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From Neuronal Differentiation of iPSCs to 3D Neuro-Organoids: Modelling and Therapy of Neurodegenerative Diseases.
In the last decade, the advances made into the reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) led to great improvements towards their use as models of diseases. In particular, in the field of neurodegenerative diseases, iPSCs technology allowed to culture in vitro all types of patient-specific neural cells, facilitating not only the investigation of diseases' etiopathology, but also the testing of new drugs and cell therapies, leading to the innovative concept of personalized medicine. Moreover, iPSCs can be differentiated and organized into 3D organoids, providing a tool which mimics the complexity of the brain's architecture. Furthermore, recent developments in 3D bioprinting allowed the study of physiological cell-to-cell interactions, given by a combination of several biomaterials, scaffolds, and cells. This technology combines bio-plotter and biomaterials in which several types of cells, such as iPSCs or differentiated neurons, can be encapsulated in order to develop an innovative cellular model. IPSCs and 3D cell cultures technologies represent the first step towards the obtainment of a more reliable model, such as organoids, to facilitate neurodegenerative diseases' investigation. The combination of iPSCs, 3D organoids and bioprinting will also allow the development of new therapeutic approaches. Indeed, on the one hand they will lead to the development of safer and patient-specific drugs testing but, also, they could be developed as cell-therapy for curing neurodegenerative diseases with a regenerative medicine approach.
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Scanning electron microscopy of the ventricular system in normal and hydrocephalic rabbits. Preliminary report and atlas.
The author used the scanning electron microscope to study the ependyma in six control rabbits and six rabbits made hydrocephalic by infusion of silicone oil into the cisterna magna. The ependymal lining of the third ventricle, head of the caudate nucleus, superior angle of the caudate, and atrium of the lateral ventricle was examined. In the hydrocephalic animals, clusters of cilia emanating from the ependyma over periventricular white matter become separated; the author believes this is secondary to ingrowth of new ependymal cell processes covered with microvilli. The addition of these cells to the ependymal surface permits ventricular dilatation without ependymal disruption and provides more surface containing microvilli, presumably capable of increased transventricular fluid transfer. No such changes occur over gray matter masses since their surfaces are not deformed by moderate ventricular dilatation. The morphological alterations in the ependyma that occur in moderate hydrocephalus do not appear to be simply manifestations of ependymal destruction but rather suggest a modification in its function from that of a surface capable of propelling cerebrospinal fluid to one capable of increased transfer of transventricular fluid. As hydrocephalus progresses, compensation may fail because of the relative decrease in microvilli so that the cell surface provides a less efficient mechanism for absorption.
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Cerebral Organoids for Modeling of HSV-1-Induced-Amyloid β Associated Neuropathology and Phenotypic Rescue.
Herpes simplex virus type I (HSV-1) infection is a potential risk factor involved in the Amyloid β (Aβ) associated neuropathology. However, further understanding of the neuropathological effects of the HSV-1 infection is hampered by the limitations of existing infection models due to the distinct differences between human brains and other mammalians' brains. Here we generated cerebral organoid models derived from pluripotent stem cells to investigate the HSV-induced Aβ associated neuropathology and the role of antiviral drugs in the phenotypic rescue. Our results identified that the HSV-1-infected cerebral organoids recapitulated Aβ associated neuropathology including the multicellular Aβ deposition, dysregulated endogenous AD mediators, reactive gliosis, neuroinflammation, and neural loss, indicating that cerebral organoids offer an opportunity for modeling the interaction of HSV-1 with the complex phenotypes across the genetic, cellular, and tissue levels of the human Alzheimer's disease (AD). Furthermore, we identified that two antiviral drugs, namely Ribavirin (RBV) and Valacyclovir (VCV), inhibited HSV-1 replication and rescued the neuropathological phenotypes associated with AD in the HSV-1-infected cerebral organoids, implying their therapeutic potential to slow down the progression of AD. Our study provides a high-fidelity human-relevant in-vitro HSV-1 infection model to reconstitute the multiscale neuropathological features associated with AD and discover therapeutic drug candidates relevant to the AD viral hypothesis.
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Bioengineering Ovarian Endocrine Function: From Follicle Modeling to Cell-Based Hormone Therapy.
Premature ovarian insufficiency (POI) is a complex endocrine disorder characterized by the loss of ovarian function before age 40, leading to infertility, hypoestrogenism, and systemic complications. Conventional hormone replacement therapies (HRTs) offer only partial relief, failing to replicate the dynamic feedback of endogenous hormone regulation. Advances in tissue engineering, stem cell technology, and microphysiological systems have catalyzed the development of bioengineered platforms that mimic native ovarian endocrine function. This review outlines progress from three-dimensional (3D) follicle-mimetic constructs and scaffold-free organoids to dynamic ovary-on-a-chip systems, emphasizing advances in steroidogenesis reconstitution, innovations in granulosa-theca co-cultures, and the design of cell-based hormone replacement therapies (cHRTs) capable of re-engaging the hypothalamic-pituitary-ovarian (HPO) axis. We also address critical translational challenges including immunoisolation, vascularization, and regulatory pathway. By bridging bioengineering and reproductive medicine, cHRTs represent a paradigm shift, offering the potential to restore endocrine health, fertility, and systemic homeostasis in a personalized and physiologically relevant manner.
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One Step Into the Future: New iPSC Tools to Advance Research in Parkinson's Disease and Neurological Disorders.
Studying Parkinson's disease (PD) in the laboratory presents many challenges, the main one being the limited availability of human cells and tissue from affected individuals. As PD is characterized by a loss of dopaminergic (DA) neurons in the brain, it is nearly impossible for researchers to access and extract these cells from living patients. Thus, in the past PD research has focused on the use of patients' post-mortem tissues, animal models, or immortalized cell lines to dissect cellular pathways of interest. While these strategies deepened our knowledge of pathological mechanisms in PD, they failed to faithfully capture key mechanisms at play in the human brain. The emergence of induced pluripotent stem cell (iPSC) technology is revolutionizing PD research, as it allows for the differentiation and growth of human DA neurons in vitro, holding immense potential not only for modelling PD, but also for identifying novel therapies. However, to reproduce the complexity of the brain's environment, researchers are recognizing the need to further develop and refine iPSC-based tools. In this review, we provide an overview of different systems now available for the study of PD, with a particular emphasis on the potential and limitations of iPSC as research tools to generate more relevant models of PD pathophysiology and advance the drug discovery process.
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Moving beyond the moral status of organoid-entities.
Ethical deliberations are unfolding for potentially controversial organoid-entities such as brain organoids and embryoids. Much of the ethical deliberation centers on the questionable moral status of such organoid-entities. However, while such work is important and appropriate, ethical deliberations may become too exclusively rooted in moral status and potentially overshadow other relevant moral dilemmas. The ethical discussion on organoid models can benefit from insights brought forth by both Judith Jarvis Thomson and Don Marquis in how they attempted to advance the abortion debate. To discuss other abortion ethical issues more fully, both Thomson and Marquis assumed differing moral status positions of the conceptus and followed lines of reasoning based on these moral status assumptions. We suggest a similar approach with controversial organoid-entities like brain organoids and embryoids. To avoid overshadowing or overlooking other relevant ethical issues, ethicists ought to first assume an organoid-entity moral status position (such as a high moral status or no moral status) and explore any possible arguments that may result from such a position. While we ought not to copy the content of Thomson and Marquis' arguments exactly for organoid-entities, it is worthwhile to translate their arguments' overarching structures. This paper explores the relevant insights of Thomson and Marquis, how they can be translated into the organoid ethics debate, and what possible lines of inquiry may be worth exploring based on particular moral status assumptions.
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Induced Pluripotent Stem Cells and Organoids in Advancing Neuropathology Research and Therapies.
This review delves into the groundbreaking impact of induced pluripotent stem cells (iPSCs) and three-dimensional organoid models in propelling forward neuropathology research. With a focus on neurodegenerative diseases, neuromotor disorders, and related conditions, iPSCs provide a platform for personalized disease modeling, holding significant potential for regenerative therapy and drug discovery. The adaptability of iPSCs, along with associated methodologies, enables the generation of various types of neural cell differentiations and their integration into three-dimensional organoid models, effectively replicating complex tissue structures in vitro. Key advancements in organoid and iPSC generation protocols, alongside the careful selection of donor cell types, are emphasized as critical steps in harnessing these technologies to mitigate tumorigenic risks and other hurdles. Encouragingly, iPSCs show promising outcomes in regenerative therapies, as evidenced by their successful application in animal models.
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Extracellular Microenvironmental Control for Organoid Assembly.
Organoids, which are multicellular clusters with similar physiological functions to living organs, have gained increasing attention in bioengineering. As organoids become more advanced, methods to form complex structures continue to develop. There is evidence that the extracellular microenvironment can regulate organoid quality. The extracellular microenvironment consists of soluble bioactive molecules, extracellular matrix, and biofluid flow. However, few efforts have been made to discuss the microenvironment optimal to engineer specific organoids. Therefore, this review article examines the extent to which engineered extracellular microenvironments regulate organoid quality. First, we summarize the natural tissue and organ's unique chemical and mechanical properties, guiding researchers to design an extracellular microenvironment used for organoid engineering. Then, we summarize how the microenvironments contribute to the formation and growth of the brain, lung, intestine, liver, retinal, and kidney organoids. The approaches to forming and evaluating the resulting organoids are also discussed in detail. Impact statement Organoids, which are multicellular clusters with similar physiological function to living organs, have been gaining increasing attention in bioengineering. As organoids become more advanced, methods to form complex structures continue to develop. This review article focuses on recent efforts to engineer the extracellular microenvironment in organoid research. We summarized the natural organ's microenvironment, which informs researchers of key factors that can influence organoid formation. Then, we summarize how these microenvironmental controls significantly contribute to the formation and growth of the corresponding brain, lung, intestine, liver, retinal, and kidney organoids. The approaches to forming and evaluating the resulting organoids are discussed in detail, including extracellular matrix choice and properties, culture methods, and the evaluation of the morphology and functionality through imaging and biochemical analysis.
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IDH1 Mutation Increases the Sensitivity of Glioma Organoids to Radiotherapy and Targeted Therapy.
INTRODUCTION: In gliomas, the Isocitrate Dehydrogenase (IDH1) mutation is a key molecular marker that can distinguish subtypes. IDH1-mutant gliomas grow more slowly, are sensitive to radiotherapy and chemotherapy, and have a better prognosis. However, there are still individual differences in treatment responses and prognosis among patients with this subtype, making traditional treatments difficult to adapt. Organoid models can simulate the characteristics of IDH1-mutant tumors and provide important support for research on their personalized treatment. MATERIALS AND METHODS: Glioma tissues were dissociated, and cells were resuspended in Matrigel before being seeded into culture dishes for IDH1-mutant organoid culture. Organoids at different culture stages were subjected to morphological observation and viability confirmation via live-dead staining. The growth curves of two-dimensional (2D) and three-dimensional (3D) cells were measured by adding CellTiter-Glo (CTG). Hematoxylin and Eosin (H&E) staining and immunohistochemistry were performed on cultured organoids and original tumor tissue sections to validate organoid phenotypes, while immunofluorescence assays confirmed the IDH1 mutation status. Drug sensitivity tests were conducted using temozolomide and vorasidenib on IDH1-mutant and IDHwildtype glioma organoids. Relative luminescence Units (RLU) were measured via CTG at various time points. Organoids were irradiated with 8 Gy γ-rays at day 0 and day 4, and cell viability was measured. RESULTS: Immunohistochemical (IHC) results of the constructed organoids were consistent with those of the original tumor tissues, and immunofluorescence confirmed the presence of IDH1 mutations in the organoids. No significant difference in sensitivity to temozolomide was observed between IDH1-mutant and wild-type organoids, whereas IDH1-mutant organoids showed significantly higher sensitivity to vorasidenib than IDH-wildtype organoids. After 4 days of γ-ray irradiation, the cell viability of IDH1-mutant glioma organoids decreased significantly, while no significant change was observed in IDH-wildtype organoids. DISCUSSION: This study generated patient-derived IDH1-mutant glioma organoids, validated their value as an individualized precision drug-testing platform by comparing drug sensitivity and radiotherapy responses with IDH-wildtype organoids, and found that IDH1-mutant organoids were more sensitive to radiotherapy and vorasidenib, advancing glioma precision treatment. CONCLUSION: By constructing an IDH1-mutated glioma organoid model and integrating accurate molecular diagnostic information, it is expected to improve treatment efficacy and promote the development of personalized glioma medicine.
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Lamination-based organoid spatially resolved transcriptomics technique for primary lung and liver organoid characterization.
Spatial-transcriptomics technologies have demonstrated exceptional performance in characterizing brain and visceral organ tissues, as well as brain and retinal organoids. However, it has not yet been proven whether spatial transcriptomics can effectively characterize primary tissue-derived organoids, as the standardized tissue sectioning or slicing methods are not applicable for such organoids. Herein, we present a technique, lamination-based organoid spatially resolved transcriptomics (LOSRT), for organoid-spatially resolved transcriptomics based on organoid lamination. Primary mouse lung and liver-derived organoids were used in this study. The organoids were formulated using the droplet-engineering method and laminated using a homemade device with weight compression. This technique preserved most cells in individual organoids while maintaining delicate epithelium structures in laminated domains that can be recognized through visual segmentation. The mouse lung and liver organoids were resolved comprising various cell types, including alveolar cells, damage-associated transient progenitor cells, basal cells, macrophages, endothelial cells, fibroblasts, hepatocytes, and hepatic stellate cells. The distribution and count of cells were confirmed using immunohistology and identified with spatial transcriptomic features. This study reports an automated and integrated spatial transcriptomics method for primary organoids. It has the potential to standardize and rapidly characterize primary tissue-derived organoids.