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Adamczyk PM, Shaw A, Morella IM, More L. Neurobiology, molecular pathways, and environmental influences in antisocial traits and personality disorders. Neuropharmacology 2025; 269:110322. [PMID: 39864585 DOI: 10.1016/j.neuropharm.2025.110322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 12/17/2024] [Accepted: 01/20/2025] [Indexed: 01/28/2025]
Abstract
Personality disorders (PDs) are psychiatric conditions characterized by enduring patterns of cognition, emotion, and behaviour that deviate significantly from cultural norms, causing distress or impairment. The aetiology of PDs is complex, involving both genetic and environmental factors. Genetic studies estimate the heritability of PDs at 30%-60%, implicating genes involved in neurotransmitter regulation, such as those for serotonin transporters and dopamine receptors. Environmental factors, including childhood trauma and chronic stress, interact with genetic predispositions to induce epigenetic modifications like DNA methylation and histone modifications, contributing to PD development. Neurobiological research has identified structural and functional abnormalities in brain regions related to emotional regulation and social cognition, such as the amygdala, prefrontal cortex, and limbic system. These abnormalities are linked to impaired emotion processing and interpersonal functioning in PDs. This review focuses on how environmental factors shape maladaptive behaviours and endophenotypes central to many PDs. It explores the interaction between the Ras-ERK, p38, and mTOR molecular pathways in response to environmental stimuli, and examines the role of oxidative stress and mitochondrial metabolism in these processes. Also reviewed are various types of PDs and existing animal models that replicate key endophenotypes, highlighting changes in neurotransmitters and neurohormones. Identifying molecular biomarkers can lead to the development of "enviromimetic" drugs, which mimic environmental influences to activate molecular pathways, facilitating targeted, personalized treatments based on the molecular profiles of individuals with PDs. Ultimately, understanding the molecular mechanisms of PDs promises to enhance diagnostic accuracy, prognosis, and therapeutic outcomes for affected individuals.
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Affiliation(s)
- Patryk M Adamczyk
- School of Pharmacy and Biomedical Sciences, The University of Central Lancashire, Preston, UK
| | - Andrew Shaw
- Institute of Biological Chemistry, Biophysics and Bioengineering, School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, UK.
| | - Ilaria M Morella
- University of Pavia, Department of Biology and Biotechnology "Lazzaro Spallanzani", Pavia, Italy; Cardiff University, School of Medicine, Division of Psychological Medicine and Clinical Neurosciences, Cardiff, UK.
| | - Lorenzo More
- School of Pharmacy and Biomedical Sciences, The University of Central Lancashire, Preston, UK.
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2
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Ye K, Guo Y, Chang N, Xu J, Qin Q, Yang X, Huang Y, Ge Q, Meng D, Zhao X. Micro-region transcriptomics profiling of cerebral organoids using a capillary-based microdissection system. ANALYTICAL METHODS : ADVANCING METHODS AND APPLICATIONS 2025; 17:3480-3489. [PMID: 40211824 DOI: 10.1039/d5ay00277j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/02/2025]
Abstract
Investigating the transcriptome while preserving cellular spatial information facilitates a comprehensive understanding of cellular fates in multicellular organisms. However, the precise and flexible isolation of micro-regions of interest (mROIs) for profiling spatial transcriptomics (ST) remains a challenge. We established a capillary-based tissue microdissection system (CMS), which enables the high-efficiency acquisition of mROIs from cultured cerebral organoids for mRNA sequencing (CMS-seq). Subsequently, neural progenitor cells (NPCs), intermediate progenitors (IPs), mature neurons, and astrocytes were annotated in the cerebral organoids at the stages of days 20 and 60, respectively. Furthermore, astrocytes in the samples from day 20 were found to exhibit a higher tendency to express the SPARC gene whereas those from day 60 showed a stronger tendency to express the NTRK2 gene. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of differentially expressed genes indicated a higher degree of neural development at the stage of day 60. Finally, a spatial annotation map of cell types of the mROIs was constructed, enabling rapid identification of the cellular composition in each mROI. Therefore, we established an efficient method for ST analysis in cerebral organoids and further exploration of the spatial developmental trajectory.
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Affiliation(s)
- Kaiqiang Ye
- State Key Laboratory of Digital Medical Engineering, School of Biological Science & Medical Engineering, Southeast University, Nanjing, Jiangsu, China.
| | - Yunxia Guo
- State Key Laboratory of Digital Medical Engineering, School of Biological Science & Medical Engineering, Southeast University, Nanjing, Jiangsu, China.
- Department of Anesthesiology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, China
| | - Ning Chang
- State Key Laboratory of Digital Medical Engineering, School of Biological Science & Medical Engineering, Southeast University, Nanjing, Jiangsu, China.
| | - Jitao Xu
- State Key Laboratory of Digital Medical Engineering, School of Biological Science & Medical Engineering, Southeast University, Nanjing, Jiangsu, China.
| | - Qingyang Qin
- State Key Laboratory of Digital Medical Engineering, School of Biological Science & Medical Engineering, Southeast University, Nanjing, Jiangsu, China.
| | - Xi Yang
- State Key Laboratory of Digital Medical Engineering, School of Biological Science & Medical Engineering, Southeast University, Nanjing, Jiangsu, China.
| | - Yan Huang
- State Key Laboratory of Digital Medical Engineering, School of Biological Science & Medical Engineering, Southeast University, Nanjing, Jiangsu, China.
| | - Qinyu Ge
- State Key Laboratory of Digital Medical Engineering, School of Biological Science & Medical Engineering, Southeast University, Nanjing, Jiangsu, China.
| | - Dianhuai Meng
- Rehabiliatation Center, The First Affiliated Hospital With Nanjing Medical University, Nanjing, China.
| | - Xiangwei Zhao
- State Key Laboratory of Digital Medical Engineering, School of Biological Science & Medical Engineering, Southeast University, Nanjing, Jiangsu, China.
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Bond ST, King EJ, Walker SM, Yang C, Liu Y, Liu KH, Zhuang A, Jurrjens AW, Fang HA, Formosa LE, Nath AP, Carmona SR, Inouye M, Duong T, Huynh K, Meikle PJ, Crawford S, Ramm G, Elahee Doomun SN, de Souza DP, Rudler DL, Calkin AC, Filipovska A, Greening DW, Henstridge DC, Drew BG. Mitochondrial damage in muscle specific PolG mutant mice activates the integrated stress response and disrupts the mitochondrial folate cycle. Nat Commun 2025; 16:2338. [PMID: 40057508 PMCID: PMC11890779 DOI: 10.1038/s41467-025-57299-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Accepted: 02/13/2025] [Indexed: 05/13/2025] Open
Abstract
During mitochondrial damage, information is relayed between the mitochondria and nucleus to coordinate precise responses to preserve cellular health. One such pathway is the mitochondrial integrated stress response (mtISR), which is known to be activated by mitochondrial DNA (mtDNA) damage. However, the causal molecular signals responsible for activation of the mtISR remain mostly unknown. A gene often associated with mtDNA mutations/deletions is Polg1, which encodes the mitochondrial DNA Polymerase γ (PolG). Here, we describe an inducible, tissue specific model of PolG mutation, which in muscle specific animals leads to rapid development of mitochondrial dysfunction and muscular degeneration in male animals from ~5 months of age. Detailed molecular profiling demonstrated robust activation of the mtISR in muscles from these animals. This was accompanied by striking alterations to enzymes in the mitochondrial folate cycle that was likely driven by a specific depletion in the folate cycle metabolite 5,10 methenyl-THF, strongly implying imbalanced folate intermediates as a previously unrecognised pathology linking the mtISR and mitochondrial disease.
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Affiliation(s)
- Simon T Bond
- Baker Heart & Diabetes Institute, Melbourne, Australia
- Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia
- School of Translational Medicine, Monash University, Melbourne, Australia
| | - Emily J King
- Baker Heart & Diabetes Institute, Melbourne, Australia
- School of Translational Medicine, Monash University, Melbourne, Australia
| | - Shannen M Walker
- Baker Heart & Diabetes Institute, Melbourne, Australia
- School of Translational Medicine, Monash University, Melbourne, Australia
| | | | - Yingying Liu
- Baker Heart & Diabetes Institute, Melbourne, Australia
| | - Kevin H Liu
- Baker Heart & Diabetes Institute, Melbourne, Australia
| | - Aowen Zhuang
- Baker Heart & Diabetes Institute, Melbourne, Australia
| | - Aaron W Jurrjens
- Baker Heart & Diabetes Institute, Melbourne, Australia
- School of Translational Medicine, Monash University, Melbourne, Australia
| | - Haoyun A Fang
- Baker Heart & Diabetes Institute, Melbourne, Australia
| | - Luke E Formosa
- Biochemistry and Molecular Biology, Monash University, Melbourne, Australia
| | - Artika P Nath
- Baker Heart & Diabetes Institute, Melbourne, Australia
| | | | | | - Thy Duong
- Baker Heart & Diabetes Institute, Melbourne, Australia
| | - Kevin Huynh
- Baker Heart & Diabetes Institute, Melbourne, Australia
- Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia
| | - Peter J Meikle
- Baker Heart & Diabetes Institute, Melbourne, Australia
- Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia
- School of Translational Medicine, Monash University, Melbourne, Australia
- Baker Department of Cardiovascular Research Translation and Implementation, La Trobe University, Melbourne, Australia
| | - Simon Crawford
- Monash Ramaciotti Centre for Cryo Electron Microscopy, Monash University, Melbourne, Australia
| | - Georg Ramm
- Biochemistry and Molecular Biology, Monash University, Melbourne, Australia
- Monash Ramaciotti Centre for Cryo Electron Microscopy, Monash University, Melbourne, Australia
| | | | | | - Danielle L Rudler
- ARC Centre of Excellence in Synthetic Biology, QEII Medical Centre, Western Australia, Nedlands, Australia
- Telethon Kids Institute, Northern Entrance, Perth Children's Hospital, 15 Hospital Avenue, Western Australia, Nedlands, Australia
| | - Anna C Calkin
- Baker Heart & Diabetes Institute, Melbourne, Australia
- Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia
| | - Aleksandra Filipovska
- ARC Centre of Excellence in Synthetic Biology, QEII Medical Centre, Western Australia, Nedlands, Australia
- Telethon Kids Institute, Northern Entrance, Perth Children's Hospital, 15 Hospital Avenue, Western Australia, Nedlands, Australia
| | - David W Greening
- Baker Heart & Diabetes Institute, Melbourne, Australia
- Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia
- School of Translational Medicine, Monash University, Melbourne, Australia
- Baker Department of Cardiovascular Research Translation and Implementation, La Trobe University, Melbourne, Australia
| | - Darren C Henstridge
- Baker Heart & Diabetes Institute, Melbourne, Australia
- School of Health Sciences, University of Tasmania, Launceston, Australia
| | - Brian G Drew
- Baker Heart & Diabetes Institute, Melbourne, Australia.
- Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia.
- School of Translational Medicine, Monash University, Melbourne, Australia.
- Baker Department of Cardiovascular Research Translation and Implementation, La Trobe University, Melbourne, Australia.
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Rubio AD, Hamilton L, Bausch M, Jin M, Papetti A, Jiang P, Yelamanchili SV. A Comprehensive Review on Utilizing Human Brain Organoids to Study Neuroinflammation in Neurological Disorders. J Neuroimmune Pharmacol 2025; 20:23. [PMID: 39987404 PMCID: PMC11846768 DOI: 10.1007/s11481-025-10181-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 01/26/2025] [Indexed: 02/24/2025]
Abstract
Most current information about neurological disorders and diseases is derived from direct patient and animal studies. However, patient studies in many cases do not allow replication of the early stages of the disease and, therefore, offer limited opportunities to understand disease progression. On the other hand, although the use of animal models allows us to study the mechanisms of the disease, they present significant limitations in developing drugs for humans. Recently, 3D-cultured in vitro models derived from human pluripotent stem cells have surfaced as a promising system. They offer the potential to connect findings from patient studies with those from animal models. In this comprehensive review, we discuss their application in modeling neurodevelopmental conditions such as Down Syndrome or Autism, neurodegenerative diseases such as Alzheimer's or Parkinson's, and viral diseases like Zika virus or HIV. Furthermore, we will discuss the different models used to study prenatal exposure to drugs of abuse, as well as the limitations and challenges that must be met to transform the landscape of research on human brain disorders.
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Affiliation(s)
- Adrian Domene Rubio
- Department of Anesthesiology, University of Nebraska Medical Center (UNMC), Omaha, NE, 68198, USA
| | - Luke Hamilton
- Department of Anesthesiology, University of Nebraska Medical Center (UNMC), Omaha, NE, 68198, USA
| | - Mark Bausch
- Department of Anesthesiology, University of Nebraska Medical Center (UNMC), Omaha, NE, 68198, USA
- University of Notre Dame, Notre Dame, IN, 46556, USA
| | - Mengmeng Jin
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, 08854, USA
| | - Ava Papetti
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, 08854, USA
| | - Peng Jiang
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ, 08854, USA
| | - Sowmya V Yelamanchili
- Department of Anesthesiology, University of Nebraska Medical Center (UNMC), Omaha, NE, 68198, USA.
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5
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Li K, Gu L, Cai H, Lu HC, Mackie K, Guo F. Human brain organoids for understanding substance use disorders. Drug Metab Pharmacokinet 2025; 60:101036. [PMID: 39567282 PMCID: PMC11825288 DOI: 10.1016/j.dmpk.2024.101036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2024]
Abstract
Substance use disorders (SUDs) are complex mental health conditions involving a problematic pattern of substance use. Challenges remain in understanding its neural mechanisms, which are likely to lead to improved SUD treatments. Human brain organoids, brain-like 3D in vitro cultures derived from human stem cells, show unique potential in recapitulating the response of a developing human brain to substances. Here, we review the recent progress in understanding SUD using human brain organoid models focusing on neurodevelopmental perspectives. We first summarize the background of SUD in humans. Moreover, we introduce the development of various human brain organoid models and then discuss current progress and findings underlying the abuse of substances like nicotine, alcohol, and other addictive drugs using organoid models. Furthermore, we review efforts to develop organ chips and microphysiological systems to engineer better human brain organoids for advancing SUD studies. Lastly, we conclude by elaborating on the current challenges and future directions of SUD studies using human brain organoids.
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Affiliation(s)
- Kangle Li
- Department of Intelligent Systems Engineering, Indiana University Bloomington, IN, 47405, USA
| | - Longjun Gu
- Department of Intelligent Systems Engineering, Indiana University Bloomington, IN, 47405, USA
| | - Hongwei Cai
- Department of Intelligent Systems Engineering, Indiana University Bloomington, IN, 47405, USA
| | - Hui-Chen Lu
- Gill Center for Biomolecular Science, Department of Psychological and Brain Sciences, Indiana University Bloomington, IN, 47405, USA
| | - Ken Mackie
- Gill Center for Biomolecular Science, Department of Psychological and Brain Sciences, Indiana University Bloomington, IN, 47405, USA
| | - Feng Guo
- Department of Intelligent Systems Engineering, Indiana University Bloomington, IN, 47405, USA.
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6
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Xiao QX, Geng MJ, Wang QL, Fang CL, Zhang JH, Liu Q, Xiong LL. Unraveling the effects of prenatal anesthesia on neurodevelopment: A review of current evidence and future directions. Neurotoxicology 2024; 105:96-110. [PMID: 39276873 DOI: 10.1016/j.neuro.2024.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Revised: 09/04/2024] [Accepted: 09/11/2024] [Indexed: 09/17/2024]
Abstract
Human brain development is a complex, multi-stage, and sensitive process, especially during the fetal stage. Animal studies over the last two decades have highlighted the potential risks of anesthetics to the developing brain, impacting its structure and function. This has raised concerns regarding the safety of anesthesia during pregnancy and its influence on fetal brain development, garnering significant attention from the anesthesiology community. Although preclinical studies predominantly indicate the neurotoxic effects of prenatal anesthesia, these findings cannot be directly extrapolated to humans due to interspecies variations. Clinical research, constrained by ethical and technical hurdles in accessing human prenatal brain tissues, often yields conflicting results compared to preclinical data. The emergence of brain organoids as a cutting-edge research tool shows promise in modeling human brain development. When integrated with single-cell sequencing, these organoids offer insights into potential neurotoxic mechanisms triggered by prenatal anesthesia. Despite several retrospective and cohort studies exploring the clinical impact of anesthesia on brain development, many findings remain inconclusive. As such, this review synthesizes preclinical and clinical evidence on the effects of prenatal anesthesia on fetal brain development and suggests areas for future research advancement.
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Affiliation(s)
- Qiu-Xia Xiao
- Department of Anesthesiology, The Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, China
| | - Min-Jian Geng
- The Second Clinical Medical College of North Sichuan Medical College, Nanchong, China
| | - Qiu-Lin Wang
- Department of Anesthesiology, The Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, China
| | - Chang-Le Fang
- Department of Anesthesiology, The Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, China
| | - Jing-Han Zhang
- Department of Anesthesiology, Southwest Medical University, Luzhou, China
| | - Qi Liu
- Department of Anesthesiology, Southwest Medical University, Luzhou, China
| | - Liu-Lin Xiong
- Department of Anesthesiology, The Third Affiliated Hospital of Zunyi Medical University (The First People's Hospital of Zunyi), Zunyi, China.
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7
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Li K, Gu L, Cai H, Lu HC, Mackie K, Guo F. Human brain organoids for understanding substance use disorders. Drug Metab Pharmacokinet 2024; 58:101031. [PMID: 39146603 DOI: 10.1016/j.dmpk.2024.101031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Revised: 07/23/2024] [Accepted: 07/26/2024] [Indexed: 08/17/2024]
Abstract
Substance use disorders (SUDs) are complex mental health conditions involving a problematic pattern of substance use. Challenges remain in understanding their neural mechanisms, which are likely to lead to improved SUD treatments. Human brain organoids, brain-like 3D in vitro cultures derived from human stem cells, show unique potential in recapitulating the response of a developing human brain to substances. Here, we review the recent progress in understanding SUDs using human brain organoid models focusing on neurodevelopmental perspectives. We first summarize the background of SUDs in humans. Moreover, we introduce the development of various human brain organoid models and then discuss current progress and findings underlying the abuse of substances like nicotine, alcohol, and other addictive drugs using organoid models. Furthermore, we review efforts to develop organ chips and microphysiological systems to engineer better human brain organoids for advancing SUD studies. Lastly, we conclude by elaborating on the current challenges and future directions of SUD studies using human brain organoids.
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Affiliation(s)
- Kangle Li
- Department of Intelligent Systems Engineering, Indiana University Bloomington, IN, 47405, United States
| | - Longjun Gu
- Department of Intelligent Systems Engineering, Indiana University Bloomington, IN, 47405, United States
| | - Hongwei Cai
- Department of Intelligent Systems Engineering, Indiana University Bloomington, IN, 47405, United States
| | - Hui-Chen Lu
- Gill Center for Biomolecular Science, Department of Psychological and Brain Sciences, Indiana University Bloomington, IN, 47405, United States
| | - Ken Mackie
- Gill Center for Biomolecular Science, Department of Psychological and Brain Sciences, Indiana University Bloomington, IN, 47405, United States
| | - Feng Guo
- Department of Intelligent Systems Engineering, Indiana University Bloomington, IN, 47405, United States.
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8
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Sandoval SO, Cappuccio G, Kruth K, Osenberg S, Khalil SM, Méndez-Albelo NM, Padmanabhan K, Wang D, Niciu MJ, Bhattacharyya A, Stein JL, Sousa AMM, Waxman EA, Buttermore ED, Whye D, Sirois CL, Williams A, Maletic-Savatic M, Zhao X. Rigor and reproducibility in human brain organoid research: Where we are and where we need to go. Stem Cell Reports 2024; 19:796-816. [PMID: 38759644 PMCID: PMC11297560 DOI: 10.1016/j.stemcr.2024.04.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2024] [Revised: 04/15/2024] [Accepted: 04/16/2024] [Indexed: 05/19/2024] Open
Abstract
Human brain organoid models have emerged as a promising tool for studying human brain development and function. These models preserve human genetics and recapitulate some aspects of human brain development, while facilitating manipulation in an in vitro setting. Despite their potential to transform biology and medicine, concerns persist about their fidelity. To fully harness their potential, it is imperative to establish reliable analytic methods, ensuring rigor and reproducibility. Here, we review current analytical platforms used to characterize human forebrain cortical organoids, highlight challenges, and propose recommendations for future studies to achieve greater precision and uniformity across laboratories.
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Affiliation(s)
- Soraya O Sandoval
- Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA; Neuroscience Training Program, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Gerarda Cappuccio
- Department of Pediatrics-Neurology, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
| | - Karina Kruth
- Department of Psychiatry, University of Iowa Health Care, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Health Care, Iowa City, IA 52242, USA
| | - Sivan Osenberg
- Department of Pediatrics-Neurology, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
| | - Saleh M Khalil
- Department of Pediatrics-Neurology, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA
| | - Natasha M Méndez-Albelo
- Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA; Molecular Cellular Pharmacology Training Program, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Krishnan Padmanabhan
- Department of Neuroscience, Center for Visual Science, Del Monte Institute for Neuroscience, University of Rochester School of Medicine and Dentistry, Rochester NY 14642, USA
| | - Daifeng Wang
- Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA; Departments of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Mark J Niciu
- Department of Psychiatry, University of Iowa Health Care, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Health Care, Iowa City, IA 52242, USA
| | - Anita Bhattacharyya
- Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Cell and Regenerative Biology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Jason L Stein
- Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - André M M Sousa
- Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Elisa A Waxman
- Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA; Center for Epilepsy and NeuroDevelopmental Disorders (ENDD), The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Elizabeth D Buttermore
- Human Neuron Core, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Boston, MA, USA; F.M. Kirby Neurobiology Department, Boston Children's Hospital, Boston, MA, USA
| | - Dosh Whye
- Human Neuron Core, Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Boston, MA, USA; F.M. Kirby Neurobiology Department, Boston Children's Hospital, Boston, MA, USA
| | - Carissa L Sirois
- Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA
| | - Aislinn Williams
- Department of Psychiatry, University of Iowa Health Care, Iowa City, IA 52242, USA; Iowa Neuroscience Institute, University of Iowa Health Care, Iowa City, IA 52242, USA.
| | - Mirjana Maletic-Savatic
- Department of Pediatrics-Neurology, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA; Center for Drug Discovery, Baylor College of Medicine, Houston, TX, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.
| | - Xinyu Zhao
- Waisman Center, University of Wisconsin-Madison, Madison, WI 53705, USA; Department of Neuroscience, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA.
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9
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Dwivedi I, Haddad GG. Investigating the neurobiology of maternal opioid use disorder and prenatal opioid exposure using brain organoid technology. Front Cell Neurosci 2024; 18:1403326. [PMID: 38812788 PMCID: PMC11133580 DOI: 10.3389/fncel.2024.1403326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 05/01/2024] [Indexed: 05/31/2024] Open
Abstract
Over the past two decades, Opioid Use Disorder (OUD) among pregnant women has become a major global public health concern. OUD has been characterized as a problematic pattern of opioid use despite adverse physical, psychological, behavioral, and or social consequences. Due to the relapsing-remitting nature of this disorder, pregnant mothers are chronically exposed to exogenous opioids, resulting in adverse neurological and neuropsychiatric outcomes. Collateral fetal exposure to opioids also precipitates severe neurodevelopmental and neurocognitive sequelae. At present, much of what is known regarding the neurobiological consequences of OUD and prenatal opioid exposure (POE) has been derived from preclinical studies in animal models and postnatal or postmortem investigations in humans. However, species-specific differences in brain development, variations in subject age/health/background, and disparities in sample collection or storage have complicated the interpretation of findings produced by these explorations. The ethical or logistical inaccessibility of human fetal brain tissue has also limited direct examinations of prenatal drug effects. To circumvent these confounding factors, recent groups have begun employing induced pluripotent stem cell (iPSC)-derived brain organoid technology, which provides access to key aspects of cellular and molecular brain development, structure, and function in vitro. In this review, we endeavor to encapsulate the advancements in brain organoid culture that have enabled scientists to model and dissect the neural underpinnings and effects of OUD and POE. We hope not only to emphasize the utility of brain organoids for investigating these conditions, but also to highlight opportunities for further technical and conceptual progress. Although the application of brain organoids to this critical field of research is still in its nascent stages, understanding the neurobiology of OUD and POE via this modality will provide critical insights for improving maternal and fetal outcomes.
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Affiliation(s)
- Ila Dwivedi
- Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, United States
| | - Gabriel G. Haddad
- Department of Pediatrics, School of Medicine, University of California, San Diego, La Jolla, CA, United States
- Department of Neurosciences, School of Medicine, University of California, San Diego, La Jolla, CA, United States
- Rady Children’s Hospital, San Diego, CA, United States
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10
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Niemis W, Peterson SR, Javier C, Nguyen A, Subiah S, Palmer RHC. On the utilization of the induced pluripotent stem cell (iPSC) model to study substance use disorders: A scoping review protocol. PLoS One 2023; 18:e0292238. [PMID: 37824561 PMCID: PMC10569547 DOI: 10.1371/journal.pone.0292238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2023] [Accepted: 09/13/2023] [Indexed: 10/14/2023] Open
Abstract
INTRODUCTION Induced pluripotent stem cells (iPSCs) are cells derived from somatic cells via reprogramming techniques. The iPSC approach has been increasingly used in neuropsychiatric research in the last decade. Though substance use disorders (SUDs) are a commonly occurring psychiatric disorder, the application of iPSC model in addiction research has been limited. No comprehensive review has been reported. We conducted a scoping review to collate existing evidence on the iPSC technologies applied to SUD research. We aim to identify current knowledge gaps and limitations in order to advance the use of iPSCs in the SUD field. METHODS AND ANALYSIS We employed a scoping review using the methodological framework first created by Arksey and O'Malley and further updated by Levac et al. and the Joanna Briggs Institute (JBI). We adopted the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Protocols (PRISMA-P) to report items for the protocol. We searched evidence from four electronic databases: PubMed®, Embase®, Web of Science™, and Scopus®. Primary research, systematic reviews, and meta-analyses were included and limited to studies published in English, at the time from 2007 to March 2022. This is an "ongoing" scoping review. Searched studies will be independently screened, selected, and extracted by two reviewers. Disagreement will be solved by the third reviewer and discussion. Extracted data will be analyzed in descriptive and quantitative approaches, then summarized and presented in appropriate formats. Results will be reported following the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guideline and disseminated through a peer-reviewed publication and conference presentations. CONCLUSION To our best knowledge, this is the first comprehensive scoping review of iPSC methods specifically applied to a broad range of addictive drugs/substances that lead to SUDs or misuse behavior. REGISTRATION This protocol is registered on Zenodo repository (https://zenodo.org/) with doi:10.5281/zenodo.7915252.
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Affiliation(s)
- Wasiri Niemis
- Behavioral Genetics of Addiction Laboratory, Department of Psychology, Emory University, Atlanta, GA, United States of America
| | - Shenita R. Peterson
- Woodruff Health Sciences Center Library, Emory University, Atlanta, GA, United States of America
| | - Chrisabella Javier
- Behavioral Genetics of Addiction Laboratory, Department of Psychology, Emory University, Atlanta, GA, United States of America
| | - Amy Nguyen
- Behavioral Genetics of Addiction Laboratory, Department of Psychology, Emory University, Atlanta, GA, United States of America
| | - Sanchi Subiah
- Behavioral Genetics of Addiction Laboratory, Department of Psychology, Emory University, Atlanta, GA, United States of America
| | - Rohan H. C. Palmer
- Behavioral Genetics of Addiction Laboratory, Department of Psychology, Emory University, Atlanta, GA, United States of America
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Chen J, Ma H, Deng Z, Luo Q, Gong H, Long B, Li X. Cerebral Organoid Arrays for Batch Phenotypic Analysis in Sections and Three Dimensions. Int J Mol Sci 2023; 24:13903. [PMID: 37762204 PMCID: PMC10530571 DOI: 10.3390/ijms241813903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 08/29/2023] [Accepted: 09/07/2023] [Indexed: 09/29/2023] Open
Abstract
Organoids can recapitulate human-specific phenotypes and functions in vivo and have great potential for research in development, disease modeling, and drug screening. Due to the inherent variability among organoids, experiments often require a large sample size. Embedding, staining, and imaging each organoid individually require a lot of reagents and time. Hence, there is an urgent need for fast and efficient methods for analyzing the phenotypic changes in organoids in batches. Here, we provide a comprehensive strategy for array embedding, staining, and imaging of cerebral organoids in both agarose sections and in 3D to analyze the spatial distribution of biomarkers in organoids in situ. We constructed several disease models, particularly an aging model, as examples to demonstrate our strategy for the investigation of the phenotypic analysis of organoids. We fabricated an array mold to produce agarose support with microwells, which hold organoids in place for live/dead imaging. We performed staining and imaging of sectioned organoids embedded in agarose and 3D imaging to examine phenotypic changes in organoids using fluorescence micro-optical sectioning tomography (fMOST) and whole-mount immunostaining. Parallel studies of organoids in arrays using the same staining and imaging parameters enabled easy and reliable comparison among different groups. We were able to track all the data points obtained from every organoid in an embedded array. This strategy could help us study the phenotypic changes in organoids in disease models and drug screening.
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Affiliation(s)
- Juan Chen
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Haihua Ma
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Zhiyu Deng
- Key Laboratory of Biomedical Engineering of Hainan Province, School of Biomedical Engineering, Hainan University, Haikou 570228, China
| | - Qingming Luo
- Key Laboratory of Biomedical Engineering of Hainan Province, School of Biomedical Engineering, Hainan University, Haikou 570228, China
| | - Hui Gong
- Britton Chance Center for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan 430074, China
- HUST-Suzhou Institute for Brainsmatics, Jiangsu Industrial Technology Research Institute, Suzhou 215125, China
| | - Ben Long
- Key Laboratory of Biomedical Engineering of Hainan Province, School of Biomedical Engineering, Hainan University, Haikou 570228, China
- HUST-Suzhou Institute for Brainsmatics, Jiangsu Industrial Technology Research Institute, Suzhou 215125, China
| | - Xiangning Li
- Key Laboratory of Biomedical Engineering of Hainan Province, School of Biomedical Engineering, Hainan University, Haikou 570228, China
- HUST-Suzhou Institute for Brainsmatics, Jiangsu Industrial Technology Research Institute, Suzhou 215125, China
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12
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Kilpatrick S, Irwin C, Singh KK. Human pluripotent stem cell (hPSC) and organoid models of autism: opportunities and limitations. Transl Psychiatry 2023; 13:217. [PMID: 37344450 PMCID: PMC10284884 DOI: 10.1038/s41398-023-02510-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 05/09/2023] [Accepted: 06/05/2023] [Indexed: 06/23/2023] Open
Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder caused by genetic or environmental perturbations during early development. Diagnoses are dependent on the identification of behavioral abnormalities that likely emerge well after the disorder is established, leaving critical developmental windows uncharacterized. This is further complicated by the incredible clinical and genetic heterogeneity of the disorder that is not captured in most mammalian models. In recent years, advancements in stem cell technology have created the opportunity to model ASD in a human context through the use of pluripotent stem cells (hPSCs), which can be used to generate 2D cellular models as well as 3D unguided- and region-specific neural organoids. These models produce profoundly intricate systems, capable of modeling the developing brain spatiotemporally to reproduce key developmental milestones throughout early development. When complemented with multi-omics, genome editing, and electrophysiology analysis, they can be used as a powerful tool to profile the neurobiological mechanisms underlying this complex disorder. In this review, we will explore the recent advancements in hPSC-based modeling, discuss present and future applications of the model to ASD research, and finally consider the limitations and future directions within the field to make this system more robust and broadly applicable.
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Affiliation(s)
- Savannah Kilpatrick
- Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, ON, Canada
- Department of Biochemistry and Biomedical Science, McMaster University, Hamilton, ON, Canada
| | - Courtney Irwin
- Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Karun K Singh
- Donald K. Johnson Eye Institute, Krembil Research Institute, University Health Network, Toronto, ON, Canada.
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
- Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON, Canada.
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Yang S, Hu H, Kung H, Zou R, Dai Y, Hu Y, Wang T, Lv T, Yu J, Li F. Organoids: The current status and biomedical applications. MedComm (Beijing) 2023; 4:e274. [PMID: 37215622 PMCID: PMC10192887 DOI: 10.1002/mco2.274] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 04/22/2023] [Accepted: 04/27/2023] [Indexed: 05/24/2023] Open
Abstract
Organoids are three-dimensional (3D) miniaturized versions of organs or tissues that are derived from cells with stem potential and can self-organize and differentiate into 3D cell masses, recapitulating the morphology and functions of their in vivo counterparts. Organoid culture is an emerging 3D culture technology, and organoids derived from various organs and tissues, such as the brain, lung, heart, liver, and kidney, have been generated. Compared with traditional bidimensional culture, organoid culture systems have the unique advantage of conserving parental gene expression and mutation characteristics, as well as long-term maintenance of the function and biological characteristics of the parental cells in vitro. All these features of organoids open up new opportunities for drug discovery, large-scale drug screening, and precision medicine. Another major application of organoids is disease modeling, and especially various hereditary diseases that are difficult to model in vitro have been modeled with organoids by combining genome editing technologies. Herein, we introduce the development and current advances in the organoid technology field. We focus on the applications of organoids in basic biology and clinical research, and also highlight their limitations and future perspectives. We hope that this review can provide a valuable reference for the developments and applications of organoids.
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Affiliation(s)
- Siqi Yang
- Division of Biliary Tract SurgeryDepartment of General SurgeryWest China HospitalSichuan UniversityChengduSichuan ProvinceChina
| | - Haijie Hu
- Division of Biliary Tract SurgeryDepartment of General SurgeryWest China HospitalSichuan UniversityChengduSichuan ProvinceChina
| | - Hengchung Kung
- Krieger School of Arts and SciencesJohns Hopkins UniversityBaltimoreMarylandUSA
| | - Ruiqi Zou
- Division of Biliary Tract SurgeryDepartment of General SurgeryWest China HospitalSichuan UniversityChengduSichuan ProvinceChina
| | - Yushi Dai
- Division of Biliary Tract SurgeryDepartment of General SurgeryWest China HospitalSichuan UniversityChengduSichuan ProvinceChina
| | - Yafei Hu
- Division of Biliary Tract SurgeryDepartment of General SurgeryWest China HospitalSichuan UniversityChengduSichuan ProvinceChina
| | - Tiantian Wang
- Key Laboratory of Rehabilitation Medicine in Sichuan ProvinceWest China HospitalSichuan UniversityChengduSichuanChina
| | - Tianrun Lv
- Division of Biliary Tract SurgeryDepartment of General SurgeryWest China HospitalSichuan UniversityChengduSichuan ProvinceChina
| | - Jun Yu
- Departments of MedicineJohns Hopkins University School of MedicineBaltimoreMarylandUSA
- Departments of OncologyJohns Hopkins University School of MedicineBaltimoreMarylandUSA
| | - Fuyu Li
- Division of Biliary Tract SurgeryDepartment of General SurgeryWest China HospitalSichuan UniversityChengduSichuan ProvinceChina
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14
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Vandana JJ, Manrique C, Lacko LA, Chen S. Human pluripotent-stem-cell-derived organoids for drug discovery and evaluation. Cell Stem Cell 2023; 30:571-591. [PMID: 37146581 PMCID: PMC10775018 DOI: 10.1016/j.stem.2023.04.011] [Citation(s) in RCA: 52] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/27/2023] [Accepted: 04/11/2023] [Indexed: 05/07/2023]
Abstract
Human pluripotent stem cells (hPSCs) and three-dimensional organoids have ushered in a new era for disease modeling and drug discovery. Over the past decade, significant progress has been in deriving functional organoids from hPSCs, which have been applied to recapitulate disease phenotypes. In addition, these advancements have extended the application of hPSCs and organoids for drug screening and clinical-trial safety evaluations. This review provides an overview of the achievements and challenges in using hPSC-derived organoids to conduct relevant high-throughput, high-contentscreens and drug evaluation. These studies have greatly enhanced our knowledge and toolbox for precision medicine.
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Affiliation(s)
- J Jeya Vandana
- Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Tri-Institutional PhD Program in Chemical Biology, Weill Cornell Medicine, The Rockefeller University, Memorial Sloan Kettering Cancer, New York, NY, USA
| | - Cassandra Manrique
- Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medical College, New York, NY, USA
| | - Lauretta A Lacko
- Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA
| | - Shuibing Chen
- Department of Surgery, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Center for Genomic Health, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA.
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15
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Bockmann EC, Brito R, Madeira LF, da Silva Sampaio L, de Melo Reis RA, França GR, Calaza KDC. The Role of Cannabinoids in CNS Development: Focus on Proliferation and Cell Death. Cell Mol Neurobiol 2023; 43:1469-1485. [PMID: 35925507 PMCID: PMC11412427 DOI: 10.1007/s10571-022-01263-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 07/15/2022] [Indexed: 11/26/2022]
Abstract
The active principles of Cannabis sativa are potential treatments for several diseases, such as pain, seizures and anorexia. With the increase in the use of cannabis for medicinal purposes, a more careful assessment of the possible impacts on embryonic development becomes necessary. Surveys indicate that approximately 3.9% of pregnant women use cannabis in a recreational and/or medicinal manner. However, although the literature has already described the presence of endocannabinoid system components since the early stages of CNS development, many of their physiological effects during this stage have not yet been established. Moreover, it is still uncertain how the endocannabinoid system can be altered in terms of cell proliferation and cell fate, neural migration, neural differentiation, synaptogenesis and particularly cell death. In relation to cell death in the CNS, knowledge about the effects of cannabinoids is scarce. Thus, the present work aims to review the role of the endocannabinoid system in different aspects of CNS development and discuss possible side effects or even opportunities for treating some conditions in the development of this tissue.
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Affiliation(s)
- Eduardo Cosendey Bockmann
- Instituto de Biologia, Departamento de Neurobiologia, Universidade Federal Fluminense, Niterói, Rio de Janeiro, Brazil
| | - Rafael Brito
- Departamento de Biologia Celular e Molecular, Instituto de Biologia, Universidade Federal Fluminense, Niterói, Rio de Janeiro, Brazil
| | - Lucianne Fragel Madeira
- Instituto de Biologia, Departamento de Neurobiologia, Universidade Federal Fluminense, Niterói, Rio de Janeiro, Brazil
| | - Luzia da Silva Sampaio
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
| | - Ricardo Augusto de Melo Reis
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
| | - Guilherme Rapozeiro França
- Departamento de Ciências Fisiológicas, Instituto Biomédico, Universidade Federal do Estado do Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil.
| | - Karin da Costa Calaza
- Instituto de Biologia, Departamento de Neurobiologia, Universidade Federal Fluminense, Niterói, Rio de Janeiro, Brazil
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Fatmous M, Rai A, Poh QH, Salamonsen LA, Greening DW. Endometrial small extracellular vesicles regulate human trophectodermal cell invasion by reprogramming the phosphoproteome landscape. Front Cell Dev Biol 2022; 10:1078096. [PMID: 36619864 PMCID: PMC9813391 DOI: 10.3389/fcell.2022.1078096] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 12/02/2022] [Indexed: 12/24/2022] Open
Abstract
A series of cyclical events within the uterus are crucial for pregnancy establishment. These include endometrial regeneration following menses, under the influence of estrogen (proliferative phase), then endometrial differentiation driven by estrogen/progesterone (secretory phase), to provide a microenvironment enabling attachment of embryo (as a hatched blastocyst) to the endometrial epithelium. This is followed by invasion of trophectodermal cells (the outer layer of the blastocyst) into the endometrium tissue to facilitate intrauterine development. Small extracellular vesicles (sEVs) released by endometrial epithelial cells during the secretory phase have been shown to facilitate trophoblast invasion; however, the molecular mechanisms that underline this process remain poorly understood. Here, we show that density gradient purified sEVs (1.06-1.11 g/ml, Alix+ and TSG101+, ∼180 nm) from human endometrial epithelial cells (hormonally primed with estrogen and progesterone vs. estrogen alone) are readily internalized by a human trophectodermal stem cell line and promote their invasion into Matrigel matrix. Mass spectrometry-based proteome analysis revealed that sEVs reprogrammed trophectoderm cell proteome and their cell surface proteome (surfaceome) to support this invasive phenotype through upregulation of pro-invasive regulators associated with focal adhesions (NRP1, PTPRK, ROCK2, TEK), embryo implantation (FBLN1, NIBAN2, BSG), and kinase receptors (EPHB4/B2, ERBB2, STRAP). Kinase substrate prediction highlighted a central role of MAPK3 as an upstream kinase regulating target cell proteome reprogramming. Phosphoproteome analysis pinpointed upregulation of MAPK3 T204/T202 phosphosites in hTSCs following sEV delivery, and that their pharmacological inhibition significantly abrogated invasion. This study provides novel molecular insights into endometrial sEVs orchestrating trophoblast invasion, highlighting the microenvironmental regulation of hTSCs during embryo implantation.
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Affiliation(s)
- Monique Fatmous
- Baker Heart and Diabetes Institute, Melbourne, VIC, Australia,Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University (LTU), Melbourne, VIC, Australia
| | - Alin Rai
- Baker Heart and Diabetes Institute, Melbourne, VIC, Australia,Central Clinical School, Monash University, Melbourne, VIC, Australia,Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, VIC, Australia,Baker Department of Cardiovascular Research, Translation and Implementation, LTU, Melbourne, VIC, Australia
| | - Qi Hui Poh
- Baker Heart and Diabetes Institute, Melbourne, VIC, Australia,Baker Department of Cardiovascular Research, Translation and Implementation, LTU, Melbourne, VIC, Australia,Department of Biochemistry and Chemistry, LTU, Melbourne, VIC, Australia
| | - Lois A. Salamonsen
- Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, VIC, Australia,Department of Molecular and Translational Medicine, Monash University, Clayton, VIC, Australia
| | - David W. Greening
- Baker Heart and Diabetes Institute, Melbourne, VIC, Australia,Central Clinical School, Monash University, Melbourne, VIC, Australia,Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, VIC, Australia,Baker Department of Cardiovascular Research, Translation and Implementation, LTU, Melbourne, VIC, Australia,Department of Biochemistry and Chemistry, LTU, Melbourne, VIC, Australia,*Correspondence: David W. Greening,
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Bassil K, De Nijs L, Rutten BPF, Van Den Hove DLA, Kenis G. In vitro modeling of glucocorticoid mechanisms in stress-related mental disorders: Current challenges and future perspectives. Front Cell Dev Biol 2022; 10:1046357. [DOI: 10.3389/fcell.2022.1046357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 11/08/2022] [Indexed: 11/29/2022] Open
Abstract
In the last decade, in vitro models has been attracting a great deal of attention for the investigation of a number of mechanisms underlying neurological and mental disorders, including stress-related disorders, for which human brain material has rarely been available. Neuronal cultures have been extensively used to investigate the neurobiological effects of stress hormones, in particular glucocorticoids. Despite great advancements in this area, several challenges and limitations of studies attempting to model and investigate stress-related mechanisms in vitro exist. Such experiments often come along with non-standardized definitions stress paradigms in vitro, variations in cell models and cell types investigated, protocols with differing glucocorticoid concentrations and exposure times, and variability in the assessment of glucocorticoid-induced phenotypes, among others. Hence, drawing consensus conclusions from in-vitro stress studies is challenging. Addressing these limitations and aligning methodological aspects will be the first step towards an improved and standardized way of conducting in vitro studies into stress-related disorders, and is indispensable to reach the full potential of in vitro neuronal models. Here, we consider the most important challenges that need to be overcome and provide initial guidelines to achieve improved use of in vitro neuronal models for investigating mechanisms underlying the development of stress-related mental disorders.
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Organoid Technologies for SARS-CoV-2 Research. CURRENT STEM CELL REPORTS 2022; 8:151-163. [PMID: 36313938 PMCID: PMC9589566 DOI: 10.1007/s40778-022-00220-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/07/2022] [Indexed: 12/05/2022]
Abstract
Purpose of Review Organoids are an emerging technology utilizing three-dimensional (3D), multi-cellular in vitro models to represent the function and physiological responses of tissues and organs. By using physiologically relevant models, more accurate tissue responses to viral infection can be observed, and effective treatments and preventive strategies can be identified. Animals and two-dimensional (2D) cell culture models occasionally result in inaccurate disease modeling outcomes. Organoids have been developed to better represent human organ and tissue systems, and accurately model tissue function and disease responses. By using organoids to study SARS-Cov-2 infection, researchers have now evaluated the viral effects on different organs and evaluate efficacy of potential treatments. The purpose of this review is to highlight organoid technologies and their ability to model SARS-Cov-2 infection and tissue responses. Recent Findings Lung, cardiac, kidney, and small intestine organoids have been examined as potential models of SARS-CoV-2 infection. Lung organoid research has highlighted that SARS-CoV-2 shows preferential infection of club cells and have shown value for the rapid screening and evaluations of multiple anti-viral drugs. Kidney organoid research suggests human recombinant soluble ACE2 as a preventative measure during early-stage infection. Using small intestine organoids, fecal to oral transmission has been evaluated as a transmission route for the virus. Lastly in cardiac organoids drug evaluation studies have found that drugs such as bromodomain, external family inhibitors, BETi, and apabetalone may be effective treatments for SARs-CoV-2 cardiac injury. Summary Organoids are an effective tool to study the effects of viral infections and for drug screening and evaluation studies. By using organoids, more accurate disease modeling can be performed, and physiological effects of infection and treatment can be better understood.
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Human Brain Organoid: A Versatile Tool for Modeling Neurodegeneration Diseases and for Drug Screening. Stem Cells Int 2022; 2022:2150680. [PMID: 36061149 PMCID: PMC9436613 DOI: 10.1155/2022/2150680] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 05/28/2022] [Accepted: 06/18/2022] [Indexed: 11/17/2022] Open
Abstract
Clinical trials serve as the fundamental prerequisite for clinical therapy of human disease, which is primarily based on biomedical studies in animal models. Undoubtedly, animal models have made a significant contribution to gaining insight into the developmental and pathophysiological understanding of human diseases. However, none of the existing animal models could efficiently simulate the development of human organs and systems due to a lack of spatial information; the discrepancy in genetic, anatomic, and physiological basis between animals and humans limits detailed investigation. Therefore, the translational efficiency of the research outcomes in clinical applications was significantly weakened, especially for some complex, chronic, and intractable diseases. For example, the clinical trials for human fragile X syndrome (FXS) solely based on animal models have failed such as mGluR5 antagonists. To mimic the development of human organs more faithfully and efficiently translate in vitro biomedical studies to clinical trials, extensive attention to organoids derived from stem cells contributes to a deeper understanding of this research. The organoids are a miniaturized version of an organ generated in vitro, partially recapitulating key features of human organ development. As such, the organoids open a novel avenue for in vitro models of human disease, advantageous over the existing animal models. The invention of organoids has brought an innovative breakthrough in regeneration medicine. The organoid-derived human tissues or organs could potentially function as invaluable platforms for biomedical studies, pathological investigation of human diseases, and drug screening. Importantly, the study of regeneration medicine and the development of therapeutic strategies for human diseases could be conducted in a dish, facilitating in vitro analysis and experimentation. Thus far, the pilot breakthrough has been made in the generation of numerous types of organoids representing different human organs. Most of these human organoids have been employed for in vitro biomedical study and drug screening. However, the efficiency and quality of the organoids in recapitulating the development of human organs have been hindered by engineering and conceptual challenges. The efficiency and quality of the organoids are essential for downstream applications. In this article, we highlight the application in the modeling of human neurodegenerative diseases (NDDs) such as FXS, Alzheimer's disease (AD), Parkinson's disease (PD), and autistic spectrum disorders (ASD), and organoid-based drug screening. Additionally, challenges and weaknesses especially for limits of the brain organoid models in modeling late onset NDDs such as AD and PD., and future perspectives regarding human brain organoids are addressed.
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Murphy SE, Sweedler JV. Metabolomics-based mass spectrometry methods to analyze the chemical content of 3D organoid models. Analyst 2022; 147:2918-2929. [PMID: 35660810 PMCID: PMC9533735 DOI: 10.1039/d2an00599a] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/19/2023]
Abstract
Metabolomics, the study of metabolites present in biological samples, can provide a global view of sample state as well as insights into biological changes caused by disease or environmental interactions. Mass spectrometry (MS) is commonly used for metabolomics analysis given its high-throughput capabilities, high sensitivity, and capacity to identify multiple compounds in complex samples simultaneously. MS can be coupled to separation methods that can handle small volumes, making it well suited for analyzing the metabolome of organoids, miniaturized three-dimensional aggregates of stem cells that model in vivo organs. Organoids are being used in research efforts to study human disease and development, and in the design of personalized drug treatments. For organoid models to be useful, they need to recapitulate morphological and chemical aspects, such as the metabolome, of the parent tissue. This review highlights the separation- and imaging-based MS-based metabolomics methods that have been used to analyze the chemical contents of organoids. Future perspectives on how MS techniques can be optimized to determine the accuracy of organoid models and expand the field of organoid research are also discussed.
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Affiliation(s)
- Shannon E Murphy
- Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois, 61801, USA.
| | - Jonathan V Sweedler
- Department of Chemistry, University of Illinois at Urbana-Champaign, 600 South Mathews Avenue, Urbana, Illinois, 61801, USA.
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Li M, Gong J, Gao L, Zou T, Kang J, Xu H. Advanced human developmental toxicity and teratogenicity assessment using human organoid models. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2022; 235:113429. [PMID: 35325609 DOI: 10.1016/j.ecoenv.2022.113429] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 03/12/2022] [Accepted: 03/16/2022] [Indexed: 06/14/2023]
Abstract
Tremendous progress has been made in the field of toxicology leading to the advance of developmental toxicity assessment. Conventional animal models and in vitro two-dimensional models cannot accurately describe toxic effects and predict actual in vivo responses due to obvious inter-species differences between humans and animals, as well as the lack of a physiologically relevant tissue microenvironment. Human embryonic stem cell (hESC)- and induced pluripotent stem cell (iPSC)-derived three-dimensional organoids are ideal complex and multicellular organotypic models, which are indispensable in recapitulating morphogenesis, cellular interactions, and molecular processes of early human organ development. Recently, human organoids have been used for drug discovery, chemical toxicity and safety in vitro assessment. This review discusses the recent advances in the use of human organoid models, (i.e., brain, retinal, cardiac, liver, kidney, lung, and intestinal organoid models) for developmental toxicity and teratogenicity assessment of distinct tissues/organs following exposure to pharmaceutical compounds, heavy metals, persistent organic pollutants, nanomaterials, and ambient air pollutants. Combining next-generation organoid models with innovative engineering technologies generates novel and powerful tools for developmental toxicity and teratogenicity assessment, and the rapid progress in this field is expected to continue.
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Affiliation(s)
- Minghui Li
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China
| | - Jing Gong
- Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing 400044, China
| | - Lixiong Gao
- Department of Ophthalmology, Third Medical Center of PLA General Hospital, Beijing 100039, China
| | - Ting Zou
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China
| | - Jiahui Kang
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China
| | - Haiwei Xu
- Southwest Hospital/Southwest Eye Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China; Key Lab of Visual Damage and Regeneration & Restoration of Chongqing, Chongqing 400038, China.
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22
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Stankovic IN, Colak D. Prenatal Drugs and Their Effects on the Developing Brain: Insights From Three-Dimensional Human Organoids. Front Neurosci 2022; 16:848648. [PMID: 35401083 PMCID: PMC8990163 DOI: 10.3389/fnins.2022.848648] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 02/01/2022] [Indexed: 11/13/2022] Open
Abstract
Decades of research have unequivocally demonstrated that fetal exposure to both recreational and prescription drugs in utero negatively impacts the developing brain. More recently, the application of cutting-edge techniques in neurodevelopmental research has attempted to identify how the fetal brain responds to specific environmental stimuli. Meanwhile, human fetal brain studies still encounter ethical considerations and technical limitations in tissue collection. Human-induced pluripotent stem cell (iPSC)-derived brain organoid technology has emerged as a powerful alternative to examine fetal neurobiology. In fact, human 3D organoid tissues recapitulate cerebral development during the first trimester of pregnancy. In this review, we aim to provide a comprehensive summary of fetal brain metabolic studies related to drug abuse in animal and human models. Additionally, we will discuss the current challenges and prospects of using brain organoids for large-scale metabolomics. Incorporating cutting-edge techniques in human brain organoids may lead to uncovering novel molecular and cellular mechanisms of neurodevelopment, direct novel therapeutic approaches, and raise new exciting questions.
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Affiliation(s)
- Isidora N. Stankovic
- Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, Cornell University, New York, NY, United States
- *Correspondence: Isidora N. Stankovic,
| | - Dilek Colak
- Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, Cornell University, New York, NY, United States
- Gale & Ira Drukier Institute for Children’s Health, Weill Cornell Medicine, Cornell University, New York, NY, United States
- Dilek Colak,
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23
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Dong J, Duchesne A, Bayne AN, Mohamed NV, Yi W, Mathur M, Chen CXQ, You Z, Abdian N, Taylor L, Fon EA, Durcan TM, Trempe JF. An Approach to Measuring Protein Turnover in Human Induced Pluripotent Stem Cell Organoids by Mass Spectrometry. Methods 2022; 203:17-27. [PMID: 35331912 DOI: 10.1016/j.ymeth.2022.03.011] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 03/15/2022] [Accepted: 03/19/2022] [Indexed: 02/06/2023] Open
Abstract
Patient-derived organoids from induced pluripotent stem cells have emerged as a model for studying human diseases beyond conventional two-dimensional (2D) cell culture. Briefly, these three-dimensional organoids are highly complex, capable of self-organizing, recapitulate cellular architecture, and have the potential to model diseases in complex organs, such as the brain. For example, the hallmark of Parkinson's disease (PD) - proteostatic dysfunction leading to the selective death of neurons in the substantia nigra - present a subtle distinction in cell type specificity that is lost in 2D cell culture models. As such, the development of robust methods to study global proteostasis and protein turnover in organoids will remain essential as organoid models evolve. To solve this problem, we have designed a workflow to reproducibly extract proteins from brain organoids, measure global turnover using mass spectrometry, and statistically investigate turnover differences between genotypes. We also provide robust methodology for data filtering and statistical treatment of turnover data. Using human midbrain organoids (hMO) as a model system, our method accurately characterized the half-lives of 773 midbrain proteins. We compared these half-lives both to Parkin knockout hMOs and to previously reported data from primary cell cultures and in vivo models. Overall, this method will facilitate the study of proteostasis in organoid models of human disease and will provide an analytical and statistical framework to measure protein turnover in organoids of all cell types.
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Affiliation(s)
- Jing Dong
- Department of Pharmacology & Therapeutics and Centre de Recherche en Biologie Structurale, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, H3G 1Y6, Canada
| | - Anthony Duchesne
- Department of Pharmacology & Therapeutics and Centre de Recherche en Biologie Structurale, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, H3G 1Y6, Canada
| | - Andrew N Bayne
- Department of Pharmacology & Therapeutics and Centre de Recherche en Biologie Structurale, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, H3G 1Y6, Canada
| | - Nguyen-Vi Mohamed
- Early Drug Discovery Unit (EDDU), Montreal Neurological Institute-Hospital, Department of Neurology and Neurosurgery, McGill University, 3801 University Street, Montreal, Quebec, H3A 2B4, Canada
| | - Wei Yi
- Early Drug Discovery Unit (EDDU), Montreal Neurological Institute-Hospital, Department of Neurology and Neurosurgery, McGill University, 3801 University Street, Montreal, Quebec, H3A 2B4, Canada
| | - Meghna Mathur
- Early Drug Discovery Unit (EDDU), Montreal Neurological Institute-Hospital, Department of Neurology and Neurosurgery, McGill University, 3801 University Street, Montreal, Quebec, H3A 2B4, Canada
| | - Carol X Q Chen
- Early Drug Discovery Unit (EDDU), Montreal Neurological Institute-Hospital, Department of Neurology and Neurosurgery, McGill University, 3801 University Street, Montreal, Quebec, H3A 2B4, Canada
| | - Zhipeng You
- Early Drug Discovery Unit (EDDU), Montreal Neurological Institute-Hospital, Department of Neurology and Neurosurgery, McGill University, 3801 University Street, Montreal, Quebec, H3A 2B4, Canada
| | - Narges Abdian
- Early Drug Discovery Unit (EDDU), Montreal Neurological Institute-Hospital, Department of Neurology and Neurosurgery, McGill University, 3801 University Street, Montreal, Quebec, H3A 2B4, Canada
| | - Lorne Taylor
- Proteomics Platform, Centre for Translational Biology, Research Institute of the McGill University Health Centre, 1001 Bd Décarie, Montréal, Quebec, H4A 3J1, Canada
| | - Edward A Fon
- Early Drug Discovery Unit (EDDU), Montreal Neurological Institute-Hospital, Department of Neurology and Neurosurgery, McGill University, 3801 University Street, Montreal, Quebec, H3A 2B4, Canada
| | - Thomas M Durcan
- Early Drug Discovery Unit (EDDU), Montreal Neurological Institute-Hospital, Department of Neurology and Neurosurgery, McGill University, 3801 University Street, Montreal, Quebec, H3A 2B4, Canada
| | - Jean-François Trempe
- Department of Pharmacology & Therapeutics and Centre de Recherche en Biologie Structurale, McGill University, 3655 Promenade Sir William Osler, Montreal, Quebec, H3G 1Y6, Canada; Proteomics Platform, Centre for Translational Biology, Research Institute of the McGill University Health Centre, 1001 Bd Décarie, Montréal, Quebec, H4A 3J1, Canada; Brain Repair and Integrative Neuroscience (BRaIN) Program, Centre for Translational Biology, Research Institute of the McGill University Health Centre, 1001 Bd Décarie, Montréal, Quebec, H4A 3J1, Canada.
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24
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Notaras M, Lodhi A, Dündar F, Collier P, Sayles NM, Tilgner H, Greening D, Colak D. Schizophrenia is defined by cell-specific neuropathology and multiple neurodevelopmental mechanisms in patient-derived cerebral organoids. Mol Psychiatry 2022; 27:1416-1434. [PMID: 34789849 PMCID: PMC9095467 DOI: 10.1038/s41380-021-01316-6] [Citation(s) in RCA: 74] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 08/03/2021] [Accepted: 09/22/2021] [Indexed: 01/02/2023]
Abstract
Due to an inability to ethically access developing human brain tissue as well as identify prospective cases, early-arising neurodevelopmental and cell-specific signatures of Schizophrenia (Scz) have remained unknown and thus undefined. To overcome these challenges, we utilized patient-derived induced pluripotent stem cells (iPSCs) to generate 3D cerebral organoids to model neuropathology of Scz during this critical period. We discovered that Scz organoids exhibited ventricular neuropathology resulting in altered progenitor survival and disrupted neurogenesis. This ultimately yielded fewer neurons within developing cortical fields of Scz organoids. Single-cell sequencing revealed that Scz progenitors were specifically depleted of neuronal programming factors leading to a remodeling of cell-lineages, altered differentiation trajectories, and distorted cortical cell-type diversity. While Scz organoids were similar in their macromolecular diversity to organoids generated from healthy controls (Ctrls), four GWAS factors (PTN, COMT, PLCL1, and PODXL) and peptide fragments belonging to the POU-domain transcription factor family (e.g., POU3F2/BRN2) were altered. This revealed that Scz organoids principally differed not in their proteomic diversity, but specifically in their total quantity of disease and neurodevelopmental factors at the molecular level. Single-cell sequencing subsequently identified cell-type specific alterations in neuronal programming factors as well as a developmental switch in neurotrophic growth factor expression, indicating that Scz neuropathology can be encoded on a cell-type-by-cell-type basis. Furthermore, single-cell sequencing also specifically replicated the depletion of BRN2 (POU3F2) and PTN in both Scz progenitors and neurons. Subsequently, in two mechanistic rescue experiments we identified that the transcription factor BRN2 and growth factor PTN operate as mechanistic substrates of neurogenesis and cellular survival, respectively, in Scz organoids. Collectively, our work suggests that multiple mechanisms of Scz exist in patient-derived organoids, and that these disparate mechanisms converge upon primordial brain developmental pathways such as neuronal differentiation, survival, and growth factor support, which may amalgamate to elevate intrinsic risk of Scz.
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Affiliation(s)
- Michael Notaras
- Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, Cornell University, New York, NY, USA
| | - Aiman Lodhi
- Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, Cornell University, New York, NY, USA
| | - Friederike Dündar
- Department of Physiology and Biophysics, Weill Cornell Medical College, Cornell University, New York, NY, USA
| | - Paul Collier
- Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, Cornell University, New York, NY, USA
| | - Nicole M Sayles
- Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, Cornell University, New York, NY, USA
| | - Hagen Tilgner
- Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, Cornell University, New York, NY, USA
| | - David Greening
- La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia
- Central Clinical School, Monash University, Melbourne, VIC, Australia
- Baker Institute & Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, VIC, Australia
| | - Dilek Colak
- Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, Cornell University, New York, NY, USA.
- Gale and Ira Drukier Institute for Children's Health, Weill Cornell Medical College, Cornell University, New York, NY, USA.
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25
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Polli FS, Kohlmeier KA. Prenatal nicotine alters development of the laterodorsal tegmentum: Possible role for attention-deficit/hyperactivity disorder and drug dependence. World J Psychiatry 2022; 12:212-235. [PMID: 35317337 PMCID: PMC8900586 DOI: 10.5498/wjp.v12.i2.212] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 08/07/2021] [Accepted: 01/14/2022] [Indexed: 02/06/2023] Open
Abstract
As we cycle between the states of wakefulness and sleep, a bilateral cholinergic nucleus in the pontine brain stem, the laterodorsal tegmentum (LDT), plays a critical role in controlling salience processing, attention, behavioral arousal, and electrophysiological signatures of the sub- and microstates of sleep. Disorders involving abnormal alterations in behavioral and motivated states, such as drug dependence, likely involve dysfunctions in LDT signaling. In addition, as the LDT exhibits connectivity with the thalamus and mesocortical circuits, as well as receives direct, excitatory input from the prefrontal cortex, a role for the LDT in cognitive symptoms characterizing attention-deficit/hyperactivity disorder (ADHD) including impulsivity, inflexibility, and dysfunctions of attention is suggested. Prenatal nicotine exposure (PNE) is associated with a higher risk for later life development of drug dependence and ADHD, suggesting alteration in development of brain regions involved in these behaviors. PNE has been shown to alter glutamate and cholinergic signaling within the LDT. As glutamate and acetylcholine are major excitatory mediators, these alterations would likely alter excitatory output to target regions in limbic motivational circuits and to thalamic and cortical networks mediating executive control. Further, PNE alters neuronal development and transmission within prefrontal cortex and limbic areas that send input to the LDT, which would compound effects of differential processing within the PNE LDT. When taken together, alterations in signaling in the LDT are likely to play a role in negative behavioral outcomes seen in PNE individuals, including a heightened risk of drug dependence and ADHD behaviors.
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Affiliation(s)
- Filip S Polli
- Drug Design and Pharmacology, University of Copenhagen, Copenhagen 2100, Denmark
| | - Kristi A Kohlmeier
- Drug Design and Pharmacology, University of Copenhagen, Copenhagen 2100, Denmark
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26
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Notaras M, Lodhi A, Fang H, Greening D, Colak D. The proteomic architecture of schizophrenia iPSC-derived cerebral organoids reveals alterations in GWAS and neuronal development factors. Transl Psychiatry 2021; 11:541. [PMID: 34667143 PMCID: PMC8526592 DOI: 10.1038/s41398-021-01664-5] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/24/2021] [Accepted: 09/30/2021] [Indexed: 12/21/2022] Open
Abstract
Schizophrenia (Scz) is a brain disorder that has a typical onset in early adulthood but otherwise maintains unknown disease origins. Unfortunately, little progress has been made in understanding the molecular mechanisms underlying neurodevelopment of Scz due to ethical and technical limitations in accessing developing human brain tissue. To overcome this challenge, we have previously utilized patient-derived Induced Pluripotent Stem Cells (iPSCs) to generate self-developing, self-maturating, and self-organizing 3D brain-like tissue known as cerebral organoids. As a continuation of this prior work, here we provide an architectural map of the developing Scz organoid proteome. Utilizing iPSCs from n = 25 human donors (n = 8 healthy Ctrl donors, and n = 17 Scz patients), we generated 3D cerebral organoids, employed 16-plex isobaric sample-barcoding chemistry, and simultaneously subjected samples to comprehensive high-throughput liquid-chromatography/mass-spectrometry (LC/MS) quantitative proteomics. Of 3,705 proteins identified by high-throughput proteomic profiling, we identified that just ~2.62% of the organoid global proteomic landscape was differentially regulated in Scz organoids. In sum, just 43 proteins were up-regulated and 54 were down-regulated in Scz patient-derived organoids. Notably, a range of neuronal factors were depleted in Scz organoids (e.g., MAP2, TUBB3, SV2A, GAP43, CRABP1, NCAM1 etc.). Based on global enrichment analysis, alterations in key pathways that regulate nervous system development (e.g., axonogenesis, axon development, axon guidance, morphogenesis pathways regulating neuronal differentiation, as well as substantia nigra development) were perturbed in Scz patient-derived organoids. We also identified prominent alterations in two novel GWAS factors, Pleiotrophin (PTN) and Podocalyxin (PODXL), in Scz organoids. In sum, this work serves as both a report and a resource that researchers can leverage to compare, contrast, or orthogonally validate Scz factors and pathways identified in observational clinical studies and other model systems.
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Affiliation(s)
- Michael Notaras
- Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, Cornell University, New York, NY, USA
| | - Aiman Lodhi
- Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, Cornell University, New York, NY, USA
| | - Haoyun Fang
- Baker Institute for Heart and Diabetes, Melbourne, VIC, Australia
| | - David Greening
- Baker Institute for Heart and Diabetes, Melbourne, VIC, Australia.
- La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC, Australia.
- Central Clinical School, Monash University, Melbourne, VIC, Australia.
- Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, VIC, Australia.
| | - Dilek Colak
- Center for Neurogenetics, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College, Cornell University, New York, NY, USA.
- Gale and Ira Drukier Institute for Children's Health, Weill Cornell Medical College, Cornell University, New York, NY, USA.
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