Our team is part of the Institute for Genomic Medicine (IGM) at the Abigail Wexner Research Institute at Nationwide Children’s Hospital, which is at the forefront of using genomic sequencing in the clinical setting to predict best health outcomes for patients and is one of the driving forces shaping precision medicine. We utilize a multidisciplinary approach in our research that encompasses genomic medicine, neuroscience, stem cell biology, biochemistry and molecular genetics to investigate the dynamic nature of the developing brain both in the context of health and neurological disease.
A specific interest of the Hester laboratory is to understand the molecular and cellular basis of pediatric epilepsy such as developmental and epileptic encephalopathy (DEE). DEEs are a class of severe brain disorders associated with early age onset and manifest with intractable and multi-form seizures. While advances in genomic medicine have allowed the identification of de novo genetic variants associated with DEEs, the underlying molecular and cellular mechanisms that cause these disorders are not well understood. Our team is leveraging several key technological tools that include the use of induced pluripotent stem cells (iPSCs), human brain organoid models, genome editing tools, OMICs technologies, and the use of novel transgenic mouse models to address this knowledge gap.
Additionally, our team is investigating molecular mechanisms underlying autism spectrum disorder (ASD) and intellectual disability (ID). Although the causes of ASD and ID are considered genetically diverse, defective synaptogenesis is emerging as a common pathological feature that may account for a significant proportion of these conditions. We are leveraging patient-specific brain organoid models and taking a ‘deep phenotyping’ approach to investigate synaptic disease mechanisms at single-cell resolution, thus enabling the identification of cell-specific responses, compensatory changes, and developmental trajectories underlying the pathophysiology of ASD and ID.
Ultimately, the long-term goal of the Hester laboratory is to rapidly translate research discoveries into lasting treatment options for pediatric patients afflicted with neurological disorders.
Research Interests: Translational Neuroscience, Human iPS Cells, Brain Organoids, 3D Bioprinting, 3D Imaging, Multi-Electrode Array Electrophysiology, Neural Circuitry Modeling, OMICs Technologies, Genome Editing, Bioengineering, Molecular Mechanisms of Epilepsy, Brain Injury, and Autism.
Publications
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Toda T, Bedrosian TA, Schafer ST, Cuoco MS, Linker SB, Ghassemzadeh S, Mitchell L, Whiteley JT, Novaresi N, McDonald AH, Gallina IS, Yoon H, Hester ME, Pena M, Lim C, Suljic E, AlFatah Mansour A, Boulard M, Parylak SL, Gage FH. Long interspersed nuclear elements safeguard neural progenitors from precocious differentiation. Cell Rep. 2024 Feb 12; 43: 113774.
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Kanke KL, Rayner RE, Abel E, Venugopalan A, Suu M, Stack JT, Nouri R, Guo G, Vetter TA, Cormet-Boyaka E, Hester ME, Vaidyanathan S. Single-Stranded DNA with Internal Base Modifications Mediates Highly Efficient Gene Insertion in Primary Cells. bioRxiv. 2024 Feb 1;
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Watanabe F, Hollingsworth EW, Bartley JM, Wisehart L, Desai R, Hartlaub AM, Hester ME, Schiapparelli P, Quiñones-Hinojosa A, Imitola J. Patient-derived organoids recapitulate glioma-intrinsic immune program and progenitor populations of glioblastoma. PNAS Nexus. 2024 Feb; 3: pgae051.
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Miller KE, Rivaldi AC, Shinagawa N, Sran S, Navarro JB, Westfall JJ, Miller AR, Roberts RD, Akkari Y, Supinger R, Hester ME, Marhabaie M, Gade M, Lu J, Rodziyevska O, Bhattacharjee MB, Von Allmen GK, Yang E, Lidov HGW, Harini C, Shah MN, Leonard J, Pindrik J, Shaikhouni A, Goldman JE, Pierson CR, Thomas DL, Boué DR, Ostendorf AP, Mardis ER, Poduri A, Koboldt DC, Heinzen EL, Bedrosian TA. Post-zygotic rescue of meiotic errors causes brain mosaicism and focal epilepsy. Nat Genet. 2023 Nov; 55: 1920-1928.
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Rajendran S, Hu Y, Canella A, Peterson C, Gross A, Cam M, Nazzaro M, Haffey A, Serin-Harmanci A, Distefano R, Nigita G, Wang W, Kreatsoulas D, Li Z, Sepeda JA, Sas A, Hester ME, Miller KE, Elemento O, Roberts RD, Holland EC, Rao G, Mardis ER, Rajappa P. Single-cell RNA sequencing reveals immunosuppressive myeloid cell diversity during malignant progression in a murine model of glioma. Cell Rep. 2023 Mar 3; 42: 112197.
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Chen S, Chang Y, Li L, Acosta D, Li Y, Guo Q, Wang C, Turkes E, Morrison C, Julian D, Hester ME, Scharre DW, Santiskulvong C, Song SX, Plummer JT, Serrano GE, Beach TG, Duff KE, Ma Q, Fu H. Spatially resolved transcriptomics reveals genes associated with the vulnerability of middle temporal gyrus in Alzheimer's disease. Acta Neuropathol Commun. 2022 Dec 21; 10: 188.
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Batzios S, Tal G, DiStasio AT, Peng Y, Charalambous C, Nicolaides P, Kamsteeg EJ, Korman SH, Mandel H, Steinbach PJ, Yi L, Fair SR, Hester ME, Drousiotou A, Kaler SG. Newly identified disorder of copper metabolism caused by variants in CTR1, a high-affinity copper transporter. Hum Mol Genet. 2022 Aug 1;
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Fair SR, Schwind W, Julian D, Biel A, Guo G, Rutherford R, Ramadesikan S, Westfall J, Miller KE, Kararoudi MN, Hickey SE, Mosher TM, McBride KL, Neinast R, Fitch J, Lee D, White P, Wilson RK, Bedrosian TA, Koboldt DC, Hester ME. Cerebral organoids containing an AUTS2 missense variant model microcephaly. Brain. 2022 Jul 8;
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Naeimi Kararoudi M, Alsudayri A, Hill CL, Elmas E, Sezgin Y, Thakkar A, Hester ME, Malleske DT, Lee DA, Neal ML, Perry MR, Harvilchuck JA, Reynolds SD. Assessment of Beta-2 Microglobulin Gene Edited Airway Epithelial Stem Cells as a treatment for Sulfur Mustard Inhalation. Front Genome Ed. 2022; 4: 781531.
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Biel A, Castanza AS, Rutherford R, Fair SR, Chifamba L, Wester JC, Hester ME, Hevner RF. AUTS2 Syndrome: Molecular Mechanisms and Model Systems. Front Mol Neurosci. 2022; 15: 858582.
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Benninger KL, Purnell J, Conroy S, Jackson K, Batterson N, Neel ML, Hester ME, Maitre NL, NCH Early Developmental Group.. Intrauterine drug exposure as a risk factor for cerebral palsy. Dev Med Child Neurol. 2021 Sep 16;
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Koboldt DC, Miller KE, Miller AR, Bush JM, McGrath S, Leraas K, Crist E, Fair S, Schwind W, Wijeratne S, Fitch J, Leonard J, Shaikhouni A, Hester ME, Magrini V, Ho ML, Pierson CR, Wilson RK, Ostendorf AP, Mardis ER, Bedrosian TA. PTEN somatic mutations contribute to spectrum of cerebral overgrowth. Brain. 2021 May 28;
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Watanabe F, Schoeffler A, Fair SR, Hester ME, Fedorko J, Imitola J. Generation of Neurosphere-Derived Organoid-Like-Aggregates (NEDAS) from Neural Stem Cells. Curr Protoc. 2021 Feb; 1: e15.
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Venkataraman L, Fair SR, McElroy CA, Hester ME, Fu H. Modeling neurodegenerative diseases with cerebral organoids and other three-dimensional culture systems: focus on Alzheimer's disease. Stem Cell Rev Rep. 2020 Nov 12;
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Fair SR, Julian D, Hartlaub AM, Pusuluri ST, Malik G, Summerfied TL, Zhao G, Hester AB, Ackerman WE 4th, Hollingsworth EW, Ali M, McElroy CA, Buhimschi IA, Imitola J, Maitre NL, Bedrosian TA, Hester ME. Electrophysiological Maturation of Cerebral Organoids Correlates with Dynamic Morphological and Cellular Development. Stem Cell Reports. 2020 Oct 13; 15: 855-868.
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Pathak S, Stewart WCL, Burd CE, Hester ME, Greenberg DA. Brd2 haploinsufficiency extends lifespan and healthspan in C57B6/J mice. PLoS One. 2020; 15: e0234910.
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Abdi HH, Maitre NL, Benninger KL, Hester ME, Slaughter JL. Gabapentin Use for Hospitalized Neonates. Pediatr Neurol. 2019 Feb 21;
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Hartlaub AM, McElroy CA, Maitre NL, Hester ME. Modeling Human Brain Circuitry Using Pluripotent Stem Cell Platforms. Front Pediatr. 2019; 7: 57.
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