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Genbacev O.,Center for Reproductive science | Genbacev O.,University of California at San Francisco | Lamb J.,Center for Reproductive science | Lamb J.,University of California at San Francisco | And 7 more authors.
Seminars in Reproductive Medicine | Year: 2013

In humans, very little is known about the factors that regulate trophoblast (TB) specification, expansion of the initial TB population, and formation of the cytotrophoblast (CTB) populations that populate the chorionic villi. The absence of human trophoblast progenitor cell (hTPC) lines that can be propagated in vitro has been a limiting factor. Because attempts to derive TB stem cells from the trophectoderm of the human blastocyst have so far failed, investigators use alternative systems as cell culture models including TBs derived from human embryonic stem cells (hESCs), immortalized CTBs, and cell lines established from TB tumors. Additionally, the characteristics of mature TBs have been extensively studied using primary cultures of CTBs and explants of placental chorionic villi. However, none of these models can be used to study TB progenitor self-renewal and differentiation. Furthermore, the propagation of human TB progenitors from villous CTBs (vCTBs) has not been achieved. The downregulation of key markers of cell cycle progression in vCTBs by the end of the first trimester of pregnancy may indicate that these cells are not a source of human TB progenitors later in pregnancy. In contrast, mesenchymal cells of the villi and chorion continue to proliferate until the end of pregnancy. We recently reported isolation of continuously self-renewing hTPCs from chorionic mesenchyme and showed that they differentiated into the mature TB cell types of the villi, evidence that they can function as TB progenitors. This new cell culture model enables a molecular analysis of the seminal steps in human TB differentiation that have yet to be studied in humans. In turn, this information can be used to trace the origins of pregnancy complications that are associated with faulty TB growth and differentiation.© Copyright 2013 by Thieme Medical Publishers, Inc.


Maltepe E.,Center for Reproductive science | Maltepe E.,University of California at San Francisco | Fisher S.J.,Center for Reproductive science | Fisher S.J.,University of California at San Francisco
Annual Review of Cell and Developmental Biology | Year: 2015

The placenta sits at the interface between the maternal and fetal vascular beds where it mediates nutrient and waste exchange to enable in utero existence. Placental cells (trophoblasts) accomplish this via invading and remodeling the uterine vasculature. Amazingly, despite being of fetal origin, trophoblasts do not trigger a significant maternal immune response. Additionally, they maintain a highly reliable hemostasis in this extremely vascular interface. Decades of research into how the placenta differentiates itself from embryonic tissues to accomplish these and other feats have revealed a previously unappreciated level of complexity with respect to the placenta's cellular composition. Additionally, novel insights with respect to roles played by the placenta in guiding fetal development and metabolism have sparked a renewed interest in understanding the interrelationship between fetal and placental well-being. Here, we present an overview of emerging research in placental biology that highlights these themes and the importance of the placenta to fetal and adult health. © 2015 by Annual Reviews. All rights reserved.


Tamaresis J.S.,Center for Reproductive science | Tamaresis J.S.,Stanford University | Irwin J.C.,Center for Reproductive science | Goldfien G.A.,Center for Reproductive science | And 6 more authors.
Endocrinology | Year: 2014

Endometriosis (E), an estrogen-dependent, progesterone-resistant, inflammatory disorder, affects 10%of reproductive-age women. It is diagnosed and staged at surgery, resulting in an 11-year latency from symptom onset to diagnosis, underscoring the need for less invasive, less expensive approaches. Because the uterine lining (endometrium) in women with E has altered molecular profiles, we tested whether molecular classification of this tissue can distinguish and stage disease. We developed classifiers using genomic data from n = 148 archived endometrial samples from women with E or without E (normal controls or with other common uterine/pelvic pathologies) across the menstrual cycle and evaluated their performance on independent sample sets. Classifiers were trained separately on samples in specific hormonal milieu, using margin tree classification, and accuracies were scored on independent validation samples. Classification of samples from women with E or no E involved 2 binary decisions, each based on expression of specific genes. These first distinguished presence or absence of uterine/pelvic pathology and then no E from E, with the latter further classified according to severity (minimal/mild or moderate/severe). Best performing classifiers identified E with 9 0%-100% accuracy,were cycle phase-specific or independent, and used relatively few genes to determine disease and severity. Differential gene expression and pathway analyses revealed immune activation, altered steroid and thyroid hormone signaling/metabolism, and growth factor signaling in endometrium of women with E. Similar findings were observed with other disorders vs controls. Thus, classifier analysis of genomic data from endometrium can detect and stage pelvic E with high accuracy, dependent or independent of hormonal milieu. We propose that limited classifier candidate genes are of high value in developing diagnostics and identifying therapeutic targets. Discovery of endometrial molecular differences in the presence of E and other uterine/pelvic pathologies raises the broader biological question of their impact on the steroid hormone response and normal functions of this tissue. Copyright © 2014 by the Endocrine Society


Robinson J.F.,Center for Reproductive science | Robinson J.F.,Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research | Fisher S.J.,Center for Reproductive science | Fisher S.J.,Eli and Edythe Broad Center for Regeneration Medicine and Stem Cell Research | Fisher S.J.,University of California at San Francisco
Cell Research | Year: 2014

Implantation involves complex signaling networks, which direct morphological and molecular transformation of the embryo and the uterus and establish the trajectory of normal pregnancy. The recent work by Zhang et al. published in Cell Research, identifies the transcriptional regulator, Rbpj, as essential for uterine closure and proper embryo alignment during implantation in the mouse, raising the possibility that aberrant Rbpj signaling could contribute to infertility in humans. © 2014 IBCB, SIBS, CAS.


Biechele S.,Center for Reproductive science | Biechele S.,University of California at San Francisco | Lin C.-J.,Center for Reproductive science | Lin C.-J.,University of California at San Francisco | And 3 more authors.
Current Opinion in Genetics and Development | Year: 2015

Within the first few days of life, the unipotent gametic genomes are rapidly reprogrammed to support emergence of pluripotent cells in the early mammalian embryo. It is now appreciated that this crucial stage of development involves dramatic changes to chromatin at multiple levels, such as DNA methylation, histone modifications, histone mobility, and higher-order chromatin organization. Technological advances are beginning to allow genome-wide views of this chromatin reprogramming, and provide new approaches to functionally dissect its regulation. Here we review recent insights into the dynamic chromatin environment of the early mouse embryo. New data challenge long-held assumptions, for example, with regards to the asymmetry of DNA methylation of the parental genomes or the onset of functional zygotic genome activation. We discuss how impaired chromatin reprogramming can lead to early embryonic lethality, but might also have delayed effects that only manifest later in embryogenesis or postnatally, potentially influencing the propensity for adult-onset diseases. © 2015 Elsevier Ltd.


Faire M.,Center for Reproductive science | Skillern A.,Center for Reproductive science | Arora R.,Center for Reproductive science | Nguyen D.H.,Center for Reproductive science | And 5 more authors.
Developmental Biology | Year: 2015

Quantitative analysis of tissues and organs can reveal large-scale patterning as well as the impact of perturbations and aging on biological architecture. Here we develop tools for imaging of single cells in intact organs and computational approaches to assess spatial relationships in 3D. In the mouse ovary, we use nuclear volume of the oocyte to read out quiescence or growth of oocyte-somatic cell units known as follicles. This in-ovary quantification of non-growing follicle dynamics from neonate to adult fits a mathematical function, which corroborates the model of fixed oocyte reserve. Mapping approaches show that radial organization of folliculogenesis established in the newborn ovary is preserved through adulthood. By contrast, inter-follicle clustering increases during aging with different dynamics depending on size. These broadly applicable tools can reveal high dimensional phenotypes and age-related architectural changes in other organs. In the adult mouse pancreas, we find stochastic radial organization of the islets of Langerhans but evidence for localized interactions among the smallest islets. © 2015 Elsevier Inc.


PubMed | University of California at San Francisco and Center for Reproductive science
Type: Journal Article | Journal: Developmental biology | Year: 2015

Quantitative analysis of tissues and organs can reveal large-scale patterning as well as the impact of perturbations and aging on biological architecture. Here we develop tools for imaging of single cells in intact organs and computational approaches to assess spatial relationships in 3D. In the mouse ovary, we use nuclear volume of the oocyte to read out quiescence or growth of oocyte-somatic cell units known as follicles. This in-ovary quantification of non-growing follicle dynamics from neonate to adult fits a mathematical function, which corroborates the model of fixed oocyte reserve. Mapping approaches show that radial organization of folliculogenesis established in the newborn ovary is preserved through adulthood. By contrast, inter-follicle clustering increases during aging with different dynamics depending on size. These broadly applicable tools can reveal high dimensional phenotypes and age-related architectural changes in other organs. In the adult mouse pancreas, we find stochastic radial organization of the islets of Langerhans but evidence for localized interactions among the smallest islets.


Barrett S.L.,Northwestern University | Barrett S.L.,Center for Reproductive Science | Shea L.D.,Northwestern University | Woodruff T.K.,Northwestern University
Biology of Reproduction | Year: 2010

Cryopreservation of oocytes and embryos is commonly used to preserve fertility. However, women undergoing cancer treatment may not have the time or may not be good candidates for these options. Ovarian cortical tissue cryopreservation and subsequent tissue transplant has been proven successful yet inefficient in preserving larger secondary follicles, and is not recommended as a fertility preservation option for women with certain cancers. We evaluated cryopreservation of individual follicles as an alternative option in rodents, nonhuman primates, and human primates. Under optimal conditions, cryopreserved mouse secondary follicles were able to reestablish granulosa cell-oocyte interactions, which are essential for subsequent follicle growth. Individual secondary follicles survived cryopreservation, were able to be cultured in a three-dimensional alginate hydrogel matrix to the antral stage, and the enclosed oocytes were competent for fertilization. Using a vital imaging technique (pol-scope) employed in many fertility centers, we were able to bioassay the thawed, cultured follicles for the presence of transzonal connections between the somatic and germ cells. Perturbations in these linkages were shown to be reversed when follicles were cryopreserved under optimal freezing conditions. We applied the optimized cryopreservation protocol to isolated rhesus monkey and human secondary follicles, and using the birefringent bioassay, we were able to show good correlation between early follicle growth and healthy somatic cell-oocyte connections. Our results suggest that ovarian follicles can be cryopreserved, thawed, and analyzed noninvasively, making follicle preservation an additional option for young cancer patients. © 2010 by the Society for the Study of Reproduction, Inc.


Levy N.,Center for Reproductive science | Paruthiyil S.,Center for Reproductive science | Zhao X.,Bionovo, Inc. | Vivar O.I.,Center for Reproductive science | And 8 more authors.
Molecular and Cellular Endocrinology | Year: 2010

Tamoxifen can stimulate the growth of some breast tumors and others can become resistant to tamoxifen. We previously showed that unliganded ERβ inhibits ERα-mediated proliferation of MCF-7 cells. We investigated if tamoxifen might have a potential negative effect on some breast cancer cells by blocking the effects of unliganded ERβ on gene regulation. Gene expression profiles demonstrated that unliganded ERβ upregulated 196 genes in MCF-7 cells. Tamoxifen significantly inhibited 73 of these genes by greater than 30%, including several growth-inhibitory genes. To explore the mechanism whereby unliganded ERβ activates genes and how tamoxifen blocks this effect, we used doxycycline-inducible U2OS-ERβ cells to produce unliganded ERβ. Doxycycline produced a dose-dependent activation of the NKG2E, MSMB and TUB3A genes, which was abolished by tamoxifen. Unliganded ERβ recruitment of SRC-2 to the NKG2E gene was blocked by tamoxifen. Our findings suggest that tamoxifen might exert a negative effect on ERβ expressing tumors due to its antagonistic action on unliganded ERβ. © 2009 Elsevier Ireland Ltd. All rights reserved.


Boehme J.,Center for Reproductive science | Maltepe E.,Center for Reproductive science
Journal of Clinical Investigation | Year: 2015

Clinical vignette: An 8-year-old boy presents to the pediatric ICU after two days of cough with increasing secretions. The patient is progressing to respiratory failure and requires noninvasive mechanical ventilation. His past medical history is remarkable for premature birth at 25 and 6/7 weeks gestational age, cerebral palsy, developmental delay, epilepsy, and gastrostomy tube dependence. His chest x-ray is remarkable for multifocal opacities that are consistent with atelectasis. A complete blood count reveals a wbc count of 9.2 with a normal differential, Hg of 11.7, and platelet count of 276,000. A respiratory viral panel from a nasal swab returns positive for rhinovirus. Additional patient history from the parents uncovers that he has been hospitalized three times over the course of the past 2 years with a similar presentation.

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