Mini Review - Clinical Schizophrenia & Related Psychoses ( 2023) Volume 17, Issue 2
Organoids and their applications in Parkinson\'s diseaseWenchao Sun1 and Junzheng Yang2*
2Department of Pharmaceutics, Consun Pharmaceutical Group, Guangzhou, China
Junzheng Yang, Department of Pharmaceutics, Consun Pharmaceutical Group, Guangzhou, China, Email: email@example.com
Received: 14-Mar-2023, Manuscript No. CSRP-23-91643; Editor assigned: 17-Mar-2023, Pre QC No. CSRP-23-91643 (PQ); Reviewed: 03-Apr-2023, QC No. CSRP-23-91643; Revised: 10-Apr-2023, Manuscript No. CSRP-23-91643(R); Published: 17-Apr-2023, DOI: 10.3371/CSRP.SWJY.041723
Parkinson's disease is the second largest neurodegenerative disease which usually causes a huge economic and living burden for the patients and their families no matter in developed countries or developing countries; so far, there is no ideal treatment for it. With the rapid development of regenerative medicine, especially stem cell technology, 3D brain organoid models have been developed and demonstrated great potential applications in pathogenesis, new drug development and new therapeutic method of nervous system diseases. Here, we will summarize the recent progress on organoid models and their application in Parkinson's disease, and discuss the challenges and the limitation of organoids application in Parkinson's disease, which may provide some clues for understanding the pathogenesis of Parkinson's disease and developing the drugs for the Parkinson's disease.
Organoids • Parkinson's disease • Stem cells • Drug development
Parkinson's Disease (PD) is one kind of common degenerative diseases of the nervous system. which commonly occurred in the elderly population aged above 60 years old, and the prevalence of PD in people over 65 years old in China is about 1.7%; the epidemic characteristics of PD are generally sporadic, less than 10% PD patients have a family history; the main pathological characteristics of PD is the degeneration and death of dopaminergic neurons in the substantia nigra of the midbrain [1-4]. So far, the exact pathogenic cause of PD is still unclear. Many influence factors including heredity, environment, aging, oxidative stress may participate in the process of degeneration and death of PD dopaminergic neurons and finally leading to PD [5-8]. For understanding the pathogenesis and the underlying mechanism of PD, there are several kinds of commonly used and classic animal models including 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP)-induced or 6-Hydroxydopamine (6-OHDA) induced PD animal model, transgenic Parkinson's animal model, and induced Pluripotent Stem Cells (iPS) induced PD animal model. In particular, with the unique characteristics of self-renewal and multi-directional differentiation, iPS could differentiate into various tissue cells under certain conditions, and iPS-induced PD animal model have incomparable advantages for PD application. However, because the complexity of PD symptoms and the unclear mechanisms of PD, different animal models can only simulate some symptoms at present.
Recently, with the rapid development of stem cell technology, scientists could obtain 3D stem cell populations (organoids) with self-renewal characteristics through special culture methods or with the help of special material structures (devices) [9,10].Organoids could provide a highly physiological related system usually contain spatial tissue structures similar to human organs and contain some special key functions of human organs. So far, scientists have been successfully applied to various tissue cultures including intestine [11,12], liver [13-15], pancreas [16,17], kidney [18,19], prostate [20,21], lung  and brain [23,24], and there are many amazing articles reported that brain organoids and its applications in PD research. In this review, we will summarize the recent research progress on preparation methods, applications and application limitations of PD organoids.
Preparation methods of PD organoids
A successful and reliable 3D organoid model is the key to the study mechanism, pathology or applications of PD. To maximize and effectively mimic the characteristics of PD patients, there are many preparation methods of PD including adding the growth factors, small molecules, transcription factors or signal pathway regulators into culture medium; coculture and special 3D culture device. The detailed information of several classical organoid preparation methods for PD organoids was listed as follows (Table 1).
|Cell lines||Culture medium||Whether needs 3D||Supplement||Refrences|
|hiPSCs, EB||Human embryonic stem
cell growth medium, neural stem cell medium
|No||Fibroblast growth factor 2 (20 ng/mL) , epidermal
growth factor (20 ng/mL) ,200 nM ascorbic acid, 20ng/mL BDNF, 100 ng/mL SHH, and
20 ng/mL GDNF
|pNSCs||Spontaneous differentiation medium (differentiationmedium with 10 ng/mL BDNF and 10 ng/mL GDNF), midbrain-specification medium(differentiation medium with 100 ng/mL Shh and 100 ng/mL FGF8)||Activin A||/|||
|hESCs, EB||DMEM/F12||Matrigel, orbital shaker||20% Knockout Serum Replacement (KSR),
3% FBS, 2 mM GlutaMAX, 1% nonessential amino acids,50 nM β-mercaptoethanol, and bFGF (4 ng/ml). ROCK inhibitor Y27632 (50 μM),1× N2 supplement, 1% nonessential amino acids, 2 mM GlutaMAX, and heparin (1μg/ml)
|hPSC||Neural induction medium, neural differentiationmedium||Orbital shaker||ROCK inhibitor Y27632, B27, SB431542, Noggin,ascorbic acid, insulin, sonic hedgehog,purmorphamine, CHIR99021, FGF8b|||
|iPSCs||N2B27 medium||Activin A||Ascorbicacid, CHIR 99021, Smoothened Agonist, SB-431542, LDN-193189, BDNF,GNDF, TGF-β3, cAMP, DAPT, Activin A|||
|hiPSC||Stem cellmedium||Matrigel, spinning bioreactor||Dorsomorphine, A83-01, WNT-3A, CHIR99021, SB-431542,2-Mercaptoenthanol, Insulin, Ascorbic Acid, TGF-β, cAMPb|||
|iPSCs||Neural induction medium, midbrain patterning medium||Matrigel, orbital shaker, PLGA or CF fiber||Noggin, SB431542, CHIR99021, FGF8, sonic hedgehog,|||
|iPSCs||Neurobasal medium||Collagen typeI||SB/noggin, retinoic acid, FGF-2, TGFβ1,DAPT|||
PD organoids as the disease models for PD research
Because of the multi-lineage differentiation potentials of stem cells including induced Pluripotent Stem Cells (iPSCs) and Mesenchymal Stem Cell (MSCs), stem cells have been widely used in the research and application of Parkinson's disease, but stem cells model as a two-dimensional model in vitro, it is difficult to mimic the 3D complex structure of human brain. Instead, organoids have the similar function and 3D structure of human organs, also could mimic the complex pathophysiological process, which provide a powerful tool for PD research, and has attracted great interest of scientists. For example, Andrea Becerra-Calixto, et al. generated a kind of αSyn gene (SNCA)-expressing PD organoids by iPSCs which came from a healthy female aged 80 years old and a female fPD patient aged 55 years old with SNCA gene triplication, and evaluation of organoid phenotype by immunohistochemistry and immunofluorescence staining found the organoids could express SOX2, Nestin, En-1, Otx2, Lmx1a, Nurr1, MAP2, and TH; the αSyn gene (SNCA)-expressing PD organoids could also mimic the pathogenesis of Lewy bodies of PD. Those data provide a method for obtaining midbrain organoids, those midbrain organoids could mimic the formation of Lewy bodies in space and morphology, and provide an evidence that the accumulation of αSyn was paralleled by the loss and apoptosis of DA neurons. Therefore, the αSyn gene (SNCA)-expressing PD organoids may be applied to relevant drug screening in the future ; for understanding the effect of LRRK2 and PINK1, Zhi Dong Zhou, et al. developed a kind of midbrain organoids from iPSCs with or without LRRK2 and PINK1 mutation, compared with transgenetic mouse and Drosophila models, found the gene LRRK2 and PINK1 have the unique regulatory mechanism in pathogenesis of PD; and David Pamies, et al. developed a kind of PD organoids from the iPSC-derived neural progenitor cells, to study the neurotoxicity of 6-OHDA, MPTP, and MPP+. After analyzed and compared by Resazurin assay, ROS assay, mitotracker, transendothelial electrical resistance recording, Immunocytochemistry, RT-qPCR, and metabolomics analysis, found that 6-OHDA, MPTP, and MPP+ have different pathological mechanisms of PD, especially 6-OHDA can effectively increase ROS production and reduce mitochondrial function in the three chemicals . These evidences demonstrated that PD organoids can be used as a powerful tool to study the pathogenesis and underlying mechanism of PD.
PD organoids applications in drug discovery and drug screening
It can be said that, the drug development involves multiple stages from molecular synthesis to clinical application, animal models are often used to verify the effectiveness and toxicity of the drug, but animal model has the obvious difference from human organ structure and physiological and pathological process of human disease, therefore, an economical and effective disease model close to human organ is often needed for drug research and development to reduce the cost and time of new drug research and development. The appearance of PD organoids has great attraction for drug discovery or drug screening. For example, Tae Hwan Kwak, et al. generated a kind of homogeneous midbrain organoids including multiple nerve cell types (neurons, astrocytes and oligodendrocytes) from ESCs with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neuron death characteristic, which may provide a neurotoxicity model in vitro for PD drug development ; Renner, H.et al. developed a kind of midbrain organoids from Human small molecule Neural Precursor Cell (smNPC), and compared the 3D midbrain organoids and 2D culture application in high throughput drug screening, found the 3D midbrain organoids have the higher sensitivity in dose-response neurotoxicity experiment ; Due to the limitation of technologies, there are many problems of organoids produced by current methods, such as lack of homogeneity. For solving this problem, Henrik Renner, et al. developed a high-throughput screening automated workflow, this kind automated workflow could obtain the organoids with homogeneous morphology, similar gene expression patterning and highly unified structure, which may provide an excellent PD drug development platform ; and Nguyen-Vi Mohamed, et al. invented a kind of organoid workflow which could produce large-scale and uniform PD organoids at one time, reduce human operation, the reagent volumes and save the cost, this method can not only meet the needs of PD research, but also be applied to the drugs screening for PD .
The main challenges of organoids applications in PD is how to obtain a large number of homogeneous organoids that are close to the structure and function of human organs according to different purposes. Because of technical limitations, the applications of PD organoids is limited to the academic research stage, which is difficult to apply to large-scale industrial production. For this reason, we think there are several problems need to solve: 1) how to obtain PD organoids with high consistency of pathophysiology characteristic and complex structure of neuron-glial interaction; 2) how to make large-scale industrial production of PD organoids; 3) how to store and transport the PD organoids, and to establish standardized operation process to reduce mechanical damage of PD organoids. Anyway, with the continuous progress and development of technologies, PD organoids will make a major breakthrough in the future, which will play a great role in mechanism study and drug development of PD.
Conflict of Interest
The authors declared that there are no conflicts of interests in this review.
- Tolosa, Eduardo, Alicia Garrido, Sonja W Scholz, and Werner Poewe. "Challenges in the Diagnosis of Parkinson's Disease." Lancet Neurol 20 (2021): 385-397.
- Tysnes, Ole-Bjørn, and Anette Storstein. "Epidemiology of Parkinson’s Disease." J Neural Transm 124 (2017): 901-905.
- Cerri, Silvia, Liudmila Mus, and Fabio Blandini. "Parkinson’s Disease in Women and Men: What’s the Difference?." J Parkinsons Dis 9 (2019): 501-515.
- Chen, Zhichun, Guanglu Li, and Jun Liu. "Autonomic Dysfunction in Parkinson’s Disease: Implications for Pathophysiology, Diagnosis, and Treatment." Neurobiol Dis 134 (2020): 104700.
- Delamarre, Anna, and Wassilios G Meissner. "Epidemiology, Environmental Risk Factors and Genetics of Parkinson's Disease." Presse Méd 46 (2017): 175-181.
- Bellou, Vanesa, Lazaros Belbasis, Ioanna Tzoulaki, and Evangelos Evangelou, et al. "Environmental Risk Factors and Parkinson's Disease: An Umbrella Review of Meta-Analyses." Parkinsonism Relat Disord 23 (2016): 1-9.
- Gao, Chao, Jun Liu, Yuyan Tan, and Shengdi Chen. "Freezing of Gait in Parkinson’s Disease: Pathophysiology, Risk Factors and Treatments." Transl Neurodegener 9 (2020): 1-12.
- Nalls, Mike A, Cornelis Blauwendraat, Costanza L Vallerga, and Karl Heilbron, et al. "Identification of Novel Risk Loci, Causal Insights, and Heritable Risk for Parkinson's Disease: A Meta-Analysis of Genome-Wide Association Studies." Lancet Neurol 18 (2019): 1091-1102.
- Rossi, Giuliana, Andrea Manfrin, and Matthias P Lutolf. "Progress and Potential in Organoid Research." Nat Rev Genet 19 (2018): 671-687.
- Garreta, Elena, Roger D Kamm, Susana M Chuva de Sousa Lopes, and Madeline A Lancaster, et al. "Rethinking Organoid Technology through Bioengineering." Nat Mater 20 (2021): 145-155.
- Artegiani, Benedetta, and Hans Clevers. "Use and Application of 3D-Organoid Technology." Hum Mol Genet 27 (2018): R99-R107.
- Nikolaev, Mikhail, Olga Mitrofanova, Nicolas Broguiere, and Sara Geraldo, et al. "Homeostatic Mini-Intestines through Scaffold-Guided Organoid Morphogenesis." Nature 585 (2020): 574-578.
- Miura, Shizuka, and Atsushi Suzuki. "Generation of Mouse and Human Organoid-Forming Intestinal Progenitor Cells by Direct Lineage Reprogramming." Cell Stem Cell 21 (2017): 456-471.
- Olgasi, Cristina, Alessia Cucci, and Antonia Follenzi. "iPSC-Derived Liver Organoids: A Journey from Drug Screening, to Disease Modeling, Arriving to Regenerative Medicine." Int J Mol Sci 21 (2020): 6215.
- Mun, Seon Ju, Jae-Sung Ryu, Mi-Ok Lee, and Ye Seul Son, et al. "Generation of Expandable Human Pluripotent Stem Cell-Derived Hepatocyte-Like Liver Organoids." J Hepatol 71 (2019): 970-985.
- Marsee, Ary, Floris JM Roos, Monique MA Verstegen, and Floris Roos, et al. "Building Consensus on Definition and Nomenclature of Hepatic, Pancreatic, and Biliary Organoids." Cell Stem Cell 28 (2021): 816-832.
- Yoshihara, Eiji, Carolyn O’Connor, Emanuel Gasser, and Zong Wei, et al. "Immune-Evasive Human Islet-Like Organoids Ameliorate Diabetes." Nature 586 (2020): 606-611.
- Homan, Kimberly A, Navin Gupta, Katharina T Kroll, and David B. Kolesky, et al. "Flow-Enhanced Vascularization and Maturation of Kidney Organoids In Vitro." Nat Methods 16 (2019): 255-262.
- Jansen, Jitske, Katharina C Reimer, James S Nagai, and Finny S Varghese, et al. "SARS-Cov-2 Infects the Human Kidney and Drives Fibrosis in Kidney Organoids." Cell Stem Cell 29 (2022): 217-231.
- Karkampouna, Sofia, Federico La Manna, Andrej Benjak, and Mirjam Kiener, et al. "Patient-Derived Xenografts and Organoids Model Therapy Response in Prostate Cancer." Nat Commun 12 (2021): 1117.
- Song, Hanbing, Hannah NW Weinstein, Paul Allegakoen, and Marc H Wadsworth, et al. "Single-Cell Analysis of Human Primary Prostate Cancer Reveals the Heterogeneity of Tumor-Associated Epithelial Cell States." Nat Commun 13 (2022): 141.
- Salahudeen, Ameen A, Shannon S Choi, Arjun Rustagi, and Junjie Zhu, et al. "Progenitor Identification and SARS-Cov-2 Infection in Human Distal Lung Organoids." Nature 588 (2020): 670-675.
- Cakir, Bilal, Yangfei Xiang, Yoshiaki Tanaka, and Mehmet H Kural, et al. "Engineering of Human Brain Organoids with a Functional Vascular-Like System." Nat Methods 16 (2019): 1169-1175.
- Velasco, Silvia, Amanda J Kedaigle, Sean K Simmons, and Allison Nash, et al. "Individual Brain Organoids Reproducibly form Cell Diversity of the Human Cerebral Cortex." Nature 570 (2019): 523-527.
- Kim, Hongwon, Hyeok Ju Park, Hwan Choi, and Yujung Chang, et al. "Modeling G2019S-LRRK2 Sporadic Parkinson's Disease in 3D Midbrain Organoids." Stem Cell Reports 12 (2019): 518-531.
- Ha, Jeongmin, Ji Su Kang, Minhyung Lee, and Areum Baek, et al. "Simplified Brain Organoids for Rapid and Robust Modeling of Brain Disease." Front Cell Dev Biol 8 (2020): 594090.
- Wulansari, Noviana, Wahyu Handoko Wibowo Darsono, Hye-Ji Woo, and Mi-Yoon Chang, et al. "Neurodevelopmental Defects and Neurodegenerative Phenotypes in Human Brain Organoids Carrying Parkinson’s Disease-Linked DNAJC6 Mutations." Sci Adv 7 (2021): eabb1540.
- Kim, Seung Won, Hye-Ji Woo, Eun Hee Kim, and Hyung Sun Kim, et al. "Neural Stem Cells Derived from Human Midbrain Organoids as a Stable Source for Treating Parkinson’s Disease: Midbrain Organoid-Nscs (Og-NSC) as a Stable Source for PD Treatment." Prog Neurobiol 204 (2021): 102086.
- Sabate-Soler, Sonia, Sarah Louise Nickels, Cláudia Saraiva, and Emanuel Berger, et al. "Microglia Integration into Human Midbrain Organoids Leads to Increased Neuronal Maturation and Functionality." Glia 70 (2022): 1267-1288.
- Qian, Xuyu, Ha Nam Nguyen, Mingxi M Song, and Christopher Hadiono, et al. "Brain-Region-Specific Organoids Using Mini-Bioreactors for Modeling ZIKV Exposure." Cell 165 (2016): 1238-1254.
- Tejchman, Anna, Agnieszka Znój, Paula Chlebanowska, and Aneta Frączek-Szczypta. "Carbon Fibers as a New Type of Scaffold for Midbrain Organoid Development." Int J Mol Sci 21 (2020): 5959.
- Zafeiriou, Maria-Patapia, Guobin Bao, James Hudson, and Rashi Halder, et al. "Developmental GABA Polarity Switch and Neuronal Plasticity in Bioengineered Neuronal Organoids." Nat Commun 11 (2020): 3791.
- Becerra-Calixto, Andrea, Abhisek Mukherjee, Santiago Ramirez, and Sofia Sepulveda, et al. "Lewy Body-Like Pathology and Loss of Dopaminergic Neurons in Midbrain Organoids Derived from Familial Parkinson’s Disease Patient." Cells 12 (2023): 625.
- Zhou, Zhi Dong, Wuan Ting Saw, Patrick Ghim Hoe Ho, and Zhi Wei Zhang, et al. "The Role of Tyrosine Hydroxylase–Dopamine Pathway in Parkinson’s Disease Pathogenesis." Cell Mol Life Sci 79 (2022): 599.
- Pamies, David, Daphne Wiersma, Moriah E Katt, and Liang Zhao, et al. "Human IPSC 3D Brain Model as a Tool to Study Chemical-Induced Dopaminergic Neuronal Toxicity." Neurobiol Dis 169 (2022): 105719.
- Kwak, Tae Hwan, Ji Hyun Kang, Sai Hali, and Jonghun Kim, et al. "Generation of Homogeneous Midbrain Organoids with In Vivo-Like Cellular Composition Facilitates Neurotoxin-Based Parkinson's Disease Modeling." Stem Cells 38 (2020): 727-740.
- Renner, Henrik, Katharina J Becker, Theresa E Kagermeier, and Martha Grabos, et al. "Cell-Type-Specific High throughput Toxicity Testing in Human Midbrain Organoids." Front Mol Neurosci 14 (2021): 715054.
- Renner, Henrik, Martha Grabos, Katharina J Becker, and Theresa E Kagermeier, et al. "A Fully Automated High-Throughput Workflow for 3D-Based Chemical Screening in Human Midbrain Organoids." Elife 9 (2020): e52904.
- Mohamed, Nguyen-Vi, Paula Lépine, María Lacalle-Aurioles, and Julien Sirois, et al. "Microfabricated Disk Technology: Rapid Scale up in Midbrain Organoid Generation." Methods 203 (2022): 465-477.
Citation: Wenchao Sun and Junzheng Yang. “ Organoids andtheir Applications in Parkinson's Disease.” Clin Schizophr Relat Psychoses 17 (2023). Doi: 10.3371/CSRP.SWJY.041723.
Copyright: � 2023 Sun W, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.