News Article | May 16, 2017
Fans of 3D printing say it has the potential to revolutionize medicine—think 3D-printed skin, ears, bone scaffolds, and heart valves. Now, prosthetic ovaries made of gelatin have allowed mice to conceive and give birth to healthy offspring. Such engineered ovaries could one day be used to help restore fertility in cancer survivors rendered sterile by radiation or chemotherapy. This “landmark study” is a “significant advance in the application of bioengineering to reproductive tissues,” says Mary Zelinski, a reproductive scientist at the Oregon National Primate Research Center in Beaverton who was not involved with the work. The researchers used a 3D printer with a nozzle that fired gelatin, derived from the collagen that’s naturally found in animal ovaries. The scientists built the ovaries by printing various patterns of overlapping gelatin filaments on glass slides—like building with Lincoln Logs, but on a miniature scale: Each scaffold measured just 15 by 15 millimeters. The team then carefully inserted mouse follicles—spherical structures containing a growing egg surrounded by hormone-producing cells—into these “scaffolds.” The scaffolds that were more tightly woven hosted a higher fraction of surviving follicles after 8 days, an effect the team attributes to the follicles having better physical support. The researchers then tested the more tightly woven scaffolds in live mice. The researchers punched out 2-millimeter circles through the scaffolds and implanted 40–50 follicles into each one, creating a “bioprosthetic” ovary. They then surgically removed the ovaries from seven mice and sutured the prosthetic ovaries in their place. The team showed that blood vessels from each mouse infiltrated the scaffolds. This vascularization is critical because it provides oxygen and nutrients to the follicles and allows hormones produced by the follicles to circulate in the blood stream. The researchers allowed the mice to mate, and three of the females gave birth to healthy litters, the team reports today in . The mice that gave birth also lactated naturally, which demonstrated that the follicles embedded in the scaffolds produced normal levels of hormones. The team is hopeful that similar bioprosthetic ovaries can be implanted in human patients to restore fertility, using a patient’s own previously extracted follicles or donated samples. But that is a long way off. Ovarian scaffolds for humans will need to be specifically designed to host blood vessels because of their larger size, a challenge any large “printed” body part will have to overcome, says Nicolas Sigaux, a surgeon focused on medical applications of 3D printing at the Lyon-Sud Hospital Center in France. “Vascularization is the main limitation to printing large pieces of functional tissue.” Once this problem is solved, ready-to-implant organs should be possible with 3D bioprinting, he notes.
Roberts Jr C.T.,Oregon Health And Science University |
Roberts Jr C.T.,Oregon National Primate Research Center |
Kurre P.,Oregon Health And Science University
Cancer Research | Year: 2013
Cell-cell communication, either in direct proximity or at a distance, generally occurs by receptor-ligand engagement and subsequent activation of downstream intracellular signaling cascades. This conventional, largely protein-based, model has long been considered necessary and sufficient to explain coordinate tissue and organismal function. Intriguing recent work indicates that many cells can also transfer RNA directly via cell-cell trafficking of nanometer-sized, lipid-bilayer vesicles. The distinct biogenesis pathways that give rise to the different vesicle types described to date are just beginning to be elucidated. Notwithstanding their diverse origin, all types of vesicles seem to contain a broad, cell-specific, nonrandom representation of cellular protein and RNA species. The cell-cell trafficking of coding and small noncoding RNAs in particular constitutes a new paradigm for the direct phenotypic modulation of cells in the local microenvironment and in distal organs. Here, we review the current understanding of RNA vesicle trafficking and its emerging role in cell-cell signaling. © 2013 American Association for Cancer Research.
Mao P.,Oregon National Primate Research Center |
Reddy P.H.,Oregon National Primate Research Center |
Reddy P.H.,Oregon Health And Science University
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2010
Multiple sclerosis (MS) is a relatively common and etiologically unknown disease with no cure. It is the leading cause of neurological disability in young adults, affecting over two million people worldwide. Traditionally, MS has been considered a chronic, inflammatory disorder of the central white matter in which ensuing demyelination results in physical disability. Recently, MS has become increasingly viewed as a neurodegenerative disorder in which axonal injury, neuronal loss, and atrophy of the central nervous system leads to permanent neurological and clinical disability. In this article, we discuss the latest developments on MS research, including etiology, pathology, genetic association, EAE animal models, mechanisms of neuronal injury and axonal transport, and therapeutics. In this article, we also focus on the mechanisms of mitochondrial dysfunction that are involved in MS, including mitochondrial DNA defects, and mitochondrial structural/functional changes. © 2009 Elsevier B.V. All rights reserved.
Gesuete R.,Oregon Health And Science University |
Kohama S.G.,Oregon National Primate Research Center |
Stenzel-Poore M.P.,Oregon Health And Science University
Journal of Neuropathology and Experimental Neurology | Year: 2014
Toll-like receptors (TLRs) are master regulators of innate immunity and play an integral role in the activation of inflammatory response during infections. In addition, TLRs influence the body's response to numerous forms of injury. Recent data have shown that TLRs play a modulating role in ischemic brain damage after stroke. Interestingly, their stimulation before ischemia induces a tolerant state that is neuroprotective. This phenomenon, referred to as TLR preconditioning, is the result of the reprogramming of TLR response to ischemic injury. This review addresses the role of TLRs in brain ischemia and the activation of endogenous neuroprotective pathways in the setting of preconditioning. We highlight the protective role of interferon-related response and the potential site of action for TLR preconditioning involving the blood-brain barrier. Pharmacologic modulation of TLR activation to promote protection against stroke is a promising approach for the development of prophylactic and immediate therapies targeting ischemic brain injury. Copyright © 2014 by the American Association of Neuropathologists, Inc.
Telfer E.E.,University of Edinburgh |
Zelinski M.B.,Oregon National Primate Research Center |
Zelinski M.B.,Oregon Health And Science University
Fertility and Sterility | Year: 2013
The removal and cryostorage of ovarian cortical biopsies is now offered as a fertility preservation option for young women. The only available option to restore fertility using this tissue is by transplantation, which may not be possible for all patients. The full potential of this tissue to restore fertility could be achieved by the development of in vitro systems that support oocyte development from the most immature stages to maturation. The techniques of in vitro growth (IVG) combined with in vitro maturation (IVM) are being developed with human tissue, but comparing different systems has been difficult because of the scarcity of tissue so nonhuman primates are being used as model systems. There are many challenges to developing a complete culture system that would support human oocyte development, and this review outlines the approaches being taken by several groups using tissue from women and nonhuman primate models to support each of the stages of oocyte development. © 2013 by American Society for Reproductive Medicine.
Coleman K.,Oregon National Primate Research Center
American Journal of Primatology | Year: 2011
Animal care for nonhuman primates (NHPs) in biomedical facilities has undergone major changes in the past few decades. Today, most primate facilities have dedicated and highly trained animal care technicians who go to great efforts to ensure the physiological and psychological well being of the primates in their charge. These caretakers work closely with the animals and, as a result, often develop strong relationships with them. Once discouraged and considered a potential threat to scientific objectivity, such positive relationships are now seen as important components to animal care. Positive interactions between caretakers and primates can benefit the primates by reducing their stress and improving their overall well being which can, in turn, help the scientific endeavor. Further, providing the best possible care is our moral responsibility. However, there can also be emotional costs associated with caring for NHPs in research facilities, particularly when animals become ill or have to be euthanized. Facilities can do much to help ease this conflict. High-quality and conscientious animal care is good for the animals, science, and public perception of research facilities. © 2010 Wiley-Liss, Inc.
Lima F.B.,Oregon National Primate Research Center |
Bethea C.L.,Oregon National Primate Research Center
Molecular Psychiatry | Year: 2010
We previously found that ovarian steroids promote neuroprotection in serotonin neurons by decreasing the expression of pro-apoptotic genes and proteins in the dorsal raphe nucleus of rhesus macaques, even in the absence of overt injury. In this study, we questioned whether these actions would lead to a reduction in DNA fragmentation in serotonin neurons. Ovariectomized (OVX) rhesus monkeys were implanted with silastic capsules that were empty (placebo) or containing estradiol (E), progesterone (P) or estradiol and progesterone (EP) for 1 month. In all animals, eight levels of the dorsal raphe nucleus in a rostral-to-caudal direction were immunostained using the terminal deoxynucleotidyl transferase nick end labeling (TUNEL) method. Two staining patterns were observed, which are referred to as type I, with complete dark staining of the nucleus, and type II, with peripheral staining in the perinuclear area. A montage of the dorsal raphe was created at each level with a Marianas Stereology Microscope and Slidebook 4.2, and the TUNEL-positive cells were counted. In direct comparison with OVX animals, P treatment and EP treatment significantly reduced the total number of TUNEL-positive cells (Mann-Whitney test, both treatments P=0.04) and EP treatment reduced the number of TUNEL-positive cells per mm3 (Mann-Whitney test, P=0.04). Double immunocytochemistry for TUNEL and tryptophan hydroxylase (TPH) indicated that DNA fragmentation was prominent in serotonin neurons. These data suggest that in the absence of ovarian steroids, a cascade of gene and protein expression leads to an increase in DNA fragmentation in serotonin neurons. Conversely, ovarian steroids have a neuroprotective role in the non-injured brain and prevent DNA fragmentation and cell death in serotonin neurons of nonhuman primates. © 2010 Nature Publishing Group All rights reserved.
Varlamov O.,Oregon National Primate Research Center
Biochimica et Biophysica Acta - Molecular Basis of Disease | Year: 2016
The evolutionary transition from hunting to farming was associated with introduction of carbohydrate-rich diets. Today, the increased consumption of simple sugars and high-fat food brought about by Western-style diet and physical inactivity are leading causes of the growing obesity epidemic in the Western society. The extension of human lifespan far beyond reproductive age increased the burden of metabolic disorders associated with overnutrition and age-related hypogonadism. Sex steroids are essential regulators of both reproductive function and energy metabolism, whereas their imbalance causes infertility, obesity, glucose intolerance, dyslipidemia, and increased appetite. Clinical and translational studies suggest that dietary restriction and weight control can improve metabolic and reproductive outcomes of sex hormone-related pathologies, including testosterone deficiency in men and natural menopause and hyperandrogenemia in women. Minimizing metabolic and reproductive decline through rationally designed diet and exercise can help extend human reproductive age and promote healthy aging. This article is part of a Special Issue entitled: Oxidative Stress and Mitochondrial Quality in Diabetes/Obesity and Critical Illness Spectrum of Diseases - edited by P. Hemachandra Reddy. © 2016.
Fisher T.E.,Oregon National Primate Research Center
Human reproduction (Oxford, England) | Year: 2013
What is the time course of production of vascular endothelial growth factor-A (VEGF-A), angiopoietin (ANGPT)-1 and ANGPT-2 by primate follicles during encapsulated three-dimensional culture, and what conditions affect their production? Primate follicles produce VEGF-A and ANGPT-2 in vitro, particularly after developing to the antral stage, with VEGF production influenced by FSH concentration and O(2) tension. Folliculogenesis, i.e. the development of primordial follicles into mature, antral follicles, requires the creation of a vascular network in the follicle wall via a process called angiogenesis. Angiogenic factors including VEGFs and ANGPTs have documented roles in angiogenesis. However, direct studies on the production and regulation of angiogenic factors by individual, growing follicles are limited. Ovaries (n = 9 pairs) were obtained from rhesus macaques during the early follicular phase of the menstrual cycle (cycle days 1-4). Secondary (125-225 μm) follicles were isolated mechanically, encapsulated into alginate (0.25% w/v) and cultured for 40 days. Individual follicles were cultured in a 5 or 20% O(2) environment in alpha minimum essential medium supplemented with recombinant human (h) FSH. Half of the follicles had recombinant hLH added to the media from Days 30 to 40. Follicle diameters were measured weekly. Follicles were categorized at Week 5 as no-grow (NG; <250 μm in diameter), slow-grow (SG; 251-499 μm) and fast-grow (FG; >500 μm). VEGF-A, ANGPT-1 and -2 concentrations in media were measured by ELISA. VEGF concentrations were low throughout the culture for NG follicles. SG and FG follicles had detectable VEGF concentrations at Week 2, which continued to rise throughout culture. VEGF concentrations were distinct (P < 0.05) among all three follicle categories during Weeks 4 and 5. VEGF concentrations were higher (P < 0.05) in SG follicles in the presence of high/mid-dose FSH at 5% O(2). In contrast, there were no dose-dependent differences in VEGF production for FG follicles based on FSH concentrations or O(2) tension. At Week 5, follicles that produced metaphase II oocytes, following exposure to an ovulatory hCG dose, secreted higher concentrations of VEGF than those containing germinal vesicle-intact oocytes. Media concentrations of ANGPT-1 were low throughout culture for all three follicle categories. ANGPT-2 concentrations were low throughout culture for NG follicles. In contrast, ANGPT-2 concentrations of SG and FG follicles continued to rise from Weeks 1 to 4. During Weeks 2-4, ANGPT-2 concentrations in FG follicles were significantly higher than those of SG and NG follicles (P < 0.05). This study reports VEGF-A, ANGPT-1 and -2 production by in vitro-developed individual primate (macaque) follicles, that is limited to the interval from the secondary to small antral stage. After VEGF and ANGPT-1 assays, the limited remaining samples did not allow assessment of the independent effects of gonadotrophin and O(2) on the ANGPT-2 production by cultured follicles. Findings await translation to human follicles. The above findings provide novel information on the process of primate follicle maturation. We hypothesize that a symbiotic relationship between elevated concentrations of ANGPT-2 and VEGF allows FG antral follicles to excel in follicle maturation, e.g. by promoting its vascularization. Elevated ANGPT-2 may also offer possible insight into future oocyte quality as early as Week 2, compared with Week 4 for VEGF and follicle size. The study was funded by the following grants: NIH U54 RR024347/HD058294/PL1-EB008542 (Oncofertility Consortium), NIH U54-HD018185 (SCCPIR), NIH ORWH/NICHD 2K12HD043488 (BIRCWH), NIH FIC TW/HD-00668, ONPRC 8P51OD011092. There are no conflicts of interest to declare.
Coleman K.,Oregon National Primate Research Center
Applied Animal Behaviour Science | Year: 2012
Effective behavioral management plans are tailored to the unique behavioral patterns of each individual species. However, even within a species behavioral needs of individuals can vary. Factors such as age, sex, and temperament can affect behavioral needs of individuals. While some of these factors, such as age and sex, are taken into account, other factors, such as an individual's temperament, are rarely specifically provided for in behavioral management plans. However, temperament may affect how animals respond to socialization, positive reinforcement training and other forms of enrichment. This review will examine how individual differences in temperament might affect, or be affected by, behavioral management practices for captive primates. Measuring temperament may help us predict the outcome of social introductions. It can also predict which animals may be difficult to train using traditional methods. Further, knowledge of temperament may help us identify individuals at risk for development of behavioral problems. Taken together, understanding individual differences in temperament of captive primates can help guide behavioral management decisions. © 2011 Elsevier B.V.