Publications by authors named "Kelly Haston"

10 Publications

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The Library of Integrated Network-Based Cellular Signatures NIH Program: System-Level Cataloging of Human Cells Response to Perturbations.

Cell Syst 2018 01 29;6(1):13-24. Epub 2017 Nov 29.

BD2K-LINCS DCIC, Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45220, USA.

The Library of Integrated Network-Based Cellular Signatures (LINCS) is an NIH Common Fund program that catalogs how human cells globally respond to chemical, genetic, and disease perturbations. Resources generated by LINCS include experimental and computational methods, visualization tools, molecular and imaging data, and signatures. By assembling an integrated picture of the range of responses of human cells exposed to many perturbations, the LINCS program aims to better understand human disease and to advance the development of new therapies. Perturbations under study include drugs, genetic perturbations, tissue micro-environments, antibodies, and disease-causing mutations. Responses to perturbations are measured by transcript profiling, mass spectrometry, cell imaging, and biochemical methods, among other assays. The LINCS program focuses on cellular physiology shared among tissues and cell types relevant to an array of diseases, including cancer, heart disease, and neurodegenerative disorders. This Perspective describes LINCS technologies, datasets, tools, and approaches to data accessibility and reusability.
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http://dx.doi.org/10.1016/j.cels.2017.11.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799026PMC
January 2018

Clinical Trials in a Dish: The Potential of Pluripotent Stem Cells to Develop Therapies for Neurodegenerative Diseases.

Annu Rev Pharmacol Toxicol 2016 28;56:489-510. Epub 2015 Oct 28.

Gladstone Institute of Neurological Disease, San Francisco, California 94158; email:

Neurodegenerative diseases are a leading cause of death. No disease-modifying therapies are available, and preclinical animal model data have routinely failed to translate into success for therapeutics. Induced pluripotent stem cell (iPSC) biology holds great promise for human in vitro disease modeling because these cells can give rise to any cell in the human brain and display phenotypes specific to neurodegenerative diseases previously identified in postmortem and clinical samples. Here, we explore the potential and caveats of iPSC technology as a platform for drug development and screening, and the future potential to use large cohorts of disease-bearing iPSCs to perform clinical trials in a dish.
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http://dx.doi.org/10.1146/annurev-pharmtox-010715-103548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868344PMC
September 2016

Imaging-based chemical screening reveals activity-dependent neural differentiation of pluripotent stem cells.

Elife 2013 Sep 10;2:e00508. Epub 2013 Sep 10.

Department of Bioengineering and Therapeutic Science , University of California, San Francisco , San Francisco , United States ; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research , University of California, San Francisco , San Francisco , United States ; Programs in Human Genetics and Biological Sciences , University of California, San Francisco , San Francisco , United States.

Mammalian pluripotent stem cells (PSCs) represent an important venue for understanding basic principles regulating tissue-specific differentiation and discovering new tools that may facilitate clinical applications. Mechanisms that direct neural differentiation of PSCs involve growth factor signaling and transcription regulation. However, it is unknown whether and how electrical activity influences this process. Here we report a high throughput imaging-based screen, which uncovers that selamectin, an anti-helminthic therapeutic compound with reported activity on invertebrate glutamate-gated chloride channels, promotes neural differentiation of PSCs. We show that selamectin's pro-neurogenic activity is mediated by γ2-containing GABAA receptors in subsets of neural rosette progenitors, accompanied by increased proneural and lineage-specific transcription factor expression and cell cycle exit. In vivo, selamectin promotes neurogenesis in developing zebrafish. Our results establish a chemical screening platform that reveals activity-dependent neural differentiation from PSCs. Compounds identified in this and future screening might prove therapeutically beneficial for treating neurodevelopmental or neurodegenerative disorders. DOI:http://dx.doi.org/10.7554/eLife.00508.001.
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http://dx.doi.org/10.7554/eLife.00508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771564PMC
September 2013

Stem cell biology and drug discovery.

BMC Biol 2011 Jun 7;9:42. Epub 2011 Jun 7.

Dept of Stem Cell and Regenerative Biology and Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.

There are many reasons to be interested in stem cells, one of the most prominent being their potential use in finding better drugs to treat human disease. This article focuses on how this may be implemented. Recent advances in the production of reprogrammed adult cells and their regulated differentiation to disease-relevant cells are presented, and diseases that have been modeled using these methods are discussed. Remaining difficulties are highlighted, as are new therapeutic insights that have emerged.
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http://dx.doi.org/10.1186/1741-7007-9-42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110139PMC
June 2011

Intact fetal ovarian cord formation promotes mouse oocyte survival and development.

BMC Dev Biol 2010 Jan 8;10. Epub 2010 Jan 8.

Institute for Stem Cell Biology and Regenerative Medicine, Department of Obstetrics and Gynecology, Stanford University, Palo Alto, CA, USA.

Background: Female reproductive potential, or the ability to propagate life, is limited in mammals with the majority of oocytes lost before birth. In mice, surviving perinatal oocytes are enclosed in ovarian follicles for subsequent oocyte development and function in the adult. Before birth, fetal germ cells of both sexes develop in clusters, or germline cysts, in the undifferentiated gonad. Upon sex determination of the fetal gonad, germ cell cysts become organized into testicular or ovarian cord-like structures and begin to interact with gonadal somatic cells. Although germline cysts and testicular cords are required for spermatogenesis, the role of cyst and ovarian cord formation in mammalian oocyte development and female fertility has not been determined.

Results: Here, we examine whether intact fetal ovarian germ and somatic cell cord structures are required for oocyte development using mouse gonad re-aggregation and transplantation to disrupt gonadal organization. We observed that germ cells from disrupted female gonad prior to embryonic day e13.5 completed prophase I of meiosis but did not survive following transplantation. Furthermore, re-aggregated ovaries from e13.5 to e15.5 developed with a reduced number of oocytes. Oocyte loss occurred before follicle formation and was associated with an absence of ovarian cord structure and ovary disorganization. However, disrupted ovaries from e16.5 or later were resistant to the re-aggregation impairment and supported robust oocyte survival and development in follicles.

Conclusions: Thus, we demonstrate a critical window of oocyte development from e13.5 to e16.5 in the intact fetal mouse ovary, corresponding to the establishment of ovarian cord structure, which promotes oocyte interaction with neighboring ovarian somatic granulosa cells before birth and imparts oocytes with competence to survive and develop in follicles. Because germline cyst and ovarian cord structures are conserved in the human fetal ovary, the identification of genetic components and molecular mechanisms of pre-follicle stage germ and somatic cell structures may be important for understanding human female infertility. In addition, this work provides a foundation for development of a robust fetal ovarian niche and transplantation based system to direct stem cell-derived oocyte differentiation as a potential therapeutic strategy for the treatment of infertility.
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http://dx.doi.org/10.1186/1471-213X-10-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2830955PMC
January 2010

Transplantation directs oocyte maturation from embryonic stem cells and provides a therapeutic strategy for female infertility.

Hum Mol Genet 2009 Nov 20;18(22):4376-89. Epub 2009 Aug 20.

Department of Obstetrics and Gynecology, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Palo Alto, CA 94304, USA.

Ten to 15% of couples are infertile, with the most common causes being linked to the production of few or no oocytes or sperm. Yet, our understanding of human germ cell development is poor, at least in part due to the inaccessibility of early stages to genetic and developmental studies. Embryonic stem cells (ESCs) provide an in vitro system to study oocyte development and potentially treat female infertility. However, most studies of ESC differentiation to oocytes have not documented fundamental properties of endogenous development, making it difficult to determine the physiologic relevance of differentiated germ cells. Here, we sought to establish fundamental parameters of oocyte development during ESC differentiation to explore suitability for basic developmental genetic applications using the mouse as a model prior to translating to the human system. We demonstrate a timeline of definitive germ cell differentiation from ESCs in vitro that initially parallels endogenous oocyte development in vivo by single-cell expression profiling and analysis of functional milestones including responsiveness to defined maturation media, shared genetic requirement of Dazl, and entry into meiosis. However, ESC-derived oocyte maturation ultimately fails in vitro. To overcome this obstacle, we transplant ESC-derived oocytes into an ovarian niche to direct their functional maturation and, thereby, present rigorous evidence of oocyte physiologic relevance and a potential therapeutic strategy for infertility.
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http://dx.doi.org/10.1093/hmg/ddp393DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2766296PMC
November 2009

Dazl functions in maintenance of pluripotency and genetic and epigenetic programs of differentiation in mouse primordial germ cells in vivo and in vitro.

PLoS One 2009 May 21;4(5):e5654. Epub 2009 May 21.

Department of Obstetrics and Gynecology, Institute for Stem Cell Biology & Regenerative Medicine, Stanford University School of Medicine, Palo Alto, California, United States of America.

Background: Mammalian germ cells progress through a unique developmental program that encompasses proliferation and migration of the nascent primordial germ cell (PGC) population, reprogramming of nuclear DNA to reset imprinted gene expression, and differentiation of mature gametes. Little is known of the genes that regulate quantitative and qualitative aspects of early mammalian germ cell development both in vivo, and during differentiation of germ cells from mouse embryonic stem cells (mESCs) in vitro.

Methodology And Principal Findings: We used a transgenic mouse system that enabled isolation of small numbers of Oct4DeltaPE:GFP-positive germ cells in vivo, and following differentiation from mESCs in vitro, to uncover quantitate and qualitative phenotypes associated with the disruption of a single translational regulator, Dazl. We demonstrate that disruption of Dazl results in a post-migratory, pre-meiotic reduction in PGC number accompanied by aberrant expression of pluripotency genes and failure to erase and re-establish genomic imprints in isolated male and female PGCs, as well as subsequent defect in progression through meiosis. Moreover, the phenotypes observed in vivo were mirrored by those in vitro, with inability of isolated mutant PGCs to establish pluripotent EG (embryonic germ) cell lines and few residual Oct-4-expressing cells remaining after somatic differentiation of mESCs carrying a Dazl null mutation. Finally, we observed that even within undifferentiated mESCs, a nascent germ cell subpopulation exists that was effectively eliminated with ablation of Dazl.

Conclusions And Significance: This report establishes the translational regulator Dazl as a component of pluripotency, genetic, and epigenetic programs at multiple time points of germ cell development in vivo and in vitro, and validates use of the ESC system to model and explore germ cell biology.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0005654PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2681483PMC
May 2009

Pesticide mixtures, endocrine disruption, and amphibian declines: are we underestimating the impact?

Environ Health Perspect 2006 Apr;114 Suppl 1:40-50

Laboratory for Integrative Studies in Amphibian Biology, Department of Integrative Biology, Museum of Vertebrate Zoology, Group in Endocrinology, University of California, Berkeley, California 94720-3140, USA.

Amphibian populations are declining globally at an alarming rate. Pesticides are among a number of proposed causes for these declines. Although a sizable database examining effects of pesticides on amphibians exists, the vast majority of these studies focus on toxicological effects (lethality, external malformations, etc.) at relatively high doses (parts per million). Very few studies focus on effects such as endocrine disruption at low concentrations. Further, most studies examine exposures to single chemicals only. The present study examined nine pesticides (four herbicides, two fungicides, and three insecticides) used on cornfields in the midwestern United States. Effects of each pesticide alone (0.1 ppb) or in combination were examined. In addition, we also examined atrazine and S-metolachlor combined (0.1 or 10 ppb each) and the commercial formulation Bicep II Magnum, which contains both of these herbicides. These two pesticides were examined in combination because they are persistent throughout the year in the wild. We examined larval growth and development, sex differentiation, and immune function in leopard frogs (Rana pipiens). In a follow-up study, we also examined the effects of the nine-compound mixture on plasma corticosterone levels in male African clawed frogs (Xenopus laevis). Although some of the pesticides individually inhibited larval growth and development, the pesticide mixtures had much greater effects. Larval growth and development were retarded, but most significantly, pesticide mixtures negated or reversed the typically positive correlation between time to metamorphosis and size at metamorphosis observed in controls: exposed larvae that took longer to metamorphose were smaller than their counterparts that metamorphosed earlier. The nine-pesticide mixture also induced damage to the thymus, resulting in immunosuppression and contraction of flavobacterial meningitis. The study in X. laevis revealed that these adverse effects may be due to an increase in plasma levels of the stress hormone corticosterone. Although it cannot be determined whether all the pesticides in the mixture contribute to these adverse effects or whether some pesticides are effectors, some are enhancers, and some are neutral, the present study revealed that estimating ecological risk and the impact of pesticides on amphibians using studies that examine only single pesticides at high concentrations may lead to gross underestimations of the role of pesticides in amphibian declines.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1874187PMC
http://dx.doi.org/10.1289/ehp.8051DOI Listing
April 2006

Atrazine-induced hermaphroditism at 0.1 ppb in American leopard frogs (Rana pipiens): laboratory and field evidence.

Environ Health Perspect 2003 Apr;111(4):568-75

Laboratory for Integrative Studies in Amphibian Biology, Group in Endocrinology, Museum of Vertebrate Zoology, and Department of Integrative Biology, University of California, Berkeley, California 94720, USA.

Atrazine is the most commonly used herbicide in the United States and probably the world. Atrazine contamination is widespread and can be present in excess of 1.0 ppb even in precipitation and in areas where it is not used. In the current study, we showed that atrazine exposure (> or = to 0.1 ppb) resulted in retarded gonadal development (gonadal dysgenesis) and testicular oogenesis (hermaphroditism) in leopard frogs (Rana pipiens). Slower developing males even experienced oocyte growth (vitellogenesis). Furthermore, we observed gonadal dysgenesis and hermaphroditism in animals collected from atrazine-contaminated sites across the United States. These coordinated laboratory and field studies revealed the potential biological impact of atrazine contamination in the environment. Combined with reported similar effects in Xenopus laevis, the current data raise concern about the effects of atrazine on amphibians in general and the potential role of atrazine and other endocrine-disrupting pesticides in amphibian declines.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1241446PMC
http://dx.doi.org/10.1289/ehp.5932DOI Listing
April 2003

Herbicides: feminization of male frogs in the wild.

Nature 2002 Oct;419(6910):895-6

Laboratory for Integrative Studies in Amphibian Biology, Museum of Vertebrate Zoology, and Department of Integrative Biology, University of California, Berkeley, California 94720-3140, USA.

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http://dx.doi.org/10.1038/419895aDOI Listing
October 2002