Cover
List of Contributors
Preface
Part I: Introduction and Overview
1. Chapter 1: The Basics of Stem Cells and Their Utility as Platforms to Model Teratogen Action and Human Developmental and Degenerative Disorders
  1. 1.1 Stem Cell Types and Basic Function
  2. 1.2 Pluripotency
  3. 1.3 In vitro Uses of Pluripotent Cells
  4. 1.4 Adult Stem Cells In vivo
  5. 1.5 Emerging Trends in Stem Cell Culture
  6. 1.6 Future Directions
  7. References
Part II: Using Pluripotent Cells for the Detection and Analysis of Teratogens
1. Chapter 2: Stem Cells and Tissue Engineering Technologies for Advancing Human Teratogen Screening
  1. Abbreviations
  2. 2.1 Introduction
  3. 2.2 Current DART Regulatory Guidelines and Methods
  4. 2.3 In vitro Animal‐Based Models for Developmental Toxicity Testing
  5. 2.4 In vitro Stem‐Cell‐Based Developmental Toxicity Models
  6. 2.5 Conclusion and Future Directions
  7. References
2. Chapter 3: Use of Embryoid Bodies for the Detection of Teratogens and Analysis of Teratogenic Mechanisms
  1. 3.1 Embryoid Body Assays: Background
  2. 3.2 Detection of Teratogens Using EBs
  3. 3.3 Teratogenic Mechanisms
  4. Acknowledgments
  5. References
3. Chapter 4: Stem‐Cell‐Based In vitro Morphogenesis Models to Investigate Developmental Toxicity of Chemical Exposures
  1. 4.1 Introduction
  2. 4.2 Stem‐Cell‐Based In vitro Morphogenesis Model
  3. 4.3 Future Directions: Enhancing Morphogenesis‐Based Assays
  4. 4.4 Concluding Remarks
  5. Acknowledgment
  6. References
4. Chapter 5: Risk Assessment Using Human Pluripotent Stem Cells: Recent Advances in Developmental Toxicity Screens
  1. 5.1 Introduction
  2. 5.2 Animal Embryo Studies to Evaluate Developmental Toxicity
  3. 5.3 Usage of Mouse Embryonic Stem Cells in Developmental Toxicity
  4. 5.4 Alternative Endpoint Read‐Out Approaches in the EST
  5. 5.5 Novel Methods and Protocols to Replicate Human Development
  6. 5.6 Future Applications
  7. Acknowledgments
  8. References
Part III: Human Developmental Pathologies Mediated by Adult Stem Cells
1. Chapter 6: Modeling the Brain in the Culture Dish: Advancements and Applications of Induced Pluripotent Stem‐Cell‐Derived Neurons
  1. 6.1 Introduction
  2. 6.2 Methods to Generate Patient‐Derived Neurons
  3. 6.3 Neuronal Induction from Fibroblasts and hiPSCs
  4. 6.4 Cerebral Organoids: Neural Modeling in Three Dimensions
  5. 6.5 Epigenetic Considerations in hiPSC Donor Cell Choice
  6. 6.6 Aging Neurons
  7. 6.7 Drug Testing Using hiPSCs
  8. 6.8 Promises in the Field
  9. 6.9 Concluding Remarks
  10. References
2. Chapter 7: Modeling Genetic and Environment Interactions Relevant to Huntington's and Parkinson's Disease in Human Induced Pluripotent Stem Cells (hiPSCs)‐Derived Neurons
  1. 7.1 Gene–Environment Interactions Assessed in hiPSC‐Derived Neurons
  2. 7.2 Modeling of Neurological Diseases with hiPSCs
  3. 7.3 Cell Viability Assays
  4. 7.4 Mitochondria
  5. 7.5 Oxidative Stress
  6. 7.6 Neurite Length by Immunocytochemistry (ICC)
  7. 7.7 Conclusions
  8. References
3. Chapter 8: Alcohol Effects on Adult Neural Stem Cells – A Novel Mechanism of Neurotoxicity and Recovery in Alcohol Use Disorders
  1. 8.1 Introduction
  2. 8.2 The “Birth” of the Study of “Neuronal Cell Birth”
  3. 8.3 Components of Adult Stem‐Cell‐Driven Neurogenesis
  4. 8.4 Alcohol Effects on Adult Neural Stem Cells and Neurogenesis
  5. 8.5 Extrinsic Factors Influence the Neurogenic Niche
  6. 8.6 Alcohol and the Niche
  7. 8.7 Conclusions
  8. References
4. Chapter 9: Fetal Alcohol Spectrum Disorders: A Stem‐Cellopathy?
  1. 9.1 Fetal Alcohol Spectrum Disorders
  2. 9.2 Stem Cells
  3. 9.3 Endoderm
  4. 9.4 Mesoderm
  5. 9.5 Ectoderm
  6. 9.6 Future Directions
  7. 9.7 Conclusion
  8. References
5. Chapter 10: Toxicological Responses in Keratinocyte Interfollicular Stem Cells
  1. 10.1 Epidermal Keratinocyte Stem Cells
  2. 10.2 Arsenic
  3. 10.3 Dioxin
  4. 10.4 Bacterial Toxins
  5. 10.5 Conclusions and Prospective Considerations
  6. References
Part IV: Recent Innovations in Stem Cell Bioassay and Platform Development
1. Chapter 11: Stem‐Cell Microscale Platforms for Toxicology Screening
  1. 11.1 Introduction
  2. 11.2 Stem Cell Models for Toxicology Assessment
  3. 11.3 Biomimetic Microscale Systems for Drug Screening
  4. 11.4 Microtechnologies for Drug Discovery
  5. 11.5 Devices for High‐Throughput Toxicology Studies
  6. 11.6 Cellular Microarray Platforms
  7. 11.7 Microfluidic Platforms
  8. 11.8 Conclusions and Future Perspectives
  9. Acknowledgments
  10. References
2. Chapter 12: HepaRG Cells as a Model for Hepatotoxicity Studies
  1. 12.1 Introduction
  2. 12.2 Characteristics of HepaRG Cells
  3. 12.3 Biotransformation and Detoxification Activities
  4. 12.4 Toxicity Studies
  5. 12.5 Conclusions and Perspectives
  6. Acknowledgments
  7. References
Index
End User License Agreement

List of Tables

Chapter 02
1. Table 2.1 Current animal‐based DART testing guidelines and study methodologies.
2. Table 2.2 In vitro animal‐based models for developmental toxicity testing.
3. Table 2.3 Current major in vitro stem cell‐based teratogen screening assays.
Chapter 10
1. Table 10.1 Expressed markers and functional characteristics for recognizing or preferentially isolating interfollicular KCs of differing mitotic reserve.

List of Illustrations

Chapter 01
1. Figure 1.1 Derivation and use of pluripotent cells for in vitro teratology and toxicology applications. ESCs are derived from the ICM of blastocyst‐stage embryos (mouse or human) and a pluripotent. Alternatively, iPSCs can be produced by factor‐mediated reprogramming of terminally differentiated somatic cells such as fibroblasts. iPSCs are also pluripotent. Pluripotent cells (ESCs or iPSCs) can be differentiated into EBs for modeling of early development and used to detect teratogens or study human genetically specified birth defect mechanisms (provided that iPSCs containing relevant genetic developmental mutations are used). In addition, both ESCs and iPSCs can be subjected to directed differentiation to detect chemically induced impacts on specific cell types. Finally, patient‐specific iPSCs can be used to detect and study individualized pharmacogenomic responses to pharmaceuticals (in terms of efficacy or toxicity).
2. Figure 1.2 Adult (endogenous) stem cells and developmental toxicity. An emerging theme is that some human disorders occur due to impacts upon endogenous adult stem cells (“stem cellopathies”). Adult stem cells arise during organogenesis, and if they are compromised during gestation, birth defects and developmental disorders that play out later in life can occur. In addition, adult stem cells are required for tissue homeostasis and organ regeneration, and insults to adult stem cell populations in the adult can also lead to human disorders, impacting a variety of organs. Successive restriction in developmental potency (from totipotency to multipotency) of endogenous stem cells and major landmarks in human development and maturation are shown.
Chapter 02
1. Figure 2.1 A representative experiment protocol of the ZEDT assay.
2. Figure 2.2 Microfabrication technologies to immobilize and perform phenotypic teratogen screening on animal embryos. (a) Immobilization of chick embryos in a porous microstructure made up of PDMS. (b) Engineered microfluidic systems to dock zebrafish embryos to perform teratogen screening under continuous perfusion culture conditions. (c) A microfabricated embryo‐trapping array to trap multiple embryos within a single microfluidic platform and perform simultaneous high‐throughput phenotypic screening of zebrafish embryos under teratogen treatment. (d) A concentration gradient generator (CGG)‐based microfluidic device to screen the dose‐dependent effect of teratogen on embryo growth on a single microfluidic device, (e) Images displaying the phenotypic dose‐dependent effect of teratogen, valproic acid, on the zebrafish embryo cultured on a microfabricated platform.
3. Figure 2.3 Cardiac differentiation in the mEST. (a) Undifferentiated mESCs. (b) EB formation using the hanging drop method. (c) Day 5 EB in suspension culture. (d) EB outgrowth on day 10 of differentiation. The center region was where the beating cardiomyocytes located.
4. Figure 2.4 The mesoendoderm pattern formation by spatially and temporally controlled hPSC differentiation and migration using the micropatterning technique. (a) Schematic representation of the μP‐hPSC colony mesoendoderm induction. (b) Phase and fluorescent images of the differentiating μP‐hPSC colonies from day 1 to day 3. T: mesoendoderm marker Brachyury. Scale bar: 200 μm. (c) A montage showing the 3‐day phase imaging on a quarter section of the μP‐hPSC colony. Scale bar, 100 μm. Source: Adapted from Xing et al. (2015).
Chapter 03
1. Figure 3.1 Workflow and considerations for EB analysis of teratogens. EBs are assembled and differentiated by sequential steps beginning with pluripotent cell culture, aggregation of pluripotent cells, growth and differentiation (during which time suspected teratogens can be added, followed by assays using a variety of endpoints). These steps and technical considerations at each step are shown here.
2. Figure 3.2 Varieties of EB compromise upon exposure to compounds. EBs can be affected in a variety of ways upon exposure to compounds, and each of these can be used as quantitative endpoints to determine EB assay outcomes. Effects observed in EBs dosed with compounds include growth retardation, growth arrest, morphological defects, and altered cellular content.
Chapter 04
1. Figure 4.1 Production and analysis of P19C5 Embryoid Bodies. (a) Hanging drop culture method to generate embryoid bodies (EBs) with P19C5 stem cells. (Top) Drops (20 μL each) of cell suspension are spotted on the inner surface of the lid of a Petri dish. (Bottom) The lid is flipped and placed over the bottom part of the Petri dish filled with phosphate‐buffered saline to maintain humidity. (b) Time course of morphogenesis of P19C5 EBs. EBs are removed from hanging drops and placed together for photographing. Scale bar = 1 mm. (c) Whole‐mount in situ hybridization of Day 4 P19C5 EBs for developmental regulator genes. An arrowhead points to the tight expression of Wnt3a. Expressions of Cdx2 and Wnt3a (markers for the posterior end of the normal embryo at E8.5) are restricted to the broader side of the EB, whereas Meox1 (a marker of somitic mesoderm, which forms more anteriorly) localized to the opposite side of the EB. (d) A schematic diagram, depicting dynamic temporal changes in expression levels of developmental regulator genes. (e) Tracing of the EB circumference using the ImageJ program for morphometric analysis. (Left) Before trace. (Right) After trace with the Polygon Selection tool, showing yellow lines connected with white nodules. (f) Temporal changes in the morphometric parameters of P19C5 EBs. Average values ±95% confidence intervals are shown (n = 44).
2. Figure 4.2 Chemical Exposure of P19C5 Embryoid Bodies. (a) Images of Day 4 P19C5 EBs that have been cultured with specific chemical exposures: acitretin (0.1 μM), 5‐fluorouracil (1 μM), and ribavirin (1 μM). (b) Images of control Day 4 EBs and those that have been treated with valproic acid (VPA) at 0.6 mM. (c) A model of the molecular mechanisms by which VPA exerts teratogenic actions. HDAC (histone deacetylase), RA (retinoic acid), RAR (retinoic acid receptor), and Ac (acetylated). (d) Time course of morphogenesis of an EB made from human embryonic stem cells (hESCs; H9 line). (e) A group of hESC EBs at Day 4, showing consistency of elongation morphogenesis. Scale bars in (d) and (e)=500 μm. (f) Temporal changes in the morphometric parameters of hESC EBs. Average values ±95% confidence intervals are shown (n = 10). (g) Immunohistochemistry for BRACHYURY protein, showing localized expression (arrowhead) in a Day 4 hESC EB.
Chapter 05
1. Figure 5.1 Schematic depiction of potential uses of stem cells for toxicity assessment. PSC, pluripotent stem cell; SC, stem cell.
Chapter 06
1. Figure 6.1 (a) Overexpression of ASCL1, NURR1, and LMX1A generates ~4% pure population of dopaminergic neurons; TuJ1 is a neuronal marker, while TH is a key enzyme in dopaminergic neurons. (b) NGN2 overexpression alone rapidly induces iPSCs and ESCs into a glutamatergic fate with near 100% efficiency; cells overexpressing NGN2 fluoresce green and demonstrate neuronal morphology. (c) Coexpression of two miRNAs and striatal‐enriched transcription factors generate medium spiny neurons from fibroblasts in 1 month; DAPI labels nuclei, while TUBB3 labels neurons and DLX5 labels medium spiny neurons.
2. Figure 6.2 Illustration of the main steps to derive cerebral organoids from hiPSCs.
3. Figure 6.3 Characteristics of aging including cell senescence, inflammation, telomere shortening and metabolic and epigenetic changes can compromise the reprogramming efficiency of aged somatic cells into hiPSCs. Inhibiting targets that show promise in reprogramming and rejuvenation efficacy may offer additional methodological avenues for hiPSC‐aging.
4. Figure 6.4 Scientists have ventured into the realm of transplantation‐based therapies using autologous iPSC dopamine neurons derived from the Cynomolgus monkey for a non‐human primate model of Parkinson’s disease. These neurons provided long‐term functional recovery and survived up to 2 years, reinnervating the host brain. This success has motivated further studies into hiPSC‐based transplantation therapies as viable treatment options for neurodegenerative diseases.
5. Figure 6.5 As research using hiPSCs advances, scientists hope to address key aspects currently challenging the creation of meaningful patient‐specific in vitro models to study brain disorders.
Chapter 07
1. Figure 7.1 hiPSC‐derived mesencephalic dopaminergic (DA) neurons. Floor plate lineage cells are differentiated from hiPSCs as described (Kumar et al., 2014; Kriks et al., 2011) with a majority expressing lineage‐selective floor plate markers Foxa2 and Lmx1A by day 11 of differentiation. At day 11, the floor plate cells start undergoing final neural maturation and by day 27 of differentiation these neurons express the neuron‐specific marker β3‐tubulin (in red), and the dopamine neuronal marker tyrosine hydroxylase (in green). Cultures were counterstained with Hoechst (in blue), a DNA stain.
2. Figure 7.2 hiPSC‐derived cortical neurons at day 53 stained with MitoTracker Red CMXRos (orange) and counterstained with Hoechst (blue). MitoTracker Red CMXRos is a red fluorescent mitochondrial fixable dye. The accumulation of this stain is dependent on the membrane potential of cells. In this image, there are distinct mitochondrial networks for cortical neurons. With exposure to 300 μM CuSO₄ for 24 h in cortical maintenance media (Shi et al., 2012a), there is fragmentation of the mitochondria and the intricate mitochondrial networks are disrupted.
3. Figure 7.3 Images of hiPSC‐derived control (a) and toxicant‐treated (d) dopaminergic (DA) neurons stained for β3‐tubulin, tyrosine hydroxylase, and counterstained with Hoechst were acquired using a Molecular Device's ImageXpress Micro XL system. β3‐tubulin‐positive neurites of control (b) and toxicant‐treated (e) neuronal cultures were quantified using the neurite length module in MetaXpress software. The traced neurites and associated nuclei of control (c) and toxicant exposed (f) neurons are shown as a red overlay.
Chapter 08
1. Figure 8.1 Sites of constitutive, adult neurogenesis. Cartoon of a sagittal section of rodent brain showing the two well‐accepted neurogenic niches, the hippocampal dentate gyrus subgranular zone and subventricular zone of the anterior lateral ventricles. Insets show the types of progenitor cells and typical markers used to identify subsets of progenitors as they mature in the subgranular zone (SGZ; left box) and subventricular zone (SVZ; right box). In the SGZ, Type‐1 neural stem cells divide asymmetrically to produce a daughter Type‐2a cell and self‐renew. Type‐2a cells divide symmetrically and can expand the pool in response to a variety of environmental stimuli. Cells become progressively more fate restricted and mature into a granule cell neuron, which is then postmitotic. In the SVZ, Type‐B cells divide asymmetrically to produce daughter transit‐amplifying Type‐C cells, which may divide and also mature into neuroblasts. Neuroblasts then migrate through the rostral migratory stream to the olfactory bulb where cells terminally differentiate into granule cell neurons primarily. (LV, lateral ventricle; RMS, rostral migratory stream; OB, olfactory bulb.)
Chapter 09
1. Figure 9.1 Alcohol exposure can affect all stages of early stem cell development. Preconception exposure to alcohol, both maternal and paternal, can affect DNA expression and cellular patterning. After zygote formation, the totipotent morula is formed. The morula further differentiates into two stem cell populations beginning with the blastocyst in which the outer, multipotent, layer goes on to make the placenta, while the inner cell mass of pluripotent stem cells goes on to make the embryo. From there, the inner cell mass grows and a primitive streak forms, through which cellular migration and differentiation occur to form a gastrula containing the three embryonic cell lineages: the endoderm, mesoderm, and ectoderm.
2. Figure 9.2 The three lineages contained in the gastrula make all of the unique tissues of the body.
3. Figure 9.3 Future directions for research in the effects of prenatal alcohol on stem cell biology include the contributions of genetic sex and hormonal milieu, effects on the prenatal formation of resident, lifelong stem cells, and the possibility for stem cell directed therapies including stem cell transplantation.
Chapter 10
1. Figure 10.1 Tiered layers of keratinocyte replication and differentiation in the epidermis. The epidermis is composed of four keratinocyte (KC) strata: basal layer bound by integrin α/β dimers to the basement membrane (BM), located above the dermis; spinous layer composed of postmitotic (PM) cells expressing early differentiation markers such as involucrin and the keratin 1 and 10 pair (K1/10); granular layer expressing late‐differentiation markers such as loricrin and filaggrin; cornified layer composed of enucleated cells (squames) shed to the environment. The most common regeneration modeling posits KC stem cells (SC) that replicate to form transit (also known as transient) amplifying (TA) cells, which undergo limited rounds of replications and ultimately produce PM cells which stratify and differentiate. Delta /Notch1 interactions on adjacent cells (trans interaction) promote the cessation of cell cycling and postmitotic, early differentiation gene expression.
2. Figure 10.2 Comparison of epidermal KC regeneration models. Two different models have been described for KC replication and daughter cell progression to PM status. The hierarchal model (a) describes stem cells (SC) having the capability to replicate into either daughter SC or transit (also known as transient) amplifying (TA) cells. TA cells give rise to daughter TA cells for a limited number of cycles and then ultimately PM cells that continue through terminal differentiation (see Figure 10.1). The stochastic model (b) describes the KC replicating population as common progenitor (CP) cells capable of giving rise to daughter CP or PM cells, the latter differentiating as in the hierarchal model. Underlying the CP model is one population of variably mitotically competent KCs able to interconvert between classes of replication (Roshan et al.,2016). A balanced replication mode supports KC renewal and replacement under homeostasis versus an expanding replication mode where production of cycling KCs is favored to fill tissue deficits such as during wound healing.
Chapter 11
1. Figure 11.1 Replica molding using soft lithography. The process for shaping a pliable polymer material such as PDMS starts by using a microsized frame or model called master mold. The mold is filled with a prepolymer, which is cross‐linked, or cured, and the resulting polymer is peeled off the mold. The master mold can then be recycled to produce multiple copies of the final object.
2. Figure 11.2 In robotic spotting, a pin or tip controlled by a robotic arm is filled with a solution of interest, and then dispenses the desired material at designated locations of the array surface. The use of computer‐assisted robotic apparatus enables to customize the resulting microarrays, because it is possible to program the printing of different combinations of materials and dispensing locations.
3. Figure 11.3 Schematics of the micropillar chip/microwell array system. The micropillar chip contains cells encapsulated in 3D Matrigel droplets, while the microwell chip contains the compounds to be tested. Stamping of the micropillar chip onto the microwell array allows for testing drug‐induced toxicity. This figure was produced using Servier Medical Art.
4. Figure 11.4 Schematics of a microfluidic culture device for high‐throughput screening of toxicity effects in stem cells or stem‐cell‐derived tissues. Typically, a microfluidic platform allows for multiparameter analysis of different concentration gradients due to transport phenomenon properties within microfluidic channels. The microfluidic unit can also be coupled with time‐lapse microscopy and automated operation. This design allows, for example, the tracking of cell proliferation, morphology, and viability. This figure was produced using Servier Medical Art.
Chapter 12
1. Figure 12.1 Schematic representation of the HepaRG cell line behavior. Each differentiation process constitutes a maturation program of normal hepatocytes.
2. Figure 12.2 Morphology of HepaRG cells. (a) Phase‐contrast microscopic appearance of proliferating bipotent progenitors. (b) Phase‐contrast microscopic appearance of HepaRG cells after differentiation: hepatocyte‐like colonies are surrounded by undifferentiated biliary cells. (c) Immunolabeling of the junctional zonula occludens protein (green); localization of this protein is restricted to bile canaliculi. (d) Fluorescent microscopy showing accumulation into bile canaliculi of carboxydichlorofluorescein diacetate (a fluorescent substrate of MRP2) after 30 min incubation. Bar = 100 μm.
3. Figure 12.3 Induction of cholestasis, steatosis, and phospholipidosis in HepaRG cells. (a) Dilatation of bile canaliculi after 2 h treatment with the cholestatic drug flucloxacillin at 4 mM (arrow). (b) Intracytoplasmic accumulation of lipids following Oil Red O staining (red) and unstained vesicles after treatment with 20 μM amiodarone for 24 h. Unstained vesicles corresponding to lamellar bodies are visible in both hepatocyte‐like and biliary‐like cells (arrow). Bar = 100 μm.

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This edition first published 2018

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Library of Congress Cataloging‐in‐Publication Data:

Names: Rasmussen, Theodore P., 1962‐ editor.

Title: Stem cells in birth defects research and developmental toxicology / [edited by] Theodore P. Rasmussen.

Description: First edition. | Hoboken, NJ : Wiley, 2018. | Includes bibliographical references and index. |

Identifiers: LCCN 2017056789 (print) | LCCN 2017059841 (ebook) | ISBN 9781119283225 (pdf) | ISBN 9781119283232 (epub) | ISBN 9781119283218 (hardback)

Classification: LCC QH588.S83 (ebook) | LCC QH588.S83 (print) | NLM QU 325 | DDC 616.02/774–dc23

LC record available at https://lccn.loc.gov/2017056789

Cover design by: Wiley

Cover images: Immunofluorescent staining of a human iPS cell colony during early stages of iPS stem cell line derivation. Green staining identifies the expression of the pluripotency‐associated transcription factor SOX2, red staining identifies LIN28, and blue staining (DAPI) allows visualization of cell nuclei. Image courtesy of A. Flamier. (Background image) © Pinghung Chen/EyeEm/Gettyimages

List of Contributors

Schahram Akbarian

Icahn School of Medicine at Mount Sinai

Department of Neuroscience

New York, NY 10029

USA

Icahn School of Medicine at Mount Sinai

Friedman Brain Institute

New York, NY 10029

USA

Icahn School of Medicine at Mount Sinai

Department of Psychiatry

New York, NY 10029

USA

Brian J. Aneskievich

University of Connecticut

Department of Pharmaceutical Sciences

69 North Eagleville Road, U‐3092 Storrs, CT 06269

USA

Aaron B. Bowman

Vanderbilt University (VU)

Department of Pediatrics and Neurology, Vanderbilt University Medical Center (VUMC)

1161 21st Avenue South, D‐4105 MCN, Nashville, TN 37232

USA

Vanderbilt University (VU)

Department of Biochemistry and Vanderbilt Brain Institute

465 21st Avenue South, 6140 MRB3 Nashville, TN 37232

USA

Kristen Brennand

Icahn School of Medicine at Mount Sinai

Department of Neuroscience

New York, NY 10029

USA

Icahn School of Medicine at Mount Sinai

Friedman Brain Institute

New York, NY 10029

USA

Icahn School of Medicine at Mount Sinai

Department of Psychiatry

New York, NY 10029

USA

Icahn School of Medicine at Mount Sinai

Department of Genetics and Genomics

New York, NY 10029

USA

Kristen Buck

Department of Molecular, Cell and Systems Biology and Stem Cell Center, College of Natural and Agricultural Sciences

University of California Riverside

1113 Biological Sciences Building Riverside, CA, 92521

USA

Joaquim M. S. Cabral

Universidade de Lisboa

Department of Bioengineering and Institute for Bioengineering and Biosciences, Instituto Superior Técnico

Avenida Rovisco Pais 1049–001, Lisbon

Portugal

Sandhya Chandrasekaran

Icahn School of Medicine at Mount Sinai

Department of Neuroscience

New York, NY 10029

USA

Friedman Brain Institute, Icahn School of Medicine at Mount Sinai

New York, NY 10029

USA

Icahn School of Medicine at Mount Sinai

Department of Psychiatry New York, NY 10029

USA

M. Diana Neely

Vanderbilt University (VU)

Department of Pediatrics and Neurology, Vanderbilt University Medical Center (VUMC)

1161 21st Avenue South, D‐4105 MCN, Nashville, TN 37232

USA

Vanderbilt University (VU)

Department of Biochemistry and Vanderbilt Brain Institute

465 21st Avenue South, 6140 MRB3 Nashville, TN 37232

USA

Tiago G. Fernandes

Universidade de Lisboa

Department of Bioengineering and Institute for Bioengineering and Biosciences, Instituto Superior Técnico

Avenida Rovisco Pais 1049–001, Lisbon

Portugal

Annette S. Fincher

Texas A&M University

Department of Neuroscience and Experimental Therapeutics Texas A&M University Health Science Center

Bryan, TX 77807

USA

Anthony Flamier

University of Montreal

Maisonneuve‐Rosemont hospital

5415 Boul. l'Assomption, Montréal QC H1T 2M4

Canada

Christiane Guguen‐Guillouzo

Université de Rennes 1, Faculté des Sciences Pharmaceutiques et Biologiques

Inserm UMR 1241, Numecan

2 avenue Prof. Léon Bernard 35043 Rennes Cedex

France

Biopredic International

Parc d’Affaires de la Brétèche, Bât. A4, Saint Grégoire

France

André Guillouzo

Université de Rennes 1, Faculté des Sciences Pharmaceutiques et Biologiques

Inserm UMR 1241, Numecan

2 avenue Prof. Léon Bernard 35043 Rennes Cedex

France

Piyush Joshi

Vanderbilt University (VU)

Department of Pediatrics and Neurology, Vanderbilt University Medical Center (VUMC)

1161 21st Avenue South, D‐4105 MCN, Nashville, TN 37232

USA

Vanderbilt University (VU)

Department of Biochemistry and Vanderbilt Brain Institute

465 21st Avenue South, 6140 MRB3 Nashville, TN 37232

USA

Andrew Klopfer

Texas A&M University

Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center

Bryan, TX 77807

USA

Soowan Lee

University of Connecticut

Department of Pharmaceutical Sciences

69. North Eagleville Road, Unit 3092, UConn Sch of Pharm Storrs, CT 06269

USA

Amanda H. Mahnke

Texas A&M University

Department of Neuroscience and Experimental Therapeutics, Women's Health in Neuroscience Program, Texas A&M University Health Science Center

Medical Research and Education Building, 8447 State Highway 47 Bryan, TX 77807‐3260

USA

Yusuke Marikawa

University of Hawaii at Manoa

John A. Burns School of Medicine Institute for Biogenesis Research

651 Ilalo Street, Biosciences Building 163A, Honolulu, HI 96813

USA

Rajesh C. Miranda

Texas A&M University

Department of Neuroscience and Experimental Therapeutics Women's Health in Neuroscience Program, Texas A&M University Health Science Center

Medical Research and Education Building, 8447 State Highway 47 Bryan, TX 77807‐3260

USA

Jessica S. Newton

University of Kentucky

Department of Pharmaceutical Sciences

789 S. Limestone, Lee T. Todd Bldg. 473, Lexington, KY 40536

USA

Kimberly Nixon

University of Kentucky

Department of Pharmaceutical Sciences

789 S. Limestone, Lee T. Todd Bldg. 473, Lexington, KY 40536

USA

Rachael A. Olsufka

University of Kentucky

Department of Pharmaceutical Sciences

789 S. Limestone, Lee T. Todd Bldg. 473, Lexington, KY 40536

USA

Hui Peng

University of Kentucky

Department of Pharmaceutical Sciences

789 S. Limestone, Lee T. Todd Bldg. 473, Lexington, KY 40536

USA

Bindu Prabhakar

University of Connecticut

Department of Pharmaceutical Sciences

69. North Eagleville Road, Unit 3092, UConn Sch of Pharm, Storrs CT 06269

USA

Prashanth Rajarajan

Icahn School of Medicine at Mount Sinai

Department of Neuroscience

New York, NY 10029

USA

Icahn School of Medicine at Mount Sinai

Friedman Brain Institute

New York, NY 10029

USA

Icahn School of Medicine at Mount Sinai

Department of Psychiatry

New York, NY 10029

USA

Icahn School of Medicine at Mount Sinai

Department of Genetics and Genomics

New York, NY 10029

USA

Theodore P. Rasmussen

University of Connecticut

Department of Pharmaceutical Sciences

69. North Eagleville Road, Unit 3092, UConn Sch of Pharm, Storrs CT 06269

USA

University of Connecticut Stem Cell Institute

400 Farmington Avenue Farmington, CT 06033

USA

University of Connecticut, Institute for Systems Genomics

Storrs, CT 06269

USA

Geetika Sahni

National University of Singapore

Department of Biomedical Engineering

4, Engineering Drive 3, Block E4 #04‐10, Singapore 117583

Singapore

Nihal A. Salem

Texas A&M University

Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center

Bryan, TX 77807

USA

Rambon Shamilov

University of Connecticut

Department of Pharmaceutical Sciences

69 North Eagleville Road, U‐3092 Storrs, CT 06269

USA

Yi‐Chin Toh

National University of Singapore

Department of Biomedical Engineering

4, Engineering Drive 3, Block E4 #04‐10, Singapore 117583

Singapore

National University of Singapore

Singapore Biomedical Institute for Global Health Research and Technology

MD6, 14 Medical Drive, #14‐01 Singapore 117599

Singapore

National University of Singapore

NUS Tissue Engineering Program

27 Medical Drive, DSO (Kent Ridge) Building, #04‐01, Singapore 117510

Singapore

National University of Singapore Centre for Life Sciences

Singapore Institute for Neurotechnology

28 medical Drive, Singapore 117456

Singapore

Alexander M. Tseng

Texas A&M University

Department of Neuroscience and Experimental Therapeutics, Texas A&M University Health Science Center

Bryan, TX 77807

USA

Jiangwa Xing

Qinghai University

Department of Basic Medical Sciences, Medical College

Xining, Qinghai, 810016

China

Nicole I. zur Nieden

University of California Riverside

Department of Molecular, Cell and Systems Biology and Stem Cell Center, College of Natural and Agricultural Sciences

1113 Biological Sciences Building Riverside, CA, 92521

USA