Recent advances and current challenges of new approach methodologies in developmental and adult neurotoxicity testing DOI Creative Commons
Melania Maria Serafini, Sara Sepehri, Miriam Midali

et al.

Archives of Toxicology, Journal Year: 2024, Volume and Issue: 98(5), P. 1271 - 1295

Published: March 13, 2024

Abstract Adult neurotoxicity (ANT) and developmental (DNT) assessments aim to understand the adverse effects underlying mechanisms of toxicants on human nervous system. In recent years, there has been an increasing focus so-called new approach methodologies (NAMs). The Organization for Economic Co-operation Development (OECD), together with European American regulatory agencies, promote use validated alternative test systems, but date, guidelines DNT ANT assessment rely primarily classical animal testing. Alternative methods include both non-animal approaches systems non-vertebrates (e.g., nematodes) or non-mammals fish). Therefore, this review summarizes advances NAMs focusing highlights potential current critical issues full implementation these in future. status vitro battery (DNT IVB) is also reviewed as a first step context. Critical such (i) need batteries method integration (from silico vivo alternatives, e.g., zebrafish, C. elegans ) requiring interdisciplinarity manage complexity, (ii) interlaboratory transferability, (iii) urgent validation are discussed.

Language: Английский

Genetic contribution to microglial activation in schizophrenia DOI Creative Commons
Marja Koskuvi, Elina Pörsti, Tristen Hewitt

et al.

Molecular Psychiatry, Journal Year: 2024, Volume and Issue: 29(9), P. 2622 - 2633

Published: March 22, 2024

Several lines of evidence indicate the involvement neuroinflammatory processes in pathophysiology schizophrenia (SCZ). Microglia are brain resident immune cells responding toward invading pathogens and injury-related products, additionally, have a critical role improving neurogenesis synaptic functions. Aberrant activation microglia SCZ is one leading hypotheses for disease pathogenesis, but due to lack proper human cell models, not well studied. We used monozygotic twins discordant healthy individuals generate induced pluripotent stem cell-derived assess transcriptional functional differences between controls, affected unaffected twins. The from had increased expression several common inflammation-related genes compared individuals. also reduced response interleukin 1 beta (IL1β) treatment, no significant migration or phagocytotic activity. Ingenuity Pathway Analysis (IPA) showed abnormalities related extracellular matrix signaling. RNA sequencing predicted downregulation structure constituent Gene Ontology (GO) terms hepatic fibrosis pathway that were shared by both twins, upregulation major histocompatibility complex (MHC) class II receptors was observed only twin microglia. Also, heterogeneous clozapine, minocycline, sulforaphane treatments. Overall, despite inflammatory genes, we clear signs hyperactivation patients with SCZ. conclude gene aberrations inflammation without contributing microglial activation.

Language: Английский

Citations

20
Minimal differences observed when comparing the morphological profiling of microglia obtained by confocal laser scanning and optical sectioning microscopy DOI Creative Commons

Sânziana Godeanu,

Mădălina Iuliana Mușat, Anja Scheller

et al.

Frontiers in Neuroanatomy, Journal Year: 2025, Volume and Issue: 18

Published: Jan. 3, 2025

While widefield microscopy has long been constrained by out-of-focus scattering, advancements have generated a solution in the form of confocal laser scanning (cLSM) and optical sectioning using structured illumination (OSM). In this study, we aim to investigate, microglia branching, if cLSM OSM can produce images with comparable morphological characteristics. By imaging somatosensory from tissue slice 3-week-old mouse establishing parameters that characterizes microglial branching pattern, were able show there is no difference total length branch tree, number branches, mean primary terminal branches. We did find area-based such as occupied area surveillance bigger isolated compared ones. Additionally, investigating acquisition time between techniques personal costs establish amortization could be made 6.11 ± 2.93 years case countries Human Development Index (HDI) = 7-9 7.06 3.13 years, respectably, for HDI < 7. As such, systems seem valid option one just wants basic histological evaluation, should considered groups demand higher resolution or volumetric images.

Language: Английский

Citations

2
Microglia-like Cells Promote Neuronal Functions in Cerebral Organoids DOI Creative Commons
Ilkka Fagerlund, Antonios Dougalis, Anastasia Shakirzyanova

et al.

Cells, Journal Year: 2021, Volume and Issue: 11(1), P. 124 - 124

Published: Dec. 30, 2021

Human cerebral organoids, derived from induced pluripotent stem cells, offer a unique in vitro research window to the development of cortex. However, key player developing brain, microglia, do not natively emerge organoids. Here we show that erythromyeloid progenitors (EMPs), differentiated migrate and mature into microglia-like cells interact with synaptic material. Patch-clamp electrophysiological recordings population supported emergence more diversified neuronal phenotypes displaying repetitive firing action potentials, low-threshold spikes activity, while multielectrode array revealed spontaneous bursting activity increased power gamma-band oscillations upon pharmacological challenge NMDA. To conclude, within organoids promote network maturation recapitulate some aspects microglia-neuron co-development vivo, indicating could be useful biorealistic human platform for studying interactions.

Language: Английский

Citations

80
Microglia in brain development and regeneration DOI Open Access
Lindsey Catherine Mehl,

Amritha Vinayak Manjally,

Ouzéna Bouadi

et al.

Development, Journal Year: 2022, Volume and Issue: 149(8)

Published: April 15, 2022

ABSTRACT It has recently emerged that microglia, the tissue-resident macrophages of central nervous system, play significant non-innate immune roles to support development, maintenance, homeostasis and repair brain. Apart from being highly specialized brain phagocytes, microglia modulate development functions neurons glial cells through both direct indirect interactions. Thus, recognizing elements influence heterogeneity in normal is crucial understanding mechanisms lead early disease pathogenesis neurodevelopmental disorders. In this Review, we discuss recent studies have elucidated physiological summarize our knowledge their tissue repair.

Language: Английский

Citations

62
Advanced human developmental toxicity and teratogenicity assessment using human organoid models DOI Creative Commons
Minghui Li, Jing Gong, Lixiong Gao

et al.

Ecotoxicology and Environmental Safety, Journal Year: 2022, Volume and Issue: 235, P. 113429 - 113429

Published: March 21, 2022

Tremendous progress has been made in the field of toxicology leading to advance developmental toxicity assessment. Conventional animal models and vitro two-dimensional cannot accurately describe toxic effects predict actual vivo responses due obvious inter-species differences between humans animals, as well lack a physiologically relevant tissue microenvironment. Human embryonic stem cell (hESC)- induced pluripotent (iPSC)-derived three-dimensional organoids are ideal complex multicellular organotypic models, which indispensable recapitulating morphogenesis, cellular interactions, molecular processes early human organ development. Recently, have used for drug discovery, chemical safety This review discusses recent advances use organoid (i.e., brain, retinal, cardiac, liver, kidney, lung, intestinal models) teratogenicity assessment distinct tissues/organs following exposure pharmaceutical compounds, heavy metals, persistent organic pollutants, nanomaterials, ambient air pollutants. Combining next-generation with innovative engineering technologies generates novel powerful tools assessment, rapid this is expected continue.

Language: Английский

Citations

52
Decoding the temporal and regional specification of microglia in the developing human brain DOI Creative Commons
Yanxin Li, Zhong‐Qiu Li, Min Yang

et al.

Cell stem cell, Journal Year: 2022, Volume and Issue: 29(4), P. 620 - 634.e6

Published: March 3, 2022

Language: Английский

Citations

47
A single-cell transcriptome atlas of glial diversity in the human hippocampus across the postnatal lifespan DOI Creative Commons
Yijing Su, Yi Zhou, Mariko L. Bennett

et al.

Cell stem cell, Journal Year: 2022, Volume and Issue: 29(11), P. 1594 - 1610.e8

Published: Nov. 1, 2022

Language: Английский

Citations

43
Human neuronal maturation comes of age: cellular mechanisms and species differences DOI
Jenelle L. Wallace, Alex A. Pollen

Nature reviews. Neuroscience, Journal Year: 2023, Volume and Issue: 25(1), P. 7 - 29

Published: Nov. 23, 2023

Language: Английский

Citations

36
Pushing the boundaries of brain organoids to study Alzheimer’s disease DOI Creative Commons

Jonas Cerneckis,

Guojun Bu, Yanhong Shi

et al.

Trends in Molecular Medicine, Journal Year: 2023, Volume and Issue: 29(8), P. 659 - 672

Published: June 22, 2023

Progression of Alzheimer's disease (AD) entails deterioration or aberrant function multiple brain cell types, eventually leading to neurodegeneration and cognitive decline. Defining how complex cell-cell interactions become dysregulated in AD requires novel human cell-based vitro platforms that could recapitulate the intricate cytoarchitecture diversity brain. Brain organoids (BOs) are 3D self-organizing tissues partially resemble architecture can AD-relevant pathology. In this review, we highlight versatile applications different types BOs model pathogenesis, including amyloid-β tau aggregation, neuroinflammation, myelin breakdown, vascular dysfunction, other phenotypes, as well accelerate therapeutic development for AD.

Language: Английский

Citations

33
Brain organoids are new tool for drug screening of neurological diseases DOI Creative Commons
Chong Gao,

Jin-Qi Zhou,

Linghui Zeng

et al.

Neural Regeneration Research, Journal Year: 2023, Volume and Issue: 0(0), P. 0 - 0

Published: Jan. 1, 2023

At the level of in vitro drug screening, development a phenotypic analysis system with high-content screening at core provides strong platform to support high-throughput screening. There are few systematic reports on brain organoids, as new three-dimensional model, terms model stability, key fingerprint, and schemes, particularly regarding strategies for massive numbers traditional Chinese medicine monomers. This paper reviews organoids advantages over induced neurons or cells simulated diseases. The also highlights prospects from induction criteria schemes based characteristics application system.

Language: Английский

Citations

29