Cerebral organoid

A cerebral organoid, or brain organoid, describes an artificially grown, in vitro, miniature organ resembling the brain. Cerebral organoids are created by culturing pluripotent stem cells in a three-dimensional rotational bioreactor, and they develop over a course of months

Using induced pluripotent stem cell (iPSC)-derived human brain organoids, we attempted to simplify the complexities and demonstrate formation of forebrain-associated bilateral optic vesicles, cellular diversity, and functionality. Around day 30, brain organoids attempt to assemble optic vesicles, which develop progressively as visible structures within 60 days. These optic vesicle-containing brain organoids (OVB-organoids) constitute a developing optic vesicle's cellular components, including primitive corneal epithelial and lens-like cells, retinal pigment epithelia, retinal progenitor cells, axon-like projections, and electrically active neuronal networks. OVB-organoids also display synapsin-1, CTIP-positive myelinated cortical neurons, and microglia. Interestingly, various light intensities could trigger photosensitive activity of OVB-organoids, and light sensitivities could be reset after transient photobleaching. Thus, brain organoids have the intrinsic ability to self-organize forebrain-associated primitive sensory structures in a topographically restricted manner and can allow interorgan interaction studies within a single organoid 1).

Liu et al., generated cerebral organoids using human induced pluripotent stem cells (iPSCs) for evaluation of neurotoxicity. Cerebral organoids were treated with different concentrations of vincristine for 48 hours and their expansion was measured. They also assayed various cell markers, microtubule associated proteins, and matrix metalloproteinases (MMP) in cerebral organoids. After treatment for 48 hours, they observed dose-dependent neurotoxicity, including reduced neuron and astrocyte numbers at high concentration. Vincristine treatment also impaired the microtubule-associated protein tubulin, and fibronectin, and downregulated MMP10 activity. Further analysis using the STRING database found that, both MMP10 and fibronectin bind with MMP9 experimentally, and text-mining indicated an interaction between MMP10 and fibronectin. The organoid model system allowed quantitative investigation of the effects of vincristine treatment. The findings indicated vincristine exhibited dose-dependent neurotoxicity, inhibited fibronectin, tubulin, and MMP10 expression in cerebral organoids 2).

da Silva et al. demonstrated that human Glioblastoma spheroids possess the ability to spontaneously infiltrate early-stage cerebral organoids (eCOs). The resulting formation of hybrid organoids demonstrated an invasive tumor phenotype that was distinct from noncancerous adult neural progenitor (NP) spheroid incorporation into eCOs. These findings provide a basis for the modeling and quantification of the Glioblastoma infiltration process using a stem-cell-based organoid approach, and may be used for the identification of anti-Glioblastoma invasion strategies 3).

To validate the preclinical applications of a 3D organoid model and mechanistic findings of inflammation-driven angiogenesis, Cui et al. screened a novel dual integrin (αvβ3) and cytokine receptor (TGFβ-R1) blockade that suppresses Glioblastoma tumor neovascularization by simultaneously targeting macrophage-associated immunosuppression, endothelial-macrophage interactions, and altered ECM. Hence, they provide an interactive and controllable Glioblastoma tumor microenvironment and highlight the importance of macrophage-associated immunosuppression in Glioblastoma angiogenesis, paving a new direction of screening novel anti-angiogenic therapies 4).

Gabriel E, Albanna W, Pasquini G, Ramani A, Josipovic N, Mariappan A, Schinzel F, Karch CM, Bao G, Gottardo M, Suren AA, Hescheler J, Nagel-Wolfrum K, Persico V, Rizzoli SO, Altmüller J, Riparbelli MG, Callaini G, Goureau O, Papantonis A, Busskamp V, Schneider T, Gopalakrishnan J. Human brain organoids assemble functionally integrated bilateral optic vesicles. Cell Stem Cell. 2021 Aug 12:S1934-5909(21)00295-2. doi: 10.1016/j.stem.2021.07.010. Epub ahead of print. PMID: 34407456.
Liu F, Huang J, Liu Z. Vincristine impairs microtubules and causes neurotoxicity in cerebral organoids. Neuroscience. 2018 Dec 29. pii: S0306-4522(18)30873-X. doi: 10.1016/j.neuroscience.2018.12.047. [Epub ahead of print] PubMed PMID: 30599272.
da Silva B, Mathew RK, Polson ES, Williams J, Wurdak H. Spontaneous Glioblastoma Spheroid Infiltration of Early-Stage Cerebral Organoids Models Brain Tumor Invasion. SLAS Discov. 2018 Mar 1:2472555218764623. doi: 10.1177/2472555218764623. [Epub ahead of print] PubMed PMID: 29543559.
Cui X, Morales RT, Qian W, Wang H, Gagner JP, Dolgalev I, Placantonakis D, Zagzag D, Cimmino L, Snuderl M, Lam RHW, Chen W. Hacking macrophage-associated immunosuppression for regulating glioblastoma angiogenesis. Biomaterials. 2018 Feb 2;161:164-178. doi: 10.1016/j.biomaterials.2018.01.053. [Epub ahead of print] PubMed PMID: 29421553.
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