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Publications (188)
The primate ovarian reserve is established during late fetal development and consists of quiescent primordial follicles in the ovarian cortex, each composed of granulosa cells surrounding an oocyte in dictate. As late stages of fetal development are not routinely accessible for study with human tissue, we exploited the evolutionary proximity of the...
Objective
To determine whether increasing the dose of ulipristal acetate (UPA)-containing emergency contraception (EC) improves pharmacodynamic outcomes in individuals with obesity.
Study design
We enrolled healthy, regularly-cycling, confirmed ovulatory, reproductive-age individuals with body mass index (BMI) >30 kg/m ² and weight >80 kg in a ran...
Huntington’s disease (HD) arises from expanded CAG repeats in exon 1 of the Huntingtin (HTT) gene. The resultant misfolded HTT protein accumulates within neuronal cells, negatively impacting their function and survival. Ultimately, HTT accumulation results in cell death, causing the development of HD. A nonhuman primate (NHP) HD model would provide...
Gene editing is a technology that has been rapidly developing and that has many applications as well as ethical and practical implications. This article is a review that outlines the history of current technology, as well as the advantages and challenges in use for somatic cell and germline gene editing. Clustered regularly interspaced short palind...
We generated and characterized a rhesus macaque induced pluripotent stem cell (iPSC) line using induced reprogramming of fibroblasts isolated from a rhesus macaque fetus. The fibroblasts were expanded and then reprogrammed using non-integrating Sendai virus technology. This line is available as riPSC05. The authenticity of riPSC05 was confirmed thr...
Problem
Anovulatory infertility is commonly associated with hyperandrogenemia (elevated testosterone, T), insulin resistance, obesity, and white adipose tissue (WAT) dysfunction associated with adipocyte hypertrophy. However, whether hyperandrogenemia and adipocyte hypertrophy per se induce a proinflammatory response is unknown.
Method of study
Yo...
Metformin is used by women during pregnancy to manage diabetes and crosses the placenta, yet its effects on the fetus are unclear. We show that the liver is a site of metformin action in fetal sheep and macaques, given relatively abundant OCT1 transporter expression and hepatic uptake following metformin infusion into fetal sheep. To determine the...
CRISPR/Cas systems are some of the most promising tools for therapeutic genome editing. The use of these systems is contingent on the optimal designs of guides and homology-directed repair (HDR) templates. While this design can be achieved in silico, validation and further optimization are usually performed with the help of reporter systems. Here,...
Maternal overnutrition increases inflammatory and metabolic disease risk in postnatal offspring. This constitutes a major public health concern due to increasing prevalence of these diseases, yet mechanisms remain unclear. Here, using nonhuman primate models, we show that maternal Western-style diet (mWSD) exposure is associated with persistent pro...
The role of prostaglandins (PGs) in the ovulatory process is known. However, the role of the ATP binding cassette subfamily C member 4 (ABCC4), transmembrane PG carrier protein, in ovulation remains unknown. We report herein that ABCC4 expression is significantly upregulated in preovulatory human granulosa cells (GCs). We found that PGE2 efflux in...
The advent of directed gene editing technologies now over ten years ago ushered in a new era of precision medicine wherein specific disease-causing mutations can be corrected. In parallel with developing new gene editing platforms, optimizing their efficiency and delivery has been remarkable. With their development, there has been interest in using...
We have previously demonstrated that the combination of chronic hyperandrogenemia (elevated circulating testosterone; T) and an obesogenic Western-style diet (WSD) exerts synergistic effects on the metabolic and reproductive axis, leading to the development of insulin resistance, visceral obesity, and ovarian dysfunction in female rhesus macaques....
Maternal obesity adversely impacts the in utero metabolic environment, but its effect on fetal hematopoiesis remains incompletely understood. During late development, the fetal bone marrow (FBM) becomes the major site where macrophages and B lymphocytes are produced via differentiation of hematopoietic stem and progenitor cells (HSPCs). Here, we an...
Polycystic ovary syndrome (PCOS) is associated with irregular menstrual cycles, hyperandrogenemia and obesity. It is currently accepted that women with PCOS are also at risk for endometriosis, but the effect of androgen and obesity on endometriosis has been underexplored. The goal of this study was to determine how testosterone (T) and an obesogeni...
In women, excess androgen causes polycystic ovary syndrome (PCOS), a common fertility disorder with comorbid metabolic dysfunctions including diabetes, obesity, and nonalcoholic fatty-liver disease (NAFLD). Using a PCOS mouse model, this study shows that chronic high androgen levels cause hepatic steatosis while hepatocyte-specific androgen recepto...
Mutations in the MYO7A gene lead to Usher syndrome type 1B (USH1B), a disease characterized by congenital deafness, vision loss, and balance impairment. To create a nonhuman primate (NHP) USH1B model, CRISPR/Cas9 was used to disrupt MYO7A in rhesus macaque zygotes. The targeting efficiency of Cas9 mRNA and hybridized crRNA-tracrRNA (hyb-gRNA) was c...
Objective:
To assess whether dose escalation (ie, doubling the dose) of emergency contraception that contains levonorgestrel (LNG) improves pharmacodynamic outcomes in individuals with obesity.
Methods:
We enrolled healthy, reproductive-age individuals with regular menstrual cycles, body mass index (BMI) higher than 30, and weight at least 176 l...
Mutations in the MYO7A gene lead to Usher syndrome type 1B (USH1B), a disease characterized by congenital deafness, vision loss, and balance impairment. To create a nonhuman primate (NHP) USH1B model, CRISPR/Cas9 was used to disrupt MYO7A in rhesus macaque zygotes. The targeting efficiency of Cas9 mRNA and hybridized crRNA-tracrRNA (hyb-gRNA) was c...
Hyperandrogenemia and obesity are common in women with polycystic ovary syndrome, but it is currently unclear how each alone or in combination contribute to reproductive dysfunction and female infertility. To distinguish the individual and combined effects of hyperandrogenemia and an obesogenic diet on ovarian function, pre-pubertal female rhesus m...
Genome engineering is a powerful tool for in vitro research, the creation of novel model organisms, and has growing clinical applications. Randomly integrating vectors, such as lentivirus or transposase-based methods, are simple and easy to use, but carry risks from insertional mutagenesis. Here we present Enhanced Specificity Tagmentation-Assisted...
Objective
To demonstrate that functional spermatids can be derived in vitro from non-human primate pluripotent stem cells.
Design
Green Fluorescent Protein (GFP)-labeled, rhesus macaque non-human primate Embryonic Stem Cells (nhpESCs) were differentiated into advanced male germ cell lineages using a modified serum-free spermatogonial stem cell cul...
The maternal decidua is an immunologically complex environment that balances maintenance of immune tolerance to fetal paternal antigens with protection of the fetus against vertical transmission of maternal pathogens. To better understand host immune determinants of congenital infection at the maternal-fetal tissue interface, we performed a compara...
Advances in assisted reproductive technologies in rhesus macaques have allowed the development of valuable models of human disease, particularly when combined with recent techniques for gene editing. While the ability to perform in vitro fertilization (IVF) in rhesus macaques is well established, this procedure has not yet been optimized. Specifica...
Objective
To determine the dose-dependent effect of contemporary marijuana exposure on female menstrual cyclicity and reproductive endocrine physiology in a nonhuman primate model.
Design
Research animal study
Setting
Research institute environment
Patient(s)
Adult female rhesus macaques (6-12 years of age; n=8)
Intervention(s)
Daily delta-9-te...
Background
Maternal obesity adversely impacts the in utero metabolic environment and offspring’s health, but its effect on fetal hematopoiesis and immune cell development remains incompletely understood, particularly in models that resemble human development.
Methods
We studied gestational day 130-135 fetuses derived from rhesus macaque dams chron...
The move from reading to writing the human genome offers new opportunities to improve human health. The United States National Institutes of Health (NIH) Somatic Cell Genome Editing (SCGE) Consortium aims to accelerate the development of safer and more-effective methods to edit the genomes of disease-relevant somatic cells in patients, even in tiss...
Gonadotropin administration during infertility treatment stimulates the growth and development of multiple ovarian follicles, yielding heterogeneous oocytes with variable capacity for fertilization, cleavage, and blastocyst formation. To determine how the intrafollicular environment affects oocyte competency, 74 individual rhesus macaque follicles...
A maternal Western-style diet (WSD) is associated with poor reproductive outcomes, but whether this is from the diet itself or underlying metabolic dysfunction is unknown. Here, we performed a longitudinal study using regularly cycling female rhesus macaques (n = 10) that underwent 2 consecutive in vitro fertilization (IVF) cycles, one while consum...
The role of Prostaglandins (PGs) in the ovulatory process is known. However, the role of the ATP binding cassette subfamily C member 4 (ABCC4), transmembrane PG carrier protein, in ovulation remains unknown. We report herein that ABCC4 expression is significantly upregulated in preovulatory human granulosa cells (GCs). We found that PGE2 efflux in...
STUDY QUESTION
What is the impact of prolonged exposure to hyperandrogenemia (T), Western-style diet (WSD) and the combination on metabolic and reproductive function in female rhesus macaques, particularly in the post-partum period?
SUMMARY ANSWER
Combined T + WSD worsened measures of insulin sensitivity and parameters of cyclicity following prolo...
Genetically modified rodent models of Huntington's disease (HD) have been especially valuable to our understanding of HD pathology and the mechanisms by which the mutant HTT gene alters physiology. However, due to inherent differences in genetics, neuroanatomy, neurocircuitry and neurophysiology, animal models do not always faithfully or fully reca...
Polycystic ovary syndrome (PCOS) often is associated with hyperandrogenemia and an increased incidence of obesity and type 2 diabetes. To understand the separate and combined effects of androgens and obesity on reproductive and metabolic parameters, our group established a nonhuman primate model consisting of animals receiving either testosterone (...
In Siberian hamsters, exposure to short days (SD, 8 h light:16 h dark) reduces reproductive function centrally by decreasing gonadotropin secretion, whereas subsequent transfer of photoinhibited hamsters to stimulatory long days (LD, 16 L:8D) promotes follicle stimulating hormone (FSH) release leading to ovarian recrudescence. Although multiple stu...
Myelination delay and remyelination failure following insults to the central nervous system (CNS) impede axonal conduction and lead to motor, sensory and cognitive impairments. Both myelination and remyelination are often inhibited or delayed due to the failure of oligodendrocyte progenitor cells (OPCs) to mature into myelinating oligodendrocytes (...
Purpose
To investigate the impact of chronically elevated androgens in the presence and absence of an obesogenic diet on oocyte quality in the naturally selected primate periovulatory follicle.
Methods
Rhesus macaques were treated using a 2-by-2 factorial design (n = 10/treatment) near the onset of menarche with implants containing either choleste...
Leukemia inhibitory factor (LIF) is required for rhesus macaque ovulation. However, it is unclear if granulosa cells within the ovarian follicle are capable of producing LIF and whether factors involved in coordinating ovulation also regulate LIF production. Thus, studies were performed to determine if isolated rhesus macaque granulosa cells secret...
A maternal high-fat diet is associated with reduced oocyte quality, fertilization, as well as altered preimplantation embryo development. It is unclear, especially in women, if these effects are due to the diet itself or the subsequent development of metabolic dysfunction. Thus, a longitudinal study was performed using the clinically relevant rhesu...
Preserving male fertility
Before chemotherapy or radiation treatment, sperm from adult men can be cryopreserved for future use. However, this is not possible for prepubertal boys. Fayomi et al. grafted cryopreserved testicular tissue from castrated pubertal rhesus macaques, placing each animal's own testis sections under the skin of the back or scr...
Purpose
To determine the effects of PGL1001, a somatostatin receptor isoform-2 (SSTR-2) antagonist, on ovarian follicle development, oocyte fertilization, and subsequent embryo developmental potential in the rhesus macaque.
Methods
Cycling female rhesus macaques (N = 8) received vehicle through one menstrual (control) cycle, followed by daily inje...
A major challenge in stem cell differentiation is the availability of bioassays to prove cell types generated in vitro are equivalent to cells in vivo. In the mouse, differentiation of primordial germ cell-like cells (PGCLCs) from pluripotent cells was validated by transplantation, leading to the generation of spermatogenesis and to the birth of of...
Corrects a typographic error in the caption of Figure 4k in which the scale of PSvi was incorrectly labeled as (x10^6 cm^{-3}) when it should have been (x10^7 cm^{-3}).
There is an increasing recognition that vitamin D plays important roles in female reproduction. Recent studies demonstrated that 1α,25-dihydroxyvitamin D3 (VD3), the biologically active form of vitamin D, improved ovarian follicle survival and growth in vitro. Therefore, we investigated the direct effects of VD3 at the specific preantral and antral...
Objective:
To determine if a combined oral contraceptive (COC) initiated shortly after ulipristal acetate (UPA) administration interferes with its mechanism of action.
Study design:
Healthy, reproductive-age women of normal BMI with proven ovulation (serum progesterone >3ng/mL) were enrolled for 3 cycles (Cycle 1, UPA only; Cycle 2 washout; Cycl...
Ovulation is the appropriately timed release of a mature developmentally competent oocyte from the ovary into the oviduct where fertilization occurs. Importantly, ovulation is tightly linked with oocyte maturation, demonstrating the interdependency of these two parallel processes both essential for female fertility. Initiated by pituitary gonadotro...
Zika virus (ZIKV) infection during pregnancy leads to an increased risk of fetal growth restriction and fetal central nervous system malformations, which are outcomes broadly referred to as the Congenital Zika Syndrome (CZS). Here we infect pregnant rhesus macaques and investigate the impact of persistent ZIKV infection on uteroplacental pathology,...
A major challenge in stem cell differentiation validation is the availability of bioassays to prove cell types generated in vitro are equivalent to cells in vivo . In the mouse model, differentiation of primordial germ cell-like cells (PGCLCs) from pluripotent cells was validated by transplantation, leading to the generation of spermatogenesis and...
The primate corpus luteum undergoes a process at the end of a nonfertile menstrual cycle termed luteolysis, which involves considerable structural and functional changes that lead to a loss in the ability to produce the steroid hormone progesterone. Because progesterone is critical for events involved in embryo implantation and sustaining pregnancy...
Our previous flow cytometry results demonstrated a significant increase in neutrophils, macrophages/monocytes and natural killer (NK) cells in dispersed rhesus monkey corpora lutea (CL) after progesterone (P4) levels had fallen below 0.3 ng/ml for ≥ 3 days during the natural menstrual cycle. In the present study, immunohistochemistry revealed the C...
Primordial germ cells (PGCs) are the earliest embryonic progenitors in the germline. Correct formation of PGCs is critical to reproductive health as an adult. Recent work has shown that primate PGCs can be differentiated from pluripotent stem cells; however, a bioassay that supports their identity as transplantable germ cells has not been reported....
Chart S1. Differentially Expressed Genes, DEGs, between Rhesus PGCs and Rhesus Somatic Liver Cells
[This corrects the article DOI: 10.1371/journal.ppat.1006219.].
Zika virus (ZIKV), an emerging flavivirus, has recently spread explosively through the Western hemisphere. In addition to symptoms including fever, rash, arthralgia, and conjunctivitis, ZIKV infection of pregnant women can cause microcephaly and other developmental abnormalities in the fetus. We report herein the results of ZIKV infection of adult...
Complete list of tissues examined for ZIKV RNA.
+: ZIKV RNA detected (see Fig 3 for values); -: ZIKV RNA below limit of detection; LN: lymph node.
(PDF)
Validation of taqman qRT-PCR quantitation of ZIKV RNA.
RNA was isolated from purified titered stock of ZIKV (PRV- ABC59). RNA yield was quantified by spectrometry and used to calculate genomes/ ?l. Focus-forming units (ffu)/ ?l was calculated based on titer of stock. ZIKV RNA was serially diluted 1:10 into Vero cell RNA (25 ng/?l) and amplified in...
ZIKV infection results in upregulation of Ki67 and granzyme B in CD4 and CD8 T cells.
The mean frequencies of Ki67 positive (Panels A and B) and granzyme B positive (Panels C and D) T cells within Naive, central memory (CM) and effector memory (EM) subsets of CD4 (Panels A and C) and CD8 (Panels B and D) in PBMC from Animals 26021 and 26023.
(TIF)
Blood chemistry for RM infected with ZIKV.
Serum chemistry analysis was performed at 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 days post infection.
(TIF)
Histological images of tissues from ZIKV-infected animals at 7 and 28 dpi.
Formalin-fixed tissue sections were stained with heamtoxylin and eosin. Shown a representative images of stained sections of (A) prostatitis in animal #27679 at 7 dpi; (B) perivascular lymphocytic infiltration in rash area of upper thorax skin of animal #27679 at 7 dpi; (C)...
Infected cell types in spleen and axillary lymph nodes of ZIKV-infected rhesus macaques.
In order to identify the origin of the infected cells present in lymph tissues, cell subpopulations were isolated by positive selection magnetic bead separation from lymphocytes isolated from the spleen and axillary lymph nodes at 28 dpi. CD14-microbeads were u...
Antibodies from infected RM primarily recognize ZIKV E and NS1 proteins.
Vero cells were infected with ZIKV at MOI = 0.5 or 5 ffu/cell. At 48 h pi, cell lysates were collected, and proteins from infected cell lysates as well as uninfected Vero cells (lanes ?-?) were resolved by SDS-PAGE. Proteins were probed by western blotting using plasma from in...
Rhesus macaque induced pluripotent stem cell (riPSC) line, UCLAi090-A (riPSC90), was generated from rhesus embryonic fibroblast (REF) cells called REF90. REF90 cells and the riPSC90 line were authenticated by short tandem repeat analysis and had a normal male (42, XY) karyotype. The riPSC90 line expressed markers of self-renewal including OCT4, NAN...
Context:
The premenopausal circulating lipid profile may be linked to the hormonal profile and ovarian lipid metabolism.
Objective:
Assess how estradiol, progesterone, and ovarian lipid metabolism contribute to the premenopausal lipid profile. Also, evaluate the acute effects of a common hormonal oral contraceptive (OC) on circulating lipids.
D...
Objective:
To investigate the direct actions of active 1,25-dihydroxy vitamin D3 (VD3) upon primate follicular development at specific stages of folliculogenesis.
Design:
Secondary preantral follicles were isolated from rhesus monkeys ovaries, encapsulated in alginate, and cultured for 40 days. Follicles were randomly assigned to experimental gr...