Presentation summariesSamantha BALLESTA, CRCL Cancer Research Center of Lyon Abstract Experimental cellular models represent a necessary prerequisite for carrying out preclinical studies and contribute to the success of fundamental research studies. This is why the 3D-ONCO platform is developing « ready-to-use » characterized and standardized 3D models, derived from different pathological or healthy patient tissues, for the scientific community. One of the main lines of development concerns brain models, in particular glioblastoma tumoroids and more recently other brain tumor indications and normal « mini-brain » which could be used in the context of different studies.
Adrien BOTACCI, ADES, Aix-Marseille Université Abstract The possibility of the future emergence of a degree of sentience or consciousness in cerebral organoids remains widely debated. Although they are still extremely simplified models of the human brain, it may nevertheless be productive to anticipate these possible developments by laying the foundations for an ethical and legal discussion of these new entities. In doing so, we will look at the current legislation applicable to cerebral organoids, and consider potential evolutions of this framework.
Erika COSSET, CRCL Cancer Research Center of Lyon Abstract
Marion DELOUS, CRNL Lyon Research Center of Neurosciences Abstract Our team is interested in the pathophysiological mechanisms leading to rare microcephalic syndromes associated with mutations in the RNU4ATAC gene. This is a non-coding gene, transcribed into the small nuclear RNA U4atac, a component of the minor spliceosome. This spliceosome, conserved in almost all species, is involved in the splicing of a minority of introns, called U12, which are located in ~750 genes in the human genome. The role of these minor introns and the very existence of the minor spliceosome remain a mystery; however, the current hypothesis is that it is required for fine control of gene expression. For this presentation, I will outline the work carried out on another gene, RTTN, for which we have identified a bi-allelic mutation in a patient presenting all the features of RNU4ATAC-associated microcephalic syndrome. By studying this particular case, we hope to be able to uncover the altered cellular mechanisms at the origin of microcephaly. To this end, we have developed models of neuronal differentiation using CRISPR/Cas9-modified iPSC cells, including cortical organoids.
Takuya ISOMURA, Riken Center for Brain Science, Saitama Japan Abstract According to the free-energy principle, the brain constructs a generative model that expresses the dynamics of external states to enable prediction and action. However, empirical applications of the free-energy principle at the cellular and synaptic levels are not straightforward because they entail a commitment to a particular process theory (i.e., neuronal basis). We addressed this issue by developing a reverse engineering technique that allows precise linking of quantities in neuronal networks to those in Bayesian inference. We showed that any canonical neural network—whose activity and plasticity minimise a common cost function—can be cast as performing (variational) Bayesian inference (Neural Comput, 2020; Commun Biol, 2022; Neurosci Res, 2022). By combining reverse engineering with an in vitro causal inference paradigm that we previously established (PLoS Comput Biol, 2015; Sci Rep, 2018), we experimentally validated the free-energy principle by showing its ability to predict the quantitative self-organisation of in vitro neural networks (Nat Commun, 2023). Our scheme provides a formal avenue for the experimental validation and application of the free-energy principle, paving the way for developing next-generation artificial intelligence and understanding the circuit mechanisms of psychiatric disorders.
Bertrand PAIN, SBRI Stem Cell and Brain Research Institute Abstract The team "Physiology and Biotechnology of Embryonic stem cells" aims to establish and characterize pluripotent stem cells (PSCs) in our historical avian models but also in mammalian species (pig, horse, bovine, bat, ... ) as well as in Human through derivating hiPSCs from control or patients. All of those PSCs help us to establish innovative cellular substrates for viral replication or toxicology studies in either 2D or 3D models. The 3D organoid approach is mainly developed in cerebral lineage to provide new in vitro models for studying a neurodegenerative disease (the CACH leukodystrophy), for evaluating the impact of opioid on cerebral development and for providing substrates for neurotropic viruses in both human and mammalian species.
LYNOPLA : LYon Neural Organoid Plateform : a project for needs Abstract
Laura PELLEGRINI, MRC Laboratory of Molecular Biology, Cambridge UK Abstract Cerebral organoids, derived from pluripotent stem cells, serve as a powerful bridge between in vivo investigations and 2D in vitro models, presenting a harmonious compromise that allows for direct study of human neural tissue. Their 3D architecture captures the intricacies of human neural development, offering profound insights into neurodevelopmental disorders like microcephaly, lissencephaly, and autism, as well as infectious diseases impacting the brain, such as Zika. Furthermore, these organoids are instrumental in decoding the influence of sex hormones on neural development. Preliminary studies have highlighted the pivotal roles of hormones such as estrogen and testosterone in directing neural differentiation, and possibly influencing gender-specific susceptibilities to neuropsychiatric conditions. Beyond neurodevelopment, the evolutionary aspects of the human brain are illuminated through comparative organoid studies, which reveal key developmental disparities between humans and non-human primates. It is important to recognise that cerebral organoids have some limitations such as incomplete cellular diversity and the lack of mature synaptic networks. Nevertheless, organoids represent a link between traditional models and actual human tissue and continue to reshape our understanding of human brain development, evolution, and pathology.
Bhuvaneish SELVARAJ, Dementia Research Institute, Edinburg UK Abstract
Cell to cell interactions is pivotal for proper function of the nervous system. Neurons are specialised cells that receive and send signals to other neurons through structures called dendrites and axons. In the case of motor neurons – those specialised spinal cord neurons that control voluntary movement - axons extend over 1m to synapse with muscle to enable muscle contraction. To achieve this, two major cell-cell communications are pivotal 1) myelination of axons which is an insulation wrapping of axons by oligodendroglia cells, thereby, enabling fast transmission of signals and 2) specialised synapse with muscle called neuromuscular junctions. Both these cellular communications are disrupted in Amyotrophic lateral Sclerosis, a rapidly progressing fatal neurodegenerative disease with no considerable disease modifying therapies. Defects in myelination is also a key aetiopathogenesis of multiple sclerosis. These highlight the importance of understanding mechanisms of these cellular interplay. Human myelination and neuromuscular junctions are intricate structures and 2D cell culture models to study these are often challenging. In this seminar, I will discuss our on-going work on human stem cell derived organoid models to study both human myelination (James et al., Dev Cell 2021) and neuromuscular junction (assembloids) and how we utilise them to better understand neurodegenerative disorders.
Emmanuele VILLA on behalf of Giuseppe TESTA, Istituto Europeo di Oncologia, Milano Italy Abstract Thanks to the exponential growth of the field, the organoid-based modeling of neuropsychiatric disorders can now tackle some of its most mature and transformative challenges. Among these, a central one is the translation of in vitro endophenotypes back to the in vivo setting, for mechanistic insight and preclinical validation alike. In parallel, new approaches are needed to scale up the disease modeling throughput in order to render experimentally tractable the polygenic architecture of the most prevalent forms of mental illness. Here I discuss recent progress towards these two goals from the work we have been spearheading in the lab by modelling a paradigmatic set of neurodevelopmental disorders caused by point mutations or dosage imbalances in transcription factors chromatin regulators that operate in inter-related pathways. These include the symmetrically opposite pair of copy number variations (CNV) at 7q11.23 causing Williams-Beuren syndrome (WBS) and 7q11.23 microduplication syndrome (7Dup). I will discuss the integration of longitudinally single cell resolved trajectories and transgenic models to establish preclinical actionability, as well as the convergence across molecular mechanisms and endophenotype layers. Finally, I will introduce recent progress sin multiplexing brain organoidogenesis for advancing modelling towards population-scale cohorts. |
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