FIB’s mission is to encourage, enable, and support research aimed at alleviating human infertility, uncovering new possible pathways to control fertility, and expanding fundamental knowledge of processes that underlie human reproduction. To this end, FIB funds basic, clinical, and translational studies to enhance our understanding of normal reproduction and reproductive pathophysiology, as well as to enable the development of more effective strategies for the diagnosis, management, and prevention of conditions that compromise male and female fertility.
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Physiomimetics and Organoids for Reproductive Health. View the recordings from
Day 1 and Day 2 of this workshop, held September 23-24, 2021, as multidisciplinary experts on physiomimetics, sometimes called “organs-on-a-chip,” and organioids—complex, self-organized 3D-cell culture models that derive from stem/progenitor cells and maintain tissue-like architecture and structure—discuss applications of these technologies for reproductive health research. View the meeting summary (PDF 469 KB) for additional information.
Advancing Bioprinting and Regenerative Medicine Solutions for Obstetric, Gynecologic, and Pediatric Applications Workshop. Watch the saved recordings of both days of this workshop, held November 16-17, 2021, as multidisciplinary experts in regenerative medicine research came together for a transdisciplinary discussion on the state-of-the-art of tissue-construct manufacturing using 3D printing of biological, cellular, and tissue-based products (a.k.a., bioprinting) and regenerative medicine in the context of obstetric, gynecologic, and pediatric applications. As a corollary to the workshop, stakeholders can still add ideas to the conversation about priority areas for future research, technology development, and resources in the 3D bioprinting and regenerative medicine fields through the Advancing Bioprinting and Regenerative Medicine Solutions for Obstetric, Gynecologic, and Pediatric Applications IdeaScale campaign .
Human Infertility Allele Database . This NICHD-funded resource lists experimentally validated benign and deleterious single nucleotide polymorphisms in genes associated with human infertility (site works best in Firefox and Chrome).
Some recent findings from FIB-supported researchers include the following:
- Gene variant involved in genome integrity and male infertility. Even though male infertility affects millions of couples, the cause of primary infertility in males remains largely unknown. In a genomic study of spermatogenic failure, FIB-funded scientists from the GEnetics of Male INfertility Initiative identified single nucleotide variants (SNVs) in germ-cell nuclear antigen (GCNA), a gene on the X chromosome critical for genome integrity in male meiosis. All of the identified SNVs had an extremely low minor allele frequency in the general population but were found in 7 men with spermatogenic failure in the cohort of approximately 2,200 participants. Five identified SNVs occur in key functional regions, suggesting that they disrupt structure and function of the GCNA protein, ultimately arresting germ-cell division. This is the first study implicating GCNA, a key genome integrity factor, in human male infertility. (PMID: 33963445)
- New in vitro system for mammalian meiosis. Despite conservation from yeast to humans of the chromosome structures and the fundamental molecules involved in meiosis, the trigger for meiosis differs across species, and for humans, is still unknown. In yeast, nutrient deprivation triggers meiosis; in mammals, retinoic acid (RA) and its downstream targets, while necessary for meiosis, are not sufficient to trigger it. This knowledge gap prevented scientists from initiating mammalian meiosis and spermatogenesis in vitro. In this FIB-funded study, Dr. Ning Wang and colleagues showed that nutrient deprivation plus RA, but neither alone, induced meiosis in primary mouse spermatocytes cultured without somatic cells. The combination induced both the expression of meiosis-specific genes and DNA double strand breaks. Switching these induced cells to a "meiotic progression" medium allowed them to develop to the early pachytene stage, and to form chromosomal synapses. Transcriptomic analysis of the nutrient-deprived cells identified 11 transcription factor genes that were upregulated, and associated with early meiosis in vivo, independently of RA. In addition to identifying key players in meiotic initiation, this work also establishes a valuable in vitro system for studying meiosis and producing male haploid gametes. (PMID: 33741948)
- TEAD4 and early pregnancy loss. Reproductive success in placental mammals relies on proper development of the trophoblast lineage. A proper balance of self-renewal versus differentiation of trophoblast progenitors is particularly critical for establishment of pregnancy. Dr. Soumen Paul and colleagues at the University of Kansas studied the role of TEAD4, a Hippo signaling effector, on trophoblast development in early post-implantation mouse embryos. They showed that loss of the Tead4 gene in trophoblast progenitors of mutant mice resulted in insufficient numbers of post-implantation trophoblasts, leading to embryo death at the developmental stage equivalent to the first trimester of human gestation. They also found that a subset of patients with unexplained recurrent pregnancy loss had attenuated TEAD4 expression. The trophoblast progenitor cells derived from the patients’ placentae were defective in self-renewal, but rescue of TEAD4 expression restored it. Taken together, these data revealed an evolutionarily conserved mechanism whereby TEAD4 maintains the stem-ness and promotes self-renewal of trophoblast progenitors in post-implantation embryos to ensure successful placentation and progression of pregnancy. (PMID: 32669432)
- Advances in understanding the timing of puberty. The mechanism through which genetic, nutritional, and environmental factors interact to control the onset of puberty is not well understood, and doctors often struggle to manage patients whose puberty is atypically early or late. Now, two new FIB-funded studies provide important insights into the mechanistic underpinnings of early puberty and possible detection of children whose puberty may be delayed.
- In one study, Dr. Ursula Kaiser and her colleagues investigated how expression of the kisspeptin gene is regulated. They found that the protein encoded by the MKRN3 gene acts as a "brake" on puberty by ubiquitinating the promoters of KISS1 (encoding kisspeptin), and another gene called TAC3, preventing their expression. When Mkrn3 levels fall, which normally occurs as puberty approaches, the lack of ubiquitination allows expression of KISS1 and TAC3, which in turn stimulate gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) release. This suggests that mutations in the gene encoding Mkrn3 could cause precocious (early onset) puberty in children. (PMID: 32407292)
- In a second study supported through the National Center for Translational Research in Reproduction and Infertility (NCTRI) at Harvard University, Dr. Stephanie Seminara and her colleagues tested whether injection of kisspeptin, which stimulates GnRH release, can be used to predict outcomes for individuals with pubertal delay. Among 3 girls and 13 boys followed longitudinally, one-half had a rise in LH in response to kisspeptin and subsequently progressed through puberty. In contrast, the other one-half had low LH responses to kisspeptin and showed no physical signs of puberty by the time they turned 18. The authors conclude that kisspeptin stimulation is a promising novel tool for predicting pubertal outcomes for children with delayed puberty. (PMID: 32232399)
- Use of assisted reproductive technologies (ART) related to placenta defects in mice. Even though millions of ART-aided births occur every year, these procedures are associated with increased risks of preeclampsia, development of an abnormal placenta, and abnormal fetal growth. Dr. Marisa Bartolomei and her colleagues at the University of Pennsylvania NCTRI tested the effects of four individual ART procedures, hormone stimulation, in vitro fertilization (IVF), embryo culture, and embryo transfer, on placental development and fetal growth in mice. All four procedures led to reduced fetal weight (with some later recovery, however), and increased placental weight, with abnormalities in the blood supply that improve during development. The IVF treatment increased levels of an anti-angiogenic factor implicated in preeclampsia, and embryo culture caused hypomethylation of placental DNA. The results support the idea that ART procedures themselves cause pregnancy complications unrelated to underlying infertility. As embryo culture had the strongest effects, future studies should focus on optimizing embryo culture to ensure healthy outcomes for both mothers and offspring. (PMID: 32471820)
- Inflammation of ovarian tissue surrounding oocytes may be related to female reproductive aging. As women age, their un-replenishable supply of oocytes declines, and the quality of their remaining oocytes declines, too. The underlying reason for these changes, however, is not clear. Dr. Francesca Duncan and her colleagues tested the novel hypothesis that the ovarian stroma, the environment surrounding the eggs, plays a key role in oocyte quality and quantity. Specifically, they hypothesized that with age, hyaluronan, a normal component of the stroma, fragments into damaging particles that drive inflammation in the stroma, which in turn compromises oocytes. They found that treating isolated ovarian stroma containing hyaluronan fragments drove accumulation of inflammatory cytokines, decreased estrogen production, damaged oocytes, and disrupted meiosis. These data demonstrate that hyaluronan fragments could contribute to female reproductive aging. (PMID: 32033185)