Organoides de cérebro como modelos de doenças de Alzheimer e Parkinson: uma revisão narrativa sobre as perspectivas para medicina regenerativa e personalizada
DOI:
https://doi.org/10.11606/issn.2176-7262.rmrp.2023.203797Palavras-chave:
Organoides, Doença de Alzheimer, Doença de Parkinson, Medicina Regenerativa, Medicina PersonalizadaResumo
Há muitos anos a cultura celular bidimensional (2D) é utilizada como modelo de estudo de doenças, possuindo grande importância na medicina regenerativa, apesar de ainda conter limitações significativas. A fim de contornar essas limitações, a cultura celular tridimensional (3D) propõe uma organização mais complexa e sustentável que pode ser produzida a partir de células-tronco adultas (ASCs), células-tronco embrionárias (ESCs) ou células-tronco pluripotentes induzidas (iPSCs). A cultura 3D possibilitou o cultivo de células em um ambiente mais próximo do fisiológico, levando à formação de distintos tecidos órgãos-específicos. Em outras palavras, a cultura de células 3D possibilita a criação de estruturas orgânicas muito semelhantes aos órgãos de um ser humano, tanto estruturalmente, quanto funcionalmente. Desse modo, tem-se o que é chamado de organoides. O uso dos organoides tem crescido exponencialmente em ambientes in vitro, permitindo a análise e observação dos diversos fenômenos fisiológicos existentes. Como exemplo, pode-se citar os organoides cerebrais (“mini-brains”) reproduzidos in vitro buscando delinear as peculiaridades e complexidades do cérebro humano, com o objetivo de compreender algumas disfunções neurológicas que acometem esse sistema, como as duas principais doenças neurodegenerativas: Doenças de Alzheimer e Parkinson. Portanto, os organoides cerebrais podem permitir notável avanço da medicina regenerativa aplicada a doenças neurodegenerativas, já que esses “mini-brains” podem ser produzidos a partir de células do próprio paciente. Isso permitirá intervenções personalizadas, como testagens farmacológicas, a fim de definir qual seria o melhor tratamento medicamentoso. Consequentemente, essa tecnologia pode permitir terapias mais eficientes e individualizadas - o que é fundamental para a Medicina Personalizada.
Downloads
Referências
Neal, J. T., & Kuo, C. J. (2016). Organoids as models for neoplastic transformation. Annual Review of Pathology: Mechanisms of Disease, 11, 199-220.
Rozich, N. S., Blair, A. B., & Burkhart, R. A. (2020). Organoids: a model for precision medicine. In Precision Medicine for Investigators, Practitioners and Providers, (Elsevier), pp. 123–129.
Clevers, H. (2016). Modeling development and disease with organoids. Cell, 165(7), 1586-1597.
Fang, Y., & Eglen, R. M. (2017). Three-dimensional cell cultures in drug discovery and development. Slas discovery: Advancing Life Sciences R&D, 22(5), 456-472.
Huch, M., Gehart, H., Van Boxtel, R., Hamer, K., Blokzijl, F., Verstegen, M. M. et al. (2015). Long-term culture of genome-stable bipotent stem cells from adult human liver. Cell, 160(1-2), 299-312.
Schutgens, F., & Clevers, H. (2020). Human organoids: tools for understanding biology and treating diseases. Annual Review of Pathology: Mechanisms of Disease, 15, 211-234.
Sato, T., Stange, D. E., Ferrante, M., Vries, R. G., Van Es, J. H., Van Den Brink, S. et al. (2011). Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett's epithelium. Gastroenterology, 141(5), 1762-1772.
Hu, H., Gehart, H., Artegiani, B., LÖpez-Iglesias, C., Dekkers, F., Basak, O. et al. (2018). Long-term expansion of functional mouse and human hepatocytes as 3D organoids. Cell, 175(6), 1591-1606.
Chang, Y., Kim, J., Park, H., Choi, H., & Kim, J. (2020). Modelling neurodegenerative diseases with 3D brain organoids. Biological Reviews, 95(5), 1497-1509.
Venkataraman, L., Fair, S. R., McElroy, C. A., Hester, M. E., & Fu, H. (2020). Modeling neurodegenerative diseases with cerebral organoids and other three-dimensional culture systems: Focus on Alzheimer’s disease. Stem Cell Reviews and Reports, 1-22.
Fyfe, I. (2021). Brain organoids shed light on APOE genotype and Alzheimer disease pathology. Nature Reviews Neurology, 17(1), 1-2.
Papaspyropoulos, A., Tsolaki, M., Foroglou, N., & Pantazaki, A. A. (2020). Modeling and targeting Alzheimer’s disease with organoids. Frontiers in pharmacology, 11, 396.
Galet, B., Cheval, H., & Ravassard, P. (2020). Patient-derived midbrain organoids to explore the molecular basis of Parkinson's disease. Frontiers in Neurology, 1005.
Smits, L. M., Reinhardt, L., Reinhardt, P., Glatza, M., Monzel, A. S., Stanslowsky, N. et al. (2019). Modeling Parkinson’s disease in midbrain-like organoids. NPJ Parkinson's disease, 5(1), 1-8.
Wulansari, N., Darsono, W. H. W., Woo, H. J., Chang, M. Y., Kim, J., Bae, E. J., ... & Lee, S. H. (2021). Neurodevelopmental defects and neurodegenerative phenotypes in human brain organoids carrying Parkinson’s disease-linked DNAJC6 mutations. Science Advances, 7(8), 1540.
Azar, J., Bahmad, H. F., Daher, D. et al. (2021). The use of stem cell-derived organoids in disease modeling: an update. Int J Mol Sci 22, doi: https://doi.org/10.3390/ijms22147667
Fatehullah, A., Tan, S. H., & Barker, N. (2016). Organoids as an in vitro model of human development and disease. Nature cell biology, 18(3), 246-254.
Krokker, L., Szabó, B., Németh, K., Tóháti, R., Sarkadi, B., Mészáros, K. et al. (2021). Three Dimensional Cell Culturing for Modeling Adrenal and Pituitary Tumors. Pathology and Oncology Research, 27.
Liu, L., Yu, L., Li, Z., Li, W., & Huang, W. (2021). Patient-derived organoid (PDO) platforms to facilitate clinical decision making. Journal of Translational Medicine, 19(1), 1-9.
Nanki, Y., Chiyoda, T., Hirasawa, A., Ookubo, A., Itoh, M., Ueno, M. et al. (2020). Patient-derived ovarian cancer organoids capture the genomic profiles of primary tumours applicable for drug sensitivity and resistance testing. Scientific Reports, 10(1), 1-11.
Pernik, M. N., Bird, C. E., Traylor, J. I., Shi, D. D., Richardson, T. E., McBrayer, S. K., & Abdullah, K. G. (2021). Patient-derived cancer organoids for precision oncology treatment. Journal of Personalized Medicine, 11(5), 423.
Takahashi, T. (2019). Organoids for drug discovery and personalized medicine. Annual review of pharmacology and toxicology, 59, 447-462.
Verjans, E. T., Doijen, J., Luyten, W., Landuyt, B., & Schoofs, L. (2018). Three‐dimensional cell culture models for anticancer drug screening: Worth the effort?. Journal of cellular physiology, 233(4), 2993-3003.
Cosset, E., Locatelli, M., Marteyn, A., Lescuyer, P., Antonia, F. D., Mor, F. M. et al. (2019). Human neural organoids for studying brain cancer and neurodegenerative diseases. JoVE (Journal of Visualized Experiments), (148).
Wray, S. (2021). Modelling neurodegenerative disease using brain organoids. In Seminars in Cell & Developmental Biology (Vol. 111, pp. 60-66). Academic Press.
Nie, J., & Hashino, E. (2017). Organoid technologies meet genome engineering. EMBO reports, 18(3), 367-376.
Wang, Z., Wang, S. N., Xu, T. Y., Miao, Z. W., Su, D. F., & Miao, C. Y. (2017). Organoid technology for brain and therapeutics research. CNS neuroscience & therapeutics, 23(10), 771-778.
De Oliveira, M., De Sibio, M. T., Costa, F. A., & Sakalem, M. E. (2021). Airway and Alveoli Organoids as Valuable Research Tools in COVID-19. ACS Biomaterials Science & Engineering, 7(8), 3487-3502.
Song, L., Yuan, X., Jones, Z., Griffin, K., Zhou, Y., Ma, T., & Li, Y. (2019). Assembly of human stem cell-derived cortical spheroids and vascular spheroids to model 3-D brain-like tissues. Scientific reports, 9(1), 1-16.
Janssens, S., Schotsaert, M., Manganaro, L., Dejosez, M., Simon, V., García‐Sastre, A., & Zwaka, T. P. (2019). FACS‐Mediated Isolation of Neuronal Cell Populations From Virus‐Infected Human Embryonic Stem Cell–Derived Cerebral Organoid Cultures. Current protocols in stem cell biology, 48(1), e65.
Magno, V., Meinhardt, A., & Werner, C. (2020). Polymer hydrogels to guide organotypic and organoid cultures. Advanced Functional Materials, 30(48), 2000097.
Choi, S. H., Kim, Y. H., Hebisch, M., Sliwinski, C., Lee, S., D’Avanzo, C. et al. (2014). A three-dimensional human neural cell culture model of Alzheimer’s disease. Nature, 515(7526), 274-278.
Cohen, R. M., Rezai-Zadeh, K., Weitz, T. M., Rentsendorj, A., Gate, D., Spivak, I. et al. (2013). A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric aβ, and frank neuronal loss. Journal of Neuroscience, 33(15), 6245-6256.
Beiske, A. G., Loge, J. H., Rønningen, A., & Svensson, E. (2009). Pain in Parkinson’s disease: prevalence and characteristics. Pain, 141(1-2), 173-177. doi: https://doi.org/10.1016/j.pain.2008.12.004
Kim, H., Park, H. J., Choi, H., Chang, Y., Park, H., Shin, J. et al. (2019). Modeling G2019S-LRRK2 sporadic Parkinson's disease in 3D midbrain organoids. Stem Cell Reports, 12(3), 518-531.
Sloan, S.A., Andersen, J., Pașca, A.M. et al.(2018). Generation and assembly of human brain region–specific three-dimensional cultures. Nat Protoc 13, 2062–2085 . https://doi.org/10.1038/s41596-018-0032-7
Lancaster, M., Knoblich, J. (2014). Generation of cerebral organoids from human pluripotent stem cells. Nat Protoc 9, 2329–2340. https://doi.org/10.1038/nprot.2014.158
A Armstrong R. (2019) Risk factors for Alzheimer's disease. Folia Neuropathol.;57(2):87-105. doi: 10.5114/fn.2019.85929. PMID: 31556570.
Mendez MF. (2019) Early-onset Alzheimer Disease and Its Variants. Continuum (Minneap Minn). Feb;25(1):34-51. doi: 10.1212/CON.0000000000000687.
Downloads
Publicado
Edição
Seção
Licença
Copyright (c) 2023 Raysa Taynara Vasconcelos de Souza, Pedro Henrique Gomes Santana, Ricardo Cambraia Parreira, Lucas Felipe Oliveira, Adrieli Oliveira Raminelli, Bruno Lemes Marques, Daniel Mendes Filho
Este trabalho está licenciado sob uma licença Creative Commons Attribution 4.0 International License.
