Objective: This study aims to develop patient-specific vascularized midbrain assembloids incorporating microglia to better model the neuroinflammatory environment of Parkinson’s disease (PD). By integrating vascular and immune components, we seek to investigate neuroinflammatory alterations in PD pathology and provide a more physiologically relevant platform for studying disease mechanisms and potential therapies.

Background: Midbrain organoids have emerged as valuable tools to model neurodegenerative diseases like PD, replicating key translational aspects and diverse cellular compositions [1,2]. However, their lack of vasculature and microglia limits oxygen and nutrient supply, impairs immune responses, and disrupts neuronal homeostasis and synaptic function.

Method: To address these limitations, we fused vascular organoids [3] with midbrain organoids and introduced human-induced pluripotent stem cell (hiPSC)-derived microglia [4] to generate vascularized immune midbrain assembloids. We assessed their structural and functional properties by analyzing cellular composition, hypoxia levels, cell death, microglia morphology, neuroinflammatory markers, and electrophysiological activity in both healthy and patient-specific PD assembloids carrying the LRRK2-G2019S mutation.

Results: The vascularized immune midbrain assembloids successfully incorporated endothelial cells, adherens junctions, pericytes, and basal lamina markers. Vascular integration reduced hypoxia and cell death while promoting microglia ramification, and microglia enhanced endothelial morphological complexity. In PD assembloids, we observed dynamic neuroinflammatory marker expression, altered microglia morphology, and impaired electrophysiological activity, indicating disrupted immune-neuronal crosstalk.

Conclusion: Our model recapitulates key cellular features of the human midbrain, including dopaminergic neurons, glia, microglia, and vascular elements. It serves as a valuable platform for studying PD-related neuroinflammation, therapeutic screening, and precision medicine. Given shared mechanisms between PD and Type 2 diabetes, including vascular dysfunction, insulin resistance, and inflammation, it may also help explore metabolic contributions to PD pathology and identify therapeutic targets.

References: [1] Smits LM, Reinhardt L, Reinhardt P, Glatza M, Monzel AS, Stanslowsky N, Rosato-Siri MD, Zanon A, Antony PM, Bellmann J, Nicklas SM, Hemmer K, Qing X, Berger E, Kalmbach N, Ehrlich M, Bolognin S, Hicks AA, Wegner F, Sterneckert JL, Schwamborn JC. Modeling Parkinson’s disease in midbrain-like organoids. NPJ Parkinsons Dis. 2019 Apr 5;5:5. doi: 10.1038/s41531-019-0078-4. PMID: 30963107; PMCID: PMC6450999.

[2] Zagare A, Barmpa K, Smajic S, Smits LM, Grzyb K, Grünewald A, Skupin A, Nickels SL, Schwamborn JC. Midbrain organoids mimic early embryonic neurodevelopment and recapitulate LRRK2-p.Gly2019Ser-associated gene expression. Am J Hum Genet. 2022 Feb 3;109(2):311-327. doi: 10.1016/j.ajhg.2021.12.009. Epub 2022 Jan 24. PMID: 35077669; PMCID: PMC8874228.

[3] Wimmer RA, Leopoldi A, Aichinger M, Wick N, Hantusch B, Novatchkova M, Taubenschmid J, Hämmerle M, Esk C, Bagley JA, Lindenhofer D, Chen G, Boehm M, Agu CA, Yang F, Fu B, Zuber J, Knoblich JA, Kerjaschki D, Penninger JM. Human blood vessel organoids as a model of diabetic vasculopathy. Nature. 2019 Jan;565(7740):505-510. doi: 10.1038/s41586-018-0858-8. Epub 2019 Jan 16. PMID: 30651639; PMCID: PMC7116578.

[4] Sabate-Soler S, Nickels SL, Saraiva C, Berger E, Dubonyte U, Barmpa K, Lan YJ, Kouno T, Jarazo J, Robertson G, Sharif J, Koseki H, Thome C, Shin JW, Cowley SA, Schwamborn JC. Microglia integration into human midbrain organoids leads to increased neuronal maturation and functionality. Glia. 2022 Jul;70(7):1267-1288. doi: 10.1002/glia.24167. Epub 2022 Mar 9. PMID: 35262217; PMCID: PMC9314680.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/patient-specific-vascularized-midbrain-assembloids-with-microglia-show-altered-neuroinflammatory-phenotypes-in-parkinsons-disease/