Organoids cover a wide range of three-dimensional multicellular in vitro human tissue constructs that are used to mimic its corresponding in vivo organ in research [1]. Drost, J. et al. Organoid single-cell genomic atlas uncovers human-specific features of brain development. Secondly, successful transplantations could open up new avenues for using organoids in regenerative medicine applications as tissue-engineered grafts. Organoids: definition, culturing methods, and clinical applications, The Hubrechts center for Organoid Technology. However, such a targeted approach requires knowledge of the regulatory networks underlying cell fate decisions, which often remains limited. Increased programmed death-ligand 1 is an early epithelial cell response to Helicobacter pylori infection. Isolation and in vitro expansion of human colonic stem cells. Adv. What are organoids and how are they used in drug discovery and preclinical development? Caluori, G. et al. High-throughput screening enhances kidney organoid differentiation from human pluripotent stem cells and enables automated multidimensional phenotyping. Taguchi, A. et al. PLoS ONE 11, e0161969 (2016). Huh, D. et al. Here, the causal mutation (in the CFTR gene) was corrected by CRISPRCas9, and the resulting organoids showed functional restoration as assessed in forskolin-induced swelling assays. Organoids are widely used to model and investigate tissue development, homeostasisand regeneration, for example, to identify factors required for stem cell differentiation into specific lineages or the molecular mechanisms underlying cell fate programs1,2,3,4. Sci. Attayek, P. J. et al. Long-term expansion of functional mouse and human hepatocytes as 3D organoids. [10] H. Uchidaet al., A xenogeneic-free system generating functional human gut organoids from pluripotent stem cells,JCI Insight, vol. The bud tip progenitor organoids are thus ideal for exploring epithelial fate decisions, while the human lung organoids can be used to model epithelial-mesenchymal cross-talk during human lung development. Organoids are three-dimensional (3D) miniature structures cultured in vitro produced from either human pluripotent stem cells (hPSCs) or adult stem cells (AdSCs) derived from healthy individuals. Studies that focus on embryonic development also benefit from organoid formation. 291, 37593766 (2016). and JavaScript. Recent advances in organoid research have also improved upon requirements for clinical relevancy. Commun. Breast Cancer Res. Intestinal organoids grown in a patterned tubular matrix organize into a crypt-like structure akin to organoids, following the predefined architecture. Nat. Its like a mass-production, economy-of-scale approach to cell culture. Biophys. 8, pp. Annu. U. S. A., vol. Moreover, gene-editing technology is complex, and genetically engineered organoids are inherently less physiologically relevant, which is especially undesirable for investigations of cellcell interactions and self-organizational processes. [33] Y. Fujimichi, K. Otsuka, M. Tomita, and T. Iwasaki, An Efficient Intestinal Organoid System of Direct Sorting to Evaluate Stem Cell Competition in Vitro,Sci. Xia, P. F., Ling, H., Foo, J. L. & Chang, M. W. Synthetic genetic circuits for programmable biological functionalities. The longevity of these mini-intestines further allows the development of rare specialized cell types that are absent in short-lived organoids. For example, organoids grown in chemically defined microfilament scaffolds adopt an elongated shape, which leads to the reproducible generation of a neuroectoderm and, ultimately, to improved cortical development compared with standard organoids generated from spherical aggregates140. Science 345, 1247125 (2014). Sci. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Regeneration of thyroid function by transplantation of differentiated pluripotent stem cells. For efficacy testing, several high-throughput methods have been developed that can generate results for drug response within a week [42], [55]. Musah, S. et al. A main challenge is to measure ultra-low volumes of cell-secreted analytes. Biomaterials 225, 119517 (2019). Non-invasive electromechanical cell-based biosensors for improved investigation of 3D cardiac models. Cell 172, 373386.e10 (2018). 8, 54765488 (2020). Commun. Artificial three-dimensional niches deconstruct pancreas development in vitro. Mol. 21, 571584 (2020). JCI Insight 2, e94954 (2017). Nat. Modeling amyloid beta and tau pathology in human cerebral organoids. These techniques include high-resolution microscopy, histology, immunofluorescence, and bulk gene expression assays [28]. Cell 181, 905913.e7 (2020). Hepatol. Ye, W., Luo, C., Li, C., Huang, J. Progenitor identification and SARS-CoV-2 infection in human distal lung organoids. For example, microfluidic devices are promising tools to integrate access channels for waste removal and nutrient supply within organoids, and to enable independent control over experimental conditions95,167. Programming self-organizing multicellular structures with synthetic cell-cell signaling. 10, 89104 (2017). The choices of cell culture conditions and the 3D matrix are critical for this complex organization. Organoids produced from patients with head and neck cancer (HNC) were used to create a biobank by researchers from the Organoid group (Hubrecht Institute) and UMC Utrecht. Cruz, N. M. et al. Induction of expansion and folding in human cerebral organoids. Exp. Genes Dev. Takebe, T., Zhang, B. Organoids were widely suggested to empower medical transplantation, by the use of healthy cells to replace diseased tissues, and, indeed, several studies in mice justify this hope14,22,28,29,30,32,33,43,44,45,50,54,58,59,89,90,91; however, the road to real-life applications is long, and several limitations have to be overcome to exploit the full promise of organoids. Organoids are an emerging technique developed in the last decade or so for the 3D culture of primary cells, typically adult stem cells or pluripotent stem cells, in a microscale structure that mimics the natural organization of cells within a tissue - Encyclopedia of Infection and Immunity. In this Review, we argue that many limitations of traditional organoid culture can be addressed by engineering approaches at all levels of organoid systems. & Huh, D. Organoids-on-a-chip. Natl Acad. Wang, Y. et al. Engineered human pluripotent-stem-cell-derived intestinal tissues with a functional enteric nervous system. Now we can create organoids from diseased cells and conduct experiments to find out if stem cells or the helper cells that talk to them are at the cause of lung disease. In particular, the high variability of self-organizing growth and restricted experimental and analytical access hamper the translatability of organoid systems. In summary, although basic niche mimicry has advanced the generation and maintenance of organoid culture systems, these organoids often exhibit highly heterogeneous shapes and stochastic variability in their level of maturity and functionality. Microphysiological Systems Conference 2023: A Deep Dive into - Benzinga Stem Cell 25, 27602769 (2007). Get what matters in translational research, free to your inbox weekly. Nature 526, 564568 (2015). Sci. Buskin, A. et al. Eiraku, M. et al. Effectively expandable liver organoids have a critical value for the cell source limitation issue of human liver tissue. Human organoids in basic research and clinical applications What are organoids and why are they important? - Particle3D Commun. Zhou, T. et al. Diabetes is a metabolic disease related to insulin, a hormone made by the pancreas that allows our cells to absorb glucose from the bloodstream. In this system, the extracellular domain of the Notch receptor is altered to recognize user-defined ligands, allowing experimental control over the inputs of the normal Notch signal transduction cascade of the cell. Gene correction in organoids was first performed on intestinal organoids derived from patients with cystic fibrosis112. Disrupted alternative splicing for genes implicated in splicing and ciliogenesis causes PRPF31 retinitis pigmentosa. Zhong, X. et al. 11901194, 2013. Protoc. Next to the ethical considerations, some animal models cannot fully recapitulate the human condition, such as with lung tissue [49]. McCracken, K. W. et al. Adv. Co, J. Y. et al. Psychiatry 23, 23632374 (2018). ISSN 2058-8437 (online). Frontiers | Standardizing Patient-Derived Organoid Generation Workflow Therefore, to be able to choose appropriate models, a set of organoids with varying levels of complexity is required. Nikolic, M. Z. et al. Nat. Organoids are a three-dimensional (3D) cell culture derived from pluripotent stem cells [PSCs, including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), tissue stem cells, adult stem cells (ASCs), or tumor stem cells] in vitro. Thus, central pathways, including cell cycle regulator genes, growth factors, receptors, tumour suppressors and oncogenes, are dysregulated. Kim, M. et al. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. 2017, no. Li, G. et al. 12, 142 (2019). Forbester, J. L. et al. Kim, J., Koo, B. K. & Knoblich, J. Therefore, the application of bioengineering strategies to traditional organoid culture protocols will usher in a new era of organoid development and facilitate their translation to real-life applications, fulfilling the many still unmet promises of the organoid field. 23, 4959 (2017). Bioeng. Takebe, T. et al. 339351. Cell. 21, no. Leslie, J. L. et al. 11, no. Genome editing could be employed to modify the intrinsic response of cells in an organoid to external stimuli with the aim of generating cell types that would otherwise be absent. Finally, we examine new approaches for the readout of functional development in organoids to allow more thorough characterization and incorporation in high-throughput assay pipelines (Fig. Therefore, efforts have been made to incorporate biosensors into small-organ model systems. Nikolaev, M. et al. USA 114, E2293E2302 (2017). A library of examples of oncogenic organoids is available, many of which are postulated by Drost et al. Development 144, 10451055 (2017). Signal. Pasca, A. M. et al. Nat. This becomes especially important when trying to study complex, intrinsically human characteristics or diseases. This work was the first long-term culture of untransformed human cells. Biomaterials 78, 110 (2016). Okkelman, I. Engineered signaling centers for the spatially controlled patterning of human pluripotent stem cells. First, in the presence of A-type cells, B-type cells are converted to C-type cells that self-aggregate owing to their high E-cad expression. Biotechnol. Nature 491, 6671 (2012). Zhang, Y. S. et al. Opin. Some of the most prominent neuropsychiatric or neurodevelopmental diseases of our time, such as schizophrenia or autism spectrum disorder, are uniquely human diseases that affect the whole human genome, explains HSCI researcher Paola Arlotta, PhD. This work reports a multi-organ microfluidics platform with automated and continuous monitoring of cultured organoids. Interestingly, the number of induced mutations correlates with the tumorigenic capacity upon xenotransplantation114; in addition, loss of the adenomatous polyposis coli and p53 is sufficient to induce chromosomal instability and aneuploidy, which are both hallmarks of cancer115. Methods 16, 255262 (2019). 15, 378386 (2005). Multisensor-integrated organs-on-chips platform for automated and continual in situ monitoring of organoid behaviors.
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