Co-Transplantation-Based Human-Mouse Chimeric Brain Models to Study Human Glial-Glial and Glial-Neuronal Interactions DOI Creative Commons
Mengmeng Jin, Ziyuan Ma,

Haiwei Zhang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: July 6, 2024

Abstract Human-mouse chimeric brain models, generated by transplanting human induced pluripotent stem cell (hiPSC)-derived neural cells, are valuable for studying the development and function of cells in vivo. Understanding glial-glial glial-neuronal interactions is essential unraveling complexities developing treatments neurological disorders. To explore these between vivo, we co-engrafted hiPSC-derived progenitor together with primitive macrophage progenitors into neonatal mouse brain. This approach creates human-mouse brains containing microglia, macroglia (astroglia oligodendroglia), neurons. Using super-resolution imaging 3D reconstruction techniques, examine dynamics neurons glia, observe microglia pruning synapses neurons, often engulfing themselves. Single-cell RNA sequencing analysis uncovers a close recapitulation glial population, along dynamic stage astroglial that mirrors processes found Furthermore, cell-cell communication highlights significant neuronal-glial macroglial-microglial interactions, especially interaction adhesion molecules neurexins neuroligins astroglia, emphasizing their key role synaptogenesis. We also observed astroglia mediated SPP1, crucial promoting growth astrogliosis, PTN-MK pathways, instrumental homeostatic maintenance macroglial progenitors. innovative co-transplantation model opens up new avenues exploring complex pathophysiological mechanisms underlying diseases. It holds particular promise disorders where non-cell-autonomous effects play roles.

Language: Английский

An integrated transcriptomic cell atlas of human neural organoids DOI Creative Commons
Zhisong He, Leander Dony, Jonas Simon Fleck

et al.

Nature, Journal Year: 2024, Volume and Issue: 635(8039), P. 690 - 698

Published: Nov. 20, 2024

Human neural organoids, generated from pluripotent stem cells in vitro, are useful tools to study human brain development, evolution and disease. However, it is unclear which parts of the covered by existing protocols, has been difficult quantitatively assess organoid variation fidelity. Here we integrate 36 single-cell transcriptomic datasets spanning 26 protocols into one integrated cell atlas totalling more than 1.7 million cells1–26. Mapping developing references27–30 shows primary types states that have estimates similarity between counterparts across protocols. We provide a programmatic interface browse query new datasets, showcase power annotate evaluate Finally, show can be used as diverse control cohort compare models disease, identifying genes pathways may underlie pathological mechanisms with models. The will fidelity, characterize perturbed diseased facilitate protocol development. A integrating counterparts, showing potential fidelity

Language: Английский

Citations

28
Vascularized human brain organoids: current possibilities and prospects DOI Creative Commons
Lois Kistemaker, Emma J. van Bodegraven, Helga E. de Vries

et al.

Trends in biotechnology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Human brain organoids (hBOs) are in vitro, 3D, self-organizing tissue structures increasingly used for modeling development and disease. Although they traditionally lack vasculature, recent bioengineering developments enable their vascularization, which partly recapitulates neurodevelopmental processes such as neural tube angiogenesis, formation of neurovascular unit (NVU)-like structures, early barriergenesis. vascularized hBOs (vhBOs) already to model (defects in) development, vascularization efficiency other outcomes differ substantially between protocols overall shortcomings should be considered. For instance, vessel-like vhBOs do not contain blood-like flow nor form a functional blood-brain barrier (BBB). Extended characterization, standardization, the new techniques may broader applications drug transport studies.

Language: Английский

Citations

8
Contributions of Genetic Variation in Astrocytes to Cell and Molecular Mechanisms of Risk and Resilience to Late‐Onset Alzheimer's Disease DOI Creative Commons
Hyo Lee, Richard V. Pearse,

Alexandra M. Lish

et al.

Glia, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 3, 2025

ABSTRACT Reactive astrocytes are associated with Alzheimer's disease (AD), and several AD genetic risk variants genes highly expressed in astrocytes. However, the contribution of within to cellular processes relevant pathogenesis remains ill‐defined. Here, we present a resource for studying using large collection induced pluripotent stem cell (iPSC) lines from deeply phenotyped individuals range neuropathological cognitive outcomes. IPSC 44 were differentiated into followed by unbiased molecular profiling RNA sequencing tandem mass tag‐mass spectrometry. We demonstrate utility this examining gene‐ pathway‐level associations clinical traits, as well analyzing resilience factors through parallel analyses iPSC‐astrocytes brain tissue same individuals. Our reveal that pathways altered iPSC‐derived concordantly dysregulated tissue. This includes increased levels prefoldin proteins, extracellular matrix factors, COPI‐mediated trafficking components reduced proteins involved respiration fatty acid oxidation. Additionally, resilient high neuropathology show elevated basal interferon response secretion gamma. Correspondingly, higher polygenic scores lower study establishes an experimental system integrates information matched iPSC data cohort identify contributions affecting resilience.

Language: Английский

Citations

3
A framework for neural organoids, assembloids and transplantation studies DOI Creative Commons
Sergiu P. Paşca, Paola Arlotta, Helen S. Bateup

et al.

Nature, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 9, 2024

As the field of neural organoids and assembloids expands, there is an emergent need for guidance advice on designing, conducting reporting experiments to increase reproducibility utility these models. In this Perspective, we present a framework experimental process that encompasses ensuring quality integrity human pluripotent stem cells, characterizing manipulating cells in vitro, transplantation techniques considerations modelling development, evolution disease. with all scientific endeavours, advocate rigorous designs tailored explicit questions as well transparent methodologies data sharing provide useful knowledge current research practices developing regulatory standards.

Language: Английский

Citations

15
Astrocyte-Mediated Neuroinflammation in Neurological Conditions DOI Creative Commons
Yanxiang Zhao, Yingying Huang,

Ying Cao

et al.

Biomolecules, Journal Year: 2024, Volume and Issue: 14(10), P. 1204 - 1204

Published: Sept. 25, 2024

Astrocytes are one of the key glial types central nervous system (CNS), accounting for over 20% total cells in brain. Extensive evidence has established their indispensable functions maintenance CNS homeostasis, as well broad involvement neurological conditions. In particular, astrocytes can participate various neuroinflammatory processes, e.g., releasing a repertoire cytokines and chemokines or specific neurotrophic factors, which result both beneficial detrimental effects. It become increasingly clear that such astrocyte-mediated neuroinflammation, together with its complex crosstalk other immune cells, designates neuronal survival functional integrity neurocircuits, thus critically contributing to disease onset progression. this review, we focus on current knowledge responses astrocytes, summarizing common features Moreover, highlight several vital questions future research promise novel insights into diagnostic therapeutic strategies against those debilitating diseases.

Language: Английский

Citations

12
Neuroligin-3 R451C induces gain-of-function gene expression in astroglia in an astroglia-enriched brain organoid model DOI Creative Commons

Rui Dang,

Mridul Dalmia,

Ziyuan Ma

et al.

Cell Regeneration, Journal Year: 2025, Volume and Issue: 14(1)

Published: Jan. 8, 2025

Abstract Astroglia are integral to brain development and the emergence of neurodevelopmental disorders. However, studying pathophysiology human astroglia using organoid models has been hindered by inefficient astrogliogenesis. In this study, we introduce a robust method for generating astroglia-enriched organoids through BMP4 treatment during neural differentiation phase development. Our RNA sequencing analysis reveals that developed within these exhibit advanced developmental characteristics enhanced synaptic functions compared those grown under traditional two-dimensional conditions, particularly highlighted increased neurexin (NRXN)-neuroligin (NLGN) signaling. Cell adhesion molecules, such as NRXN NLGN, essential in regulating interactions between neurons. We further discovered derived from embryonic stem cells (hESCs) harboring autism-associated NLGN3 R451C mutation Notably, demonstrate branching, indicating more intricate morphology. Interestingly, our data suggest mutant significantly upregulate pathways support when isogenic wild-type astroglia. findings establish novel model, offering valuable platform probing roles related

Language: Английский

Citations

2
Organoids from pluripotent stem cells and human tissues: When two cultures meet each other DOI Creative Commons
Benedetta Artegiani, Delilah Hendriks

Developmental Cell, Journal Year: 2025, Volume and Issue: 60(4), P. 493 - 511

Published: Feb. 1, 2025

Language: Английский

Citations

1
Human Glial Cells as Innovative Targets for the Therapy of Central Nervous System Pathologies DOI Creative Commons
Giulia Magni, Benedetta Riboldi, Stefania Ceruti

et al.

Cells, Journal Year: 2024, Volume and Issue: 13(7), P. 606 - 606

Published: March 30, 2024

In vitro and preclinical in vivo research the last 35 years has clearly highlighted crucial physiopathological role of glial cells, namely astrocytes/microglia/oligodendrocytes satellite cells/Schwann cells central peripheral nervous system, respectively. Several possible pharmacological targets to various neurodegenerative disorders painful conditions have therefore been successfully identified, including receptors enzymes, mediators neuroinflammation. However, translation these promising data a clinical setting is often hampered by both technical biological difficulties, making it necessary perform experiments on human models diseases. this review we will, therefore, summarize most relevant contribution pathologies their modulation based obtained post-mortem tissues iPSC-derived brain organoids. The possibility an visualization glia reaction neuroinflammation patients will be also discussed.

Language: Английский

Citations

6
Modeling Alzheimer’s disease using human cell derived brain organoids and 3D models DOI Creative Commons
Sarah Fernandes, Jasmin S. Revanna,

Joshua Pratt

et al.

Frontiers in Neuroscience, Journal Year: 2024, Volume and Issue: 18

Published: Aug. 1, 2024

Age-related neurodegenerative diseases, like Alzheimer's disease (AD), are challenging diseases for those affected with no cure and limited treatment options. Functional, human derived brain tissues that represent the diverse genetic background cellular subtypes contributing to sporadic AD (sAD) limited. Human stem cell organoids recapitulate some features of cytoarchitecture AD-like pathology, providing a tool illuminating relationship between pathology neural dysregulation leading cognitive decline. In this review, we explore current strategies implementing in study as well challenges associated investigating age-related using organoid models.

Language: Английский

Citations

5
Emerging approaches to enhance human brain organoid physiology DOI Creative Commons
Anna Pagliaro, Benedetta Artegiani, Delilah Hendriks

et al.

Trends in Cell Biology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Brain organoids are important 3D models for studying human brain development, disease, and evolution. To overcome some of the existing limitations that affect organoid quality, reproducibility, characteristics, in vivo resemblance, current efforts directed to improve their physiological relevance by exploring different, yet interconnected, routes. In this review, these approaches latest developments discussed, including stem cell optimization, refining morphogen administration strategies, altering extracellular matrix (ECM) niche, manipulating tissue architecture mimic morphogenesis. Additionally, strategies increase diversity enhance maturation, such as establishing co-cultures, assembloids, xenotransplantation, reviewed. We explore how various factors can be tuned intermingled speculate on future avenues towards even more physiologically-advanced organoids.

Language: Английский

Citations

0