birth One reason ovarian follicles struggle to re-establish a cyclical hierarchy after chemotherapy or radiation rigidity, therefore, we adopted the emerging technique therapy may be related to the disruption of intrafollicular of magnetic resonance elastography (MRE), which uses signaling pathways. Learning about the factors involved sound waves to construct images of tissue-level stiffness in this interfollicular communication may provide in vivo (Wood et al. 2015). We initially invented an MRE new inroads into supporting ovarian health in cancer driver that focuses waves to the ovary, but eventually survivors. This work also informed our development of were able to collect and publish data using conventional an ovarian bioprosthetic (Laronda et al. 2015, 2017, MRE drivers, comparing ovarian rigidity in women Jakus et al. 2017). The integration of multiple follicle with normal or PCOS ovaries. These data consistently types into the 3D printed bioprosthetic enabled the showed a stiffer tissue profile associated with the PCOS resulting ovarian tissue to function through ovulation ovary compared with normally cycling women. The and lactation and have remaining subordinate follicles ultimate utility of these metrics may emerge in the ready for a new round of selection. These bioprosthetics pediatric and adolescent population, where the PCOS are creating new ways for soft tissue function to be phenotype is appreciated only after durable menstrual restored and for fundamental new knowledge to be issues that may go unrecognized and complicate the created using anatomically inclusive models of ovarian spectrum of androgen-affected tissue fates. If ovarian function. While reductionism works to understand first rigidity is indeed a clinically relevant measure, having principles (the autonomous nature of follicles once an alternative to transvaginal ultrasound for noninvasive activated), to understand the overall workings of the assessment will be important for these populations. ovary, an intact tissue architecture is critical. We also modeled the physiological effects of physical rigidity in our eIVFG system, by changing alginate Primordial follicle activation is the next frontier concentration, altering alginate length and introducing various combinations of biomaterials and extracellular While primordial follicles represent the dominant matrix components or whole molecules (Table 2) follicle type in the ovary, they are also the most elusive (Pangas et al. 2003, Kreeger et al. 2005, 2006, Xu et al. in terms of biology. We created a triple transgenic 2006a,b, 2009a,b,c, 2011, 2013, West et al. 2007, mouse to see if we could ‘fate map’ follicle activation. https://rep.bioscientifica.com Reproduction (2019) 158 F113–F126
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We showed that the first wave of follicles activated in dominated by repressive factors. More is to be learned in the developing ovary is located in a specific region of this area of active research, and elucidating the specific the ovary (Cordeiro et al. 2015). We also created an way in which the break and the accelerator drive the animal model with a constitutively active allele of the ovarian reserve will be an important undertaking. PI3 kinase subunit (PI3K-Ca) (Kim et al. 2015), based Important advances in primordial follicles came on Dr So-Youn Kim’s efforts to create an oocyte-specific from altering the biomaterial environment and physical transgenic mouse. I was a bit reluctant to travel down this rigidity and led to the development of systems that particular path, because I predicted the PI3K-Ca mouse support folliculogenesis from these earliest stage follicles follicle activation profile would phenocopy that of the in multiple species (Table 2). PTEN knockout. Dr Kim wanted to test this hypothesis directly, predicting instead that the repressive pathway (PTEN) would be dominant over the activating (PI3K) Integrating hormones into organ culture pathway. In the end, she was correct. While knocking out changes everything the ‘break’ to follicle activation (PTEN) results in rapid activation of the entire follicle cohort with early POI, Interestingly, our ovarian follicle models provided an knocking in an active version of the ‘accelerator’ (PI3K) opportunity to link the endocrine hormones to follicle results in a larger number of follicles activated over unit biology, but we required the development of a new time, but not a simultaneous activation of all follicles as platform for linking reproductive tissue constructs in seen in the PTEN knockout. The PI3K-Ca mouse ovarian vitro. The key for this project was the fact that our ovarian reserve remained intact through 60 days of life, at which follicles not only grow in culture, producing estradiol point the local effect of constitutively active PI3K leads and inhibin along the way, they also ovulate in vitro and to the onset of a fully penetrant granulosa cell cancer the granulosa cells transform into the luteal tissue that (Kim et al. 2016). This study points out how cagey makes progesterone. We collaborated with the Draper ovarian follicle biology can be and also reinforces the Laboratories to invent and deploy four microfluidic notion that regulation of the primordial follicle pool is platforms (MFPs): Solo-MFP, Duet-MFP, MyCure-MFP
Table 3 Contributions to follicle biology.
Follicle biology Follicle maturation is autonomous Theca cells differentation is autonomous to the follicle Ovulation is autonomous to the follicle Physical rigidity alone can alter the hormone synthesis ratio (increasing rigidity favors androgen over estrogen) The ovulation rupture zone is a unique site Follicles reconstruct a holostructure after rupture in an autonomous manner The granulosa to luteal transition does not require exogenous cells Mouse follicles can function on a 28-day cycle First live birth in mouse from in vitro-grown 3D follicles First human MII eggs from in vitro-grown human follicles First ovarian bioprosthetic First microfluidic system that integrates ovarian function with reproductive tract tissues Zinc biology 20 billion zinc atoms are concentrated during meiotic maturation in the egg Telophase includes a zinc-depending zinc switch Zinc is exocytosed at the time of fertilization (zinc spark) Zinc is the cytoplasmic maturation factor Zinc is the factor responsible for the fast block to polyspermy Egg biology Meiotic chromosomes are ten times stiffer than mitotic chromosomes Meiotic chromosomes become more stiff with age Genes in polar body 1 and polar body 2 are indicative of egg maturity Terms coined Oncofertility – field of medicine at the intersection of cancer and reproductive care Bioprosthesis – tissue construct that restores soft organ function; originally ovarian bioprosthetic but term appropriate to any biologically constructed tissue Repropedia – short definitions, images or videos of reproductive terms; can be linked to any website Reprotopia – aggregate site for educational tools in the reproductive sciences EVATAR – name of microfluidic system connecting ovary, fallopian tube, uterus, cervix and liver tissue constructs; functions for 28 days Zinc spark – term for exocytotic release of zinc atoms at the time of fertilization Policies addressed Inclusion of sex as a biological variable in biomedical research Economic gaps for women in science Need for rational policies on the use of human gametes in research Insurance and reimbursment for oncofertility care Coordinated oncofertility science and medicine
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(a duet that recirculates) and a Quintet-MFP (Xiao et al. in a variety of cell types. While these phenomena are 2017). In these systems, we cultured mouse ovarian well documented for alkali and alkaline earth metals follicles and ovaries along with human fallopian tubes, such as potassium and calcium, a similar signaling role uterus, cervix and liver organoids (Laronda et al. 2013, for transition metals like zinc has not been documented Eddie et al. 2014, Arslan et al. 2015, Eddie et al. 2015, until now. We described the zinc physiology of the Zhu et al. 2016, Olalekan et al. 2017). This was a mammalian oocyte as it completes maturation and fascinating project and it took 5 years to invent a device initiates early embryonic development. We made three that could support tissue-level function using fluidic fundamental discoveries regarding the physiology of zinc channels that could manage the long-term (over 30 in the egg. First, single-cell elemental analysis revealed days), accurate movement of media between tissues. that zinc is the most abundant transition metal in the This undertaking reminded me how remarkable our own fully grown mouse oocyte, egg and early embryo, and circulatory system is, with arteries and veins, capillaries its total intracellular levels fluctuate dynamically during and tissues integrated into a microfluidic system. We the developmental transitions between stages. We were able to have all tissues in the system function discovered that the pathways controlled through MTF-1 for at least 30 days and produce the expected rise and and MTF-2 are downregulated after the oocyte becomes fall of follicular and luteal hormones, punctuated by meiotically competent, which mechanistically explains ovulation at midcycle. Downstream tissues functioned the unrestrained zinc influx. Second, we found that an in response to the changing hormones, making this one increase in the zinc quota during meiotic maturation is of the most important and exciting studies my lab has necessary to drive exit from meiosis I; induction of zinc done. The ability to study tissue-level function in the insufficiency in maturing oocytes via small-molecule face of changing reproductive hormones is a true game- chelators results in premature meiotic arrest at telophase changer for biology. Up to this point, the fluctuating I. We showed that zinc is the developmental switch that endocrine hormones in males and females have never controls the activity of the zinc-binding meiotic regulator been recapitulated in cell cultures, which are all usually Emi2. Fundamentally, Emi2 acts as a zinc sensor, with composed of individual cell types grown on flat plastic. fluxes in cellular zinc driving meiotic transitions. This is I predict a new level of biological discovery will come the first case in which zinc was shown to bind directly from this work, rewriting the textbooks regarding signal to a protein that transmits its signal associated with a transduction events and leading to a better framework cellular function that is not related to transcriptional or for understanding and interrogating the biological basis translational regulation. Finally, an abrupt decrease in the of health and disease. zinc quota upon egg activation is achieved through an intense exocytosis event called a ‘zinc spark’. The lower intracellular level of zinc after the spark is necessary to Discovery of zinc fluxes during meiotic maturation permit cell cycle resumption; an artificial increase in There are few discoveries that have no antecedent intracellular zinc levels leads to the maintenance of a experimental basis. The release of zinc from a mature metaphase arrest in activated eggs. This represents a new human egg at the time of fertilization is that rare biological paradigm for zinc and identifies a key signaling discovery that came about because an inorganic chemist role for this ligand during meiotic progression. and a reproductive biologist had a conversation about We also found that zinc is the most abundant sperm. Zinc is known to concentrate in the semen, and transition metal in the mammalian preimplantation when pressed with the teleological question about why embryo; perturbation of zinc homeostasis in cleavage this should be, a remarkable collaboration began that stage embryos disrupts mitotic progression; and zinc provided not only evidence of a new meiotic checkpoint chelation in the early embryo causes altered chromatin in the oocyte, but a series of tools that are now poised to structure and global transcription defects. Taken together, unlock the biology of zinc as a cell signal within the cell we have identified a new biology, a new signal and new and a paracrine factor outside the cell (Kim et al. 2010, signaling mechanisms that are necessary for oocyte 2011, Bernhardt et al. 2011, 2012, Kong et al. 2012, meiosis, at a time when transcription is quiescent. 2014, 2015, Hong et al. 2014, Que et al. 2015, Duncan et al. 2016, Zhang et al. 2016, Mendoza et al. 2017, Summary Que et al. 2017, 2019). Perhaps most importantly, this new area of chemical biology revealed an extracellular My work in the field of ovarian follicle biology and oocyte marker (the ‘zinc spark’) that predicts the potential of health has relied on cross-disciplinary collaborations an egg to become an embryo. The development and that span material science, chemistry, bioengineering application of this observation may provide IVF clinics and pure engineering. By integrating new perspectives with earlier and more precise insights into the quality and applying new tools to biological questions, we of eggs and a way to select a single embryo for transfer. have learned much more than we might have if we had Fluctuations in the intracellular concentration of focused only on one kind of scientific inquiry (Table 3). inorganic elements are essential signaling mechanisms Ultimately, it is my hope that this work will be translated to https://rep.bioscientifica.com Reproduction (2019) 158 F113–F126
Downloaded from Bioscientifica.com at 09/30/2021 03:49:35PM via free access F124 T K Woodruff inform the field of oncofertility and fertility preservation, de Graaf R 1672 De Mulierum Organis Generationi Inservientibus Tractatus and the basic science discoveries associated with zinc Novus. Leiden: Ex Officina Hackiana. Duncan FE, Que EL, Zhang N, Feinberg EC, O’Halloran TV & Woodruff TK fluxes in meiotic maturation, the live birth from the first- 2016 The zinc spark is an inorganic signature of human egg activation. ever soft tissue ovarian bioprosthetic and the creation of Scientific Reports 6 24737. (https://doi.org/10.1038/srep24737) the microfluidic platform and the EVATAR reproductive Eddie SL, Kim JJ, Woodruff TK & Burdette JE 2014 Microphysiological modeling of the reproductive tract: a fertile endeavor. tract will be lasting imprints on the most important field Experimental Biology and Medicine 239 1192–1202. (https://doi. for our literal future – reproduction. org/10.1177/1535370214529387) Eddie SL, Quartuccio SM, Zhu J, Shepherd JA, Kothari R, Kim JJ, Woodruff TK & Burdette JE 2015 Three-dimensional modeling of the Declaration of interest human fallopian tube fimbriae. Gynecologic Oncology 136 348–354. (https://doi.org/10.1016/j.ygyno.2014.12.015) The authors declare that there is no conflict of interest that could Hirshfeld-Cytron JE, Duncan FE, Xu M, Jozefik JK, Shea LD & Woodruff TK be perceived as prejudicing the impartiality of this review. 2011 Animal age, weight and estrus cycle stage impact the quality of in vitro grown follicles. Human Reproduction 26 2473–2485. (https://doi. org/10.1093/humrep/der183) Hong YP, Gleber SC, O’Halloran TV, Que EL, Bleher R, Vogt S, Funding Woodruff TK & Jacobsen C 2014 Alignment of low-dose X-ray fluorescence tomography images using differential phase contrast. This work did not receive any specific grant from any funding Journal of Synchrotron Radiation 21 229–234. (https://doi.org/10.1107/ agency in the public, commercial, or not-for-profit sector. S1600577513029512) Hornick JE, Duncan FE, Shea LD & Woodruff TK 2012 Isolated primate primordial follicles require a rigid physical environment to survive Acknowledgements and grow in vitro. Human Reproduction 27 1801–1810. (https://doi. org/10.1093/humrep/der468) I am delighted to be included in this special edition of Hornick JE, Duncan FE, Shea LD & Woodruff TK 2013 Multiple follicle Reproduction and acknowledge that all of the works culture supports primary follicle growth through paracrine-acting signals. Reproduction 145 19–32. (https://doi.org/10.1530/REP-12-0233) described above were done collaboratively with my mentors, Jakus AE, Laronda MM, Rashedi AS, Robinson CM, Lee C, Jordan SW, collaborators and my tremendous lab members over 24 years Orwig KE, Woodruff TK & Shah RN 2017 ‘Tissue Papers’ from organ- of running an independent lab. Every co-author is a friend and specific decellularized extracellular matrices.Advanced Functional colleague and has created a meaningful narrative of friendship Materials 27 1700992. (https://doi.org/10.1002/adfm.201700992) Jin S, Lei L, Shea LD, Zelinski MB, Stouffer RL & Woodruff TK 2010a and learning over my career. I want to note, in particular, Markers of growth and development in primate primordial follicles are my mentors Kelly Mayo and Neena Schwartz, longstanding preserved after slow cryopreservation. Fertility and Sterility 93 2627– collaborator Lonnie Shea and my zinc co-discoverer, Tom 2632. (https://doi.org/10.1016/j.fertnstert.2009.11.029) O’Halloran. This narrative review is told from the perspective Jin SY, Lei L, Shikanov A, Shea LD & Woodruff TK 2010b A novel two- of my laboratory and its contributions to the discipline of step strategy for in vitro culture of early-stage ovarian follicles in the mouse. Fertility and Sterility 93 2633–2639. (https://doi.org/10.1016/j. reproduction and there are also many groups world wide who fertnstert.2009.10.027) have made leaps in discoveries that aligned and propel this Kim AM, Vogt S, O’Halloran TV & Woodruff TK 2010 Zinc availability work. To my colleagues, thank you for making this a collegial regulates exit from meiosis in maturing mammalian oocytes. Nature field in which knowledge can prosper. Chemical Biology 6 674–681. (https://doi.org/10.1038/nchembio.419) Kim AM, Bernhardt ML, Kong BY, Ahn RW, Vogt S, Woodruff TK & O’Halloran TV 2011 Zinc sparks are triggered by fertilization and References facilitate cell cycle resumption in mammalian eggs. ACS Chemical Biology 6 716–723. (https://doi.org/10.1021/cb200084y) Arslan SY, Yu Y, Burdette JE, Pavone ME, Hope TJ, Woodruff TK & Kim JJ Kim SY, Ebbert K, Cordeiro MH, Romero M, Zhu J, Serna VA, Whelan KA, 2015 Novel three dimensional human endocervix cultures respond to Woodruff TK & Kurita T 2015 Cell autonomous phosphoinositide 28-day hormone treatment. Endocrinology 156 1602–1609. (https://doi. 3-kinase activation in oocytes disrupts normal ovarian function through org/10.1210/en.2014-1840) promoting survival and overgrowth of ovarian follicles. Endocrinology Bernhardt ML, Kim AM, O’Halloran TV & Woodruff TK 2011 Zinc 156 1464–1476. (https://doi.org/10.1210/en.2014-1926) requirement during meiosis I-meiosis II transition in mouse oocytes is Kim SY, Ebbert K, Cordeiro MH, Romero MM, Whelan KA, Suarez AA, independent of the MOS-MAPK pathway. Biology of Reproduction 84 Woodruff TK & Kurita T 2016 Constitutive activation of PI3K in oocyte 526–536. (https://doi.org/10.1095/biolreprod.110.086488) induces ovarian granulosa cell tumors. Cancer Research 76 3851–3861. Bernhardt ML, Kong BY, Kim AM, O’Halloran TV & Woodruff TK 2012 A (https://doi.org/10.1158/0008-5472.CAN-15-3358) zinc-dependent mechanism regulates meiotic progression in mammalian Kniazeva E, Hardy AN, Boukaidi SA, Woodruff TK, Jeruss JS & Shea LD oocytes. Biology of Reproduction 86 114. 2015 Primordial follicle transplantation within designer biomaterial Cook RW, Thompson TB, Kurup SP, Jardetzky TS & Woodruff TK 2005 grafts produce live births in a mouse infertility model. Scientific Reports Structural basis for a functional antagonist in the transforming growth 5 17709. (https://doi.org/10.1038/srep17709) factor beta superfamily. Journal of Biological Chemistry 280 40177– Kong BY, Bernhardt ML, Kim AM, O’Halloran TV & Woodruff TK 2012 40186. (https://doi.org/10.1074/jbc.M504591200) Zinc maintains prophase I arrest in mouse oocytes through regulation of Cordeiro MH, Kim SY, Ebbert K, Duncan FE, Ramalho-Santos J & the MOS-MAPK pathway. Biology of Reproduction 87 11, 1–12. (https:// Woodruff TK 2015 Geography of follicle formation in the embryonic doi.org/10.1095/biolreprod.112.099390) mouse ovary impacts activation pattern during the first wave of Kong BY, Duncan FE, Que EL, Kim AM, O’Halloran TV & Woodruff TK folliculogenesis. Biology of Reproduction 93 88. (https://doi.org/10. 2014 Maternally-derived zinc transporters ZIP6 and ZIP10 drive the 1095/biolreprod.115.131227) mammalian oocyte-to-egg transition. Molecular Human Reproduction D’Agostino J, Woodruff TK, Mayo KE & Schwartz NB 1989 Unilateral 20 1077–1089. (https://doi.org/10.1093/molehr/gau066) ovariectomy increases inhibin messenger ribonucleic acid levels in Kong BY, Duncan FE, Que EL, Xu Y, Vogt S, O’Halloran TV & Woodruff TK newly recruited follicles. Endocrinology 124 310–317. (https://doi. 2015 The inorganic anatomy of the mammalian preimplantation org/10.1210/endo-124-1-310) embryo and the requirement of zinc during the first mitotic divisions.
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Developmental Dynamics 244 935–947. (https://doi.org/10.1002/ cell-oocyte complexes. Tissue Engineering 9 1013–1021. (https://doi. dvdy.24285) org/10.1089/107632703322495655) Kreeger PK, Woodruff TK & Shea LD 2003 Murine granulosa cell Parrish EM, Siletz A, Xu M, Woodruff TK & Shea LD 2011 Gene expression morphology and function are regulated by a synthetic Arg–Gly–Asp in mouse ovarian follicle development in vivo versus an ex vivo alginate matrix. Molecular and Cellular Endocrinology 205 1–10. (https://doi. culture system. Reproduction 142 309–318. (https://doi.org/10.1530/ org/10.1016/S0303-7207(03)00209-0) REP-10-0481) Kreeger PK, Fernandes NN, Woodruff TK & Shea LD 2005 Regulation of Que EL, Bleher R, Duncan FE, Kong BY, Gleber SC, Vogt S, Chen S, mouse follicle development by follicle-stimulating hormone in a three- Garwin SA, Bayer AR, Dravid VP et al. 2015 Quantitative mapping dimensional in vitro culture system is dependent on follicle stage and of zinc fluxes in the mammalian egg reveals the origin of fertilization- dose. Biology of Reproduction 73 942–950. (https://doi.org/10.1095/ induced zinc sparks. Nature Chemistry 7 130–139. (https://doi. biolreprod.105.042390) org/10.1038/nchem.2133) Kreeger PK, Deck JW, Woodruff TK & Shea LD 2006 The in vitro Que EL, Duncan FE, Bayer AR, Philips SJ, Roth EW, Bleher R, Gleber SC, regulation of ovarian follicle development using alginate-extracellular Vogt S, Woodruff TK & O’Halloran TV 2017 Zinc sparks induce matrix gels. Biomaterials 27 714–723. (https://doi.org/10.1016/j. physiochemical changes in the egg zona pellucida that prevent biomaterials.2005.06.016) polyspermy. Integrative Biology 9 135–144. (https://doi.org/10.1039/ Laronda MM, Burdette JE, Kim J & Woodruff TK 2013 Recreating the female c6ib00212a) reproductive tract in vitro using iPSC technology in a linked microfluidics Que EL, Duncan FE, Lee HC, Hornick JE, Vogt S, Fissore RA, O’Halloran TV environment. Stem Cell Research and Therapy 4 (Supplement 1) S13. & Woodruff TK 2019 Bovine eggs release zinc in response to (https://doi.org/10.1186/scrt374) parthenogenetic and sperm-induced egg activation. Theriogenology 127 Laronda MM, Duncan FE, Hornick JE, Xu M, Pahnke JE, Whelan KA, 41–48. (https://doi.org/10.1016/j.theriogenology.2018.12.031) Shea LD & Woodruff TK 2014 Alginate encapsulation supports the Rios PD, Kniazeva E, Lee HC, Xiao S, Qakes RS, Saito E, Jeruss JS, growth and differentiation of human primordial follicles within ovarian Shikanov A, Woodruff TK & Shea LD 2018 Retrievable hydrogels for cortical tissue. Journal of Assisted Reproduction and Genetics 31 1013– ovarian follicle transplantation and oocyte collection. Biotechnology 1028. (https://doi.org/10.1007/s10815-014-0252-x) and Bioengineering 115 2075–2086. (https://doi.org/10.1002/ Laronda MM, Jakus AE, Whelan KA, Wertheim JA, Shah RN & bit.26721) Woodruff TK 2015 Initiation of puberty in mice following decellularized Shikanov A, Xu M, Woodruff TK & Shea LD 2009 Interpenetrating fibrin- ovary transplant. Biomaterials 50 20–29. (https://doi.org/10.1016/j. alginate matrices for in vitro ovarian follicle development. Biomaterials biomaterials.2015.01.051) 30 5476–5485. (https://doi.org/10.1016/j.biomaterials.2009.06.054) Laronda MM, Rutz AL, Xiao S, Whelan KA, Duncan FE, Roth EW, Shikanov A, Smith RM, Xu M, Woodruff TK & Shea LD 2011a Hydrogel Woodruff TK & Shah RN 2017 A bioprosthetic ovary created using 3D network design using multifunctional macromers to coordinate tissue printed microporous scaffolds restores ovarian function in sterilized maturation in ovarian follicle culture. Biomaterials 32 2524–2531. mice. Nature Communications 8 15261. (https://doi.org/10.1038/ (https://doi.org/10.1016/j.biomaterials.2010.12.027) ncomms15261) Shikanov A, Xu M, Woodruff TK & Shea LD 2011b A method for ovarian Lerch TF, Shimasaki S, Woodruff TK & Jardetzky TS 2007a Structural and follicle encapsulation and culture in a proteolytically degradable 3 biophysical coupling of heparin and activin binding to follistatin isoform dimensional system. Journal of Visualized Experiments 49 e2695. (https:// functions. Journal of Biological Chemistry 282 15930–15939. (https:// doi.org/10.3791/2695) doi.org/10.1074/jbc.M700737200) Shikanov A, Zhang Z, Xu M, Smith RM, Rajan A, Woodruff TK & Shea LD Lerch TF, Xu M, Jardetzky TS, Mayo KE, Radhakrishnan I, Kazer R, Shea LD 2011c Fibrin encapsulation and vascular endothelial growth factor & Woodruff TK 2007b The structures that underlie normal reproductive delivery promotes ovarian graft survival in mice. Tissue Engineering: Part function. Molecular and Cellular Endocrinology 267 1–5. (https://doi. A 17 3095–3104. (https://doi.org/10.1089/ten.TEA.2011.0204) org/10.1016/j.mce.2006.10.018) Skory RM, Bernabé BP, Galdones E, Broadbelt LJ, Shea LD & Woodruff TK Lin SJ, Lerch TF, Cook RW, Jardetzky TS & Woodruff TK 2006 The 2013 Microarray analysis identifies COMP as the most differentially structural basis of TGF-beta, bone morphogenetic protein, and activin regulated transcript throughout in vitro follicle growth. Molecular ligand binding. Reproduction 132 179–190. (https://doi.org/10.1530/ Reproduction and Development 80 132–144. (https://doi.org/10.1002/ rep.1.01072) mrd.22144) Lin SJ, Hu Y, Zhu J, Woodruff TK & Jardetzky TS 2011 Structure of Skory RM, Xu Y, Shea LD & Woodruff TK 2015 Engineering the ovarian betaglycan zona pellucida (ZP)-C domain provides insights into ZP- cycle using in vitro follicle culture. Human Reproduction 30 1386– mediated protein polymerization and TGF-beta binding. PNAS 108 1395. (https://doi.org/10.1093/humrep/dev052) 5232–5236. (https://doi.org/10.1073/pnas.1010689108) Smith RM, Shikanov A, Kniazeva E, Ramadurai D, Woodruff TK & Shea LD Makanji Y, Tagler D, Pahnke J, Shea LD & Woodruff TK 2014a Hypoxia- 2014 Fibrin-mediated delivery of an ovarian follicle pool in a mouse mediated carbohydrate metabolism and transport promote early-stage model of infertility. Tissue Engineering: Part A 20 3021–3030. (https:// murine follicle growth and survival. American Journal of Physiology: doi.org/10.1089/ten.TEA.2013.0675) Endocrinology and Metabolism 306 E893–E903. (https://doi. Tagler D, Tu T, Smith RM, Anderson NR, Tingen CM, Woodruff TK & org/10.1152/ajpendo.00484.2013) Shea LD 2012 Embryonic fibroblasts enable the culture of primary Makanji Y, Zhu J, Mishra R, Holmquist C, Wong WP, Schwartz NB, ovarian follicles within alginate hydrogels. Tissue Engineering: Part A 18 Mayo KE & Woodruff TK 2014b Inhibin at 90: from discovery to clinical 1229–1238. (https://doi.org/10.1089/ten.TEA.2011.0418) application, a historical review. Endocrine Reviews 35 747–794. (https:// Tagler D, Makanji Y, Anderson NR, Woodruff TK & Shea LD 2013 doi.org/10.1210/er.2014-1003) Supplemented αMEM/F12-based medium enables the survival and Mayo KE, Cerelli GM, Spiess J, Rivier J, Rosenfeld MG, Evans RM & Vale W growth of primary ovarian follicles encapsulated in alginate hydrogels. 1986 Inhibin A-subunit cDNAs from porcine ovary and human placenta. Biotechnology and Bioengineering 110 3258–3268. (https://doi. PNAS 83 5849–5853. (https://doi.org/10.1073/pnas.83.16.5849) org/10.1002/bit.24986) Mendoza AD, Woodruff TK, Wignall SM & O’Halloran TV 2017 Zinc Tagler D, Makanji Y, Tu T, Bernabe BP, Lee R, Zhu J, Kniazeva E, Hornick JE, availability during germline development impacts embryo viability in Woodruff TK & Shea LD 2014 Promoting extracellular matrix remodeling Caenorhabditis elegans. Comparative Biochemistry and Physiology: via ascorbic acid enhances the survival of primary ovarian follicles Toxicology and Pharmacology 191 194–202. (https://doi.org/10.1016/j. encapsulated in alginate hydrogels. Biotechnology and Bioengineering cbpc.2016.09.007) 111 1417–1429. (https://doi.org/10.1002/bit.25181) Olalekan SA, Burdette JE, Getsios S, Woodruff TK & Kim JJ 2017 Thompson TB, Woodruff TK & Jardetzky TS 2003 Structures of an Development of a novel human recellularized endometrium that ActRIIB:activin A complex reveal a novel binding mode for TGF-beta responds to a 28-day hormone treatment. Biology of Reproduction 96 ligand:receptor interactions. EMBO Journal 22 1555–1566. (https://doi. 971–981. (https://doi.org/10.1093/biolre/iox039) org/10.1093/emboj/cdg156) Pangas SA, Saudye H, Shea LD & Woodruff TK 2003 Novel Thompson TB, Lerch TF, Cook RW, Woodruff TK & Jardetzky TS 2005 The approach for the three-dimensional culture of granulosa structure of the follistatin:activin complex reveals antagonism of both https://rep.bioscientifica.com Reproduction (2019) 158 F113–F126
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type I and type II receptor binding. Developmental Cell 9 535–543. Xu M, Kreeger PK, Shea LD & Woodruff TK 2006a Tissue-engineered (https://doi.org/10.1016/j.devcel.2005.09.008) follicles produce live, fertile offspring. Tissue Engineering 12 2739– Tingen CM, Kiesewetter SE, Jozefik J, Thomas C, Tagler D, Shea L& 2746. (https://doi.org/10.1089/ten.2006.12.2739) Woodruff TK 2011 A macrophage and theca cell-enriched stromal cell Xu M, West E, Shea LD & Woodruff TK 2006b Identification of a stage- population influences growth and survival of immature murine follicles specific permissive in vitro culture environment for follicle growth and in vitro. Reproduction 141 809–820. (https://doi.org/10.1530/REP-10- oocyte development. Biology of Reproduction 75 916–923. (https://doi. 0483) org/10.1095/biolreprod.106.054833) West ER, Xu M, Woodruff TK & Shea LD 2007 Physical properties of alginate Xu M, Banc A, Woodruff TK & Shea LD 2009a Secondary follicle growth hydrogels and their effects on in vitro follicle development. Biomaterials and oocyte maturation by culture in alginate hydrogel following 28 4439–4448. (https://doi.org/10.1016/j.biomaterials.2007.07.001) cryopreservation of the ovary or individual follicles. Biotechnology and West-Farrell ER, Xu M, Gomberg MA, Chow YH, Woodruff TK & Bioengineering 103 378–386. (https://doi.org/10.1002/bit.22250) Shea LD 2009 The mouse follicle microenvironment regulates antrum Xu M, Barrett SL, West-Farrell E, Kondapalli LA, Kiesewetter SE, Shea LD & formation and steroid production: alterations in gene expression Woodruff TK 2009b In vitro grown human ovarian follicles from cancer profiles. Biology of Reproduction 80 432–439. (https://doi.org/10.1095/ patients support oocyte growth. Human Reproduction 24 2531–2540. biolreprod.108.071142) (https://doi.org/10.1093/humrep/dep228) Wood CD, Vijayvergia M, Miller FH, Carroll T, Fasanati C, Shea LD, Xu M, West-Farrell ER, Stouffer RL, Shea LD, Woodruff TK & Zelinski MB Brinson LC & Woodruff TK 2015 Multi-modal magnetic resonance 2009c Encapsulated three-dimensional culture supports development elastography for noninvasive assessment of ovarian tissue rigidity of nonhuman primate secondary follicles. Biology of Reproduction 81 in vivo. Acta Biomaterialia 13 295–300. (https://doi.org/10.1016/j. 587–594. (https://doi.org/10.1095/biolreprod.108.074732) actbio.2014.11.022) Xu M, Fazleabas AT, Shikanov A, Jackson E, Barrett SL, Hirshfeld-Cytron J, Woodruff TK & Mayo KE 1990 Regulation of inhibin synthesis in the Kiesewetter SE, Shea LD & Woodruff TK 2011 In vitro oocyte maturation rat ovary. Annual Review of Physiology 52 807–821. (https://doi. and preantral follicle culture from the luteal-phase baboon ovary org/10.1146/annurev.ph.52.030190.004111) produce mature oocytes. Biology of Reproduction 84 689–697. (https:// Woodruff TK, Meunier H, Jones PB, Hsueh AJ & Mayo KE 1987 Rat doi.org/10.1095/biolreprod.110.088674) inhibin: molecular cloning of alpha- and beta-subunit complementary Xu J, Xu M, Bernuci MP, Fisher TE, Shea LD, Woodruff TK, Zelinski MB & deoxyribonucleic acids and expression in the ovary. Molecular Stouffer RL 2013 Primate follicular development and oocyte maturation Endocrinology 1 561–568. (https://doi.org/10.1210/mend-1-8-561) in vitro. Advances in Experimental Medicine and Biology 761 43–67. Woodruff TK, D’Agostino J, Schwartz NB & Mayo KE 1988 Dynamic (https://doi.org/10.1007/978-1-4614-8214-7_5) changes in inhibin messenger RNAs in rat ovarian follicles during the Zhang N, Duncan FE, Que EL, O’Halloran TV & Woodruff TK 2016 The reproductive cycle. Science 239 1296–1299. (https://doi.org/10.1126/ fertilization-induced zinc spark is a novel biomarker of mouse embryo science.3125611) quality and early development. Scientific Reports 6 22772. (https://doi. Woodruff TK, D’Agostino J, Schwartz NB & Mayo KE 1989 Decreased org/10.1038/srep22772) inhibin gene expression in preovulatory follicles requires primary Zhu J, Braun EL, Kohno S, Antenos M, Xu EY, Cook RW, Lin SJ, Moore BC, gonadotropin surges. Endocrinology 124 2193–2199. (https://doi. Guillette Jr LJ, Jardetzky TS et al. 2010 Phylogenomic analyses reveal org/10.1210/endo-124-5-2193) the evolutionary origin of the inhibin alpha-subunit, a unique TGFbeta Woodruff TK, Ackland J, Rahal JO, Schwartz NB & Mayo KE 1991 superfamily antagonist. PLoS ONE 5 e9457. (https://doi.org/10.1371/ Expression of ovarian inhibin during pregnancy in the rat. Endocrinology journal.pone.0009457) 128 1647–1654. (https://doi.org/10.1210/endo-128-3-1647) Zhu J, Xu Y, Rashedi AS, Pavone ME, Kim JJ, Woodruff TK & Burdette JE Xiao S, Duncan FE, Bai L, Nguyen CT, Shea LD & Woodruff TK 2015a 2016 Human fallopian tube epithelium co-culture with murine ovarian Size-specific follicle selection improves mouse oocyte reproductive follicles reveals crosstalk in the reproductive cycle. Molecular Human outcomes. Reproduction 150 183–192. (https://doi.org/10.1530/REP- Reproduction 22 756–767. (https://doi.org/10.1093/molehr/gaw041) 15-0175) Xiao S, Zhang J, Romero MM, Smith KN, Shea LD & Woodruff TK 2015b In vitro follicle growth supports human oocyte meiotic maturation. Scientific Reports 5 17323. (https://doi.org/10.1038/srep17323) Xiao S, Coppeta JR, Rogers HB, Isenberg BC, Zhu J, Olalekan SA, Received 25 April 2019 McKinnon KE, Dokic D, Rashedi AS, Haisenleder DJ et al. 2017 A First decision 17 May 2019 microfluidic culture model of the human reproductive tract and 28- day menstrual cycle. Nature Communications 8 14584. (https://doi. Revised manuscript received 25 June 2019 org/10.1038/ncomms14584) Accepted 15 July 2019
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