If Human Brain Organoids Are the Answer to Understanding Dementia, What Are the Questions?

Because our beliefs regarding our individuality, autonomy, and personhood are intimately bound up with our brains, there is a public fascination with cerebral organoids, the “mini-brain,” the “brain in a dish”. At the same time, the ethical issues around organoids are only now being explored. What are the prospects of using human cerebral organoids to better understand, treat, or prevent dementia? Will human organoids represent an improvement on the current, less-than-satisfactory, animal models? When considering these questions, two major issues arise. One is the general challenge associated with using any stem cell–generated preparation for in vitro modelling (challenges amplified when using organoids compared with simpler cell culture systems). The other relates to complexities associated with defining and understanding what we mean by the term “dementia.” We discuss 10 puzzles, issues, and stumbling blocks to watch for in the quest to model “dementia in a dish.”

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Cryo-EM structures of amyloid-β 42 filaments from human brains

Science ◽

10.1126/science.abm7285 ◽

2022 ◽

Vol 375 (6577) ◽

pp. 167-172

Author(s):

Yang Yang ◽

Diana Arseni ◽

Wenjuan Zhang ◽

Melissa Huang ◽

Sofia Lövestam ◽

...

Keyword(s):

Electron Microscopy ◽

Animal Models ◽

Human Brain ◽

Amyloid Β ◽

Aβ Peptides ◽

Cryo Electron Microscopy ◽

Specificity And Sensitivity ◽

Human Brains ◽

The Brain

Hi-res view of human Aβ42 filaments Alzheimer’s disease is characterized by a loss of memory and other cognitive functions and the filamentous assembly of Aβ and tau in the brain. The assembly of Aβ peptides into filaments that end at residue 42 is a central event. Yang et al . used electron cryo–electron microscopy to determine the structures of Aβ42 filaments from human brain (see the Perspective by Willem and Fändrich). They identified two types of related S-shaped filaments, each consisting of two identical protofilaments. These structures will inform the development of better in vitro and animal models, inhibitors of Aβ42 assembly, and imaging agents with increased specificity and sensitivity. —SMH

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Editorial: 3D Cell Culture Systems for Cardiovascular Tissue Engineering: In vitro Modelling and in vivo Regenerative Therapies

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.675676 ◽

2021 ◽

Vol 8 ◽

Author(s):

Sanika Joshi ◽

Won Hee Lee ◽

Pu Chen ◽

Vahid Serpooshan ◽

Huaxiao Yang

Keyword(s):

Tissue Engineering ◽

Cell Culture ◽

3D Cell Culture ◽

Cardiovascular Tissue ◽

Culture Systems ◽

Cell Culture Systems ◽

Regenerative Therapies ◽

In Vitro Modelling

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Three-dimensional cell culture systems as an in vitro platform for cancer and stem cell modeling

World Journal of Stem Cells ◽

10.4252/wjsc.v11.i12.1065 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1065-1083 ◽

Cited By ~ 25

Author(s):

Nipha Chaicharoenaudomrung ◽

Phongsakorn Kunhorm ◽

Parinya Noisa

Keyword(s):

Cell Culture ◽

Stem Cell ◽

Three Dimensional ◽

Culture Systems ◽

Cell Culture Systems ◽

Cell Modeling ◽

Dimensional Cell

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Disturbed Copper Bioavailability in Alzheimer's Disease

International Journal of Alzheimer s Disease ◽

10.4061/2011/345614 ◽

2011 ◽

Vol 2011 ◽

pp. 1-5 ◽

Cited By ~ 15

Author(s):

Daniela Kaden ◽

Ashley I. Bush ◽

Ruth Danzeisen ◽

Thomas A. Bayer ◽

Gerd Multhaup

Keyword(s):

Clinical Trial ◽

Cell Culture ◽

Transgenic Mice ◽

Beneficial Effect ◽

Diagnostic Marker ◽

Amyloidogenic Processing ◽

Cell Culture Systems ◽

Metal Levels ◽

The Brain

Recent data from in vitro, animal, and human studies have shed new light on the positive roles of copper in many aspects of AD. Copper promotes the non-amyloidogenic processing of APP and thereby lowers the Aβproduction in cell culture systems, and it increases lifetime and decreases soluble amyloid production in APP transgenic mice. In a clinical trial with Alzheimer patients, the decline of Aβlevels in CSF, which is a diagnostic marker, is diminished in the verum group (8 mg copper/day), indicating a beneficial effect of the copper treatment. These observations are in line with the benefit of treatment with compounds aimed at normalizing metal levels in the brain, such as PBT2. The data reviewed here demonstrate that there is an apparent disturbance in metal homeostasis in AD. More research is urgently needed to understand how this disturbance can be addressed therapeutically.

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Recent Progress in Prediction Systems for Drug-induced Liver Injury Using in vitro Cell Culture

Drug Metabolism Letters ◽

10.2174/1872312814666201202112610 ◽

2020 ◽

Vol 14 ◽

Author(s):

Shogo Ozawa ◽

Toshitaka Miura ◽

Jun Terashima ◽

Wataru Habano ◽

Seiichi Ishida

Keyword(s):

Cell Culture ◽

Recent Progress ◽

Inflammatory Cells ◽

Protein Adducts ◽

In Vitro Assays ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Culture Systems ◽

Cell Culture Systems

Background: In order to avoid drug-induced liver injury (DILI), in vitro assays, which enable the assessment of both metabolic activation and immune reaction processes that ultimately result in DILI, are needed. Objective: In this study, the recent progress in the application of in vitro assays using cell culture systems is reviewed for potential DILI-causing drugs/xenobiotics and a mechanistic study on DILI, as well as for the limitations of in vitro cell culture systems for DILI research. Methods: Information related to DILI was collected through a literature search of the PubMed database. Results: The initial biological event for the onset of DILI is the formation of cellular protein adducts after drugs have been metabolically activated by drug metabolizing enzymes. The damaged peptides derived from protein adducts lead to the activation of CD4+ helper T lymphocytes and recognition by CD8+ cytotoxic T lymphocytes, which destroy hepatocytes through immunological reactions. Because DILI is a major cause of drug attrition and drug withdrawal, numerous in vitro systems consisting of hepatocytes and immune/inflammatory cells, or spheroids of human primary hepatocytes containing non-parenchymal cells have been developed. These cellular-based systems have identified DILIinducing drugs with approximately 50% sensitivity and 90% specificity. Conclusion: Different co-culture systems consisting of human hepatocyte-derived cells and other immune/inflammatory cells have enabled the identification of DILI-causing drugs and of the actual mechanisms of action.

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Is There a Brain Microbiome?

Neuroscience Insights ◽

10.1177/26331055211018709 ◽

2021 ◽

Vol 16 ◽

pp. 263310552110187

Author(s):

Christopher D Link

Keyword(s):

Animal Models ◽

Human Brain ◽

Neurodegenerative Diseases ◽

Ground Truth ◽

Healthy Human ◽

Strong Motivation ◽

The Many ◽

The Brain

Numerous studies have identified microbial sequences or epitopes in pathological and non-pathological human brain samples. It has not been resolved if these observations are artifactual, or truly represent population of the brain by microbes. Given the tempting speculation that resident microbes could play a role in the many neuropsychiatric and neurodegenerative diseases that currently lack clear etiologies, there is a strong motivation to determine the “ground truth” of microbial existence in living brains. Here I argue that the evidence for the presence of microbes in diseased brains is quite strong, but a compelling demonstration of resident microbes in the healthy human brain remains to be done. Dedicated animal models studies may be required to determine if there is indeed a “brain microbiome.”

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Mammary gland 3D cell culture systems in farm animals

Veterinary Research ◽

10.1186/s13567-021-00947-5 ◽

2021 ◽

Vol 52 (1) ◽

Author(s):

Laurence Finot ◽

Eric Chanat ◽

Frederic Dessauge

Keyword(s):

Cell Culture ◽

Mammary Gland ◽

Bacterial Infections ◽

Three Dimensional ◽

3D Cell Culture ◽

Farm Animals ◽

Culture Systems ◽

Cell Culture Systems

AbstractIn vivo study of tissue or organ biology in mammals is very complex and progress is slowed by poor accessibility of samples and ethical concerns. Fortunately, however, advances in stem cell identification and culture have made it possible to derive in vitro 3D “tissues” called organoids, these three-dimensional structures partly or fully mimicking the in vivo functioning of organs. The mammary gland produces milk, the source of nutrition for newborn mammals. Milk is synthesized and secreted by the differentiated polarized mammary epithelial cells of the gland. Reconstructing in vitro a mammary-like structure mimicking the functional tissue represents a major challenge in mammary gland biology, especially for farm animals for which specific agronomic questions arise. This would greatly facilitate the study of mammary gland development, milk secretion processes and pathological effects of viral or bacterial infections at the cellular level, all with the objective of improving milk production at the animal level. With this aim, various 3D cell culture models have been developed such as mammospheres and, more recently, efforts to develop organoids in vitro have been considerable. Researchers are now starting to draw inspiration from other fields, such as bioengineering, to generate organoids that would be more physiologically relevant. In this chapter, we will discuss 3D cell culture systems as organoids and their relevance for agronomic research.

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Role of SHH in Patterning Human Pluripotent Cells towards Ventral Forebrain Fates

Cells ◽

10.3390/cells10040914 ◽

2021 ◽

Vol 10 (4) ◽

pp. 914

Author(s):

Melanie V. Brady ◽

Flora M. Vaccarino

Keyword(s):

Stem Cell ◽

Human Brain ◽

Human Development ◽

Disease Modeling ◽

Model Systems ◽

Advantages And Disadvantages ◽

Technical Ability ◽

Cellular Phenotypes

The complexities of human neurodevelopment have historically been challenging to decipher but continue to be of great interest in the contexts of healthy neurobiology and disease. The classic animal models and monolayer in vitro systems have limited the types of questions scientists can strive to answer in addition to the technical ability to answer them. However, the tridimensional human stem cell-derived organoid system provides the unique opportunity to model human development and mimic the diverse cellular composition of human organs. This strategy is adaptable and malleable, and these neural organoids possess the morphogenic sensitivity to be patterned in various ways to generate the different regions of the human brain. Furthermore, recapitulating human development provides a platform for disease modeling. One master regulator of human neurodevelopment in many regions of the human brain is sonic hedgehog (SHH), whose expression gradient and pathway activation are responsible for conferring ventral identity and shaping cellular phenotypes throughout the neural axis. This review first discusses the benefits, challenges, and limitations of using organoids for studying human neurodevelopment and disease, comparing advantages and disadvantages with other in vivo and in vitro model systems. Next, we explore the range of control that SHH exhibits on human neurodevelopment, and the application of SHH to various stem cell methodologies, including organoids, to expand our understanding of human development and disease. We outline how this strategy will eventually bring us much closer to uncovering the intricacies of human neurodevelopment and biology.

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THE PATHOLOGIC EFFECTS OF STREPTOCOCCI FROM CASES OF POLIOMYELITIS AND OTHER SOURCES

Journal of Experimental Medicine ◽

10.1084/jem.25.4.557 ◽

1917 ◽

Vol 25 (4) ◽

pp. 557-580 ◽

Cited By ~ 25

Author(s):

Carroll G. Bull

Keyword(s):

Spinal Cord ◽

Guinea Pigs ◽

The Other ◽

Laboratory Animals ◽

Histological Changes ◽

Other Hand ◽

Brain And Spinal Cord ◽

The Brain

Streptococci cultivated from the tonsils of thirty-two cases of poliomyelitis were used to inoculate various laboratory animals. In no case was a condition induced resembling poliomyelitis clinically or pathologically in guinea pigs, dogs, cats, rabbits, or monkeys. On the other hand, a considerable percentage of the rabbits and a smaller percentage of some of the other animals developed lesions due to streptococci. These lesions consisted of meningitis, meningo-encephalitis, abscess of the brain, arthritis, tenosynovitis, myositis, abscess of the kidney, endocarditis, pericarditis, and neuritis. No distinction in the character or frequency of the lesions could be determined between the streptococci derived from poliomyelitic patients and from other sources. Streptococci isolated from the poliomyelitic brain and spinal cord of monkeys which succumbed to inoculation with the filtered virus failed to induce in monkeys any paralysis or the characteristic histological changes of poliomyelitis. These streptococci are regarded as secondary bacterial invaders of the nervous organs. Monkeys which have recovered from infection with streptococci derived from cases of poliomyelitis are not protected from infection with the filtered virus, and their blood does not neutralize the filtered virus in vitro. We have failed to detect any etiologic or pathologic relationship between streptococci and epidemic poliomyelitis in man or true experimental poliomyelitis in the monkey.

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