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Human striatal organoids derived from pluripotent stem cells recapitulate striatal development and compartments [1]

['Xinyu Chen', 'Department Of Anatomy', 'Histology', 'Embryology', 'School Of Basic Medical Sciences', 'Fudan University', 'Shanghai', 'P.R. China', 'Hexige Saiyin', 'State Key Laboratory Of Genetic Engineering']

Date: 2022-11 

The striatum links neuronal circuits in the human brain, and its malfunction causes neuronal disorders such as Huntington’s disease (HD). A human striatum model that recapitulates fetal striatal development is vital to decoding the pathogenesis of striatum-related neurological disorders and developing therapeutic strategies. Here, we developed a method to construct human striatal organoids (hStrOs) from human pluripotent stem cells (hPSCs), including hStrOs-derived assembloids. Our hStrOs partially replicated the fetal striatum and formed striosome and matrix-like compartments in vitro. Single-cell RNA sequencing revealed distinct striatal lineages in hStrOs, diverging from dorsal forebrain fate. Using hStrOs-derived assembloids, we replicated the striatal targeting projections from different brain parts. Furthermore, hStrOs can serve as hosts for striatal neuronal allografts to test allograft neuronal survival and functional integration. Our hStrOs are suitable for studying striatal development and related disorders, characterizing the neural circuitry between different brain regions, and testing therapeutic strategies.

Here, we describe a 3D culturing system to generate human brain organoids resembling the striatum using facile techniques. We characterized the development of hStrOs by enhancing phenotypic analyses. The data from single-cell RNA-sequencing (scRNA-seq) of Day 110 hStrOs also showed similar cellular organizations and developmental trajectories similar to those of the developing human striatum. Mainly, we reported a self-organized regionalization in developing hStrO, which was similar to the compartmentalization in developing striatum. Moreover, we have expanded the potential applications of hStrOs, including using fused organoids to reconstruct the projection target striatum and disease modeling in vitro.

The striatum, the gateway of the basal ganglia, receives inputs from the cerebral cortex and the thalamus while forming a complicated projection relationship with the substantia nigra and the pallidum in the midbrain [ 12 , 13 ]. It develops from the lateral ganglionic eminences (LGEs) located ventral to the developing forebrain [ 14 ]. The mature striatum contains 95% medium spiny neurons (MSNs) [ 15 ]. Striatal development is a complex process followed by 2 distinct yet complimentary basic, organizational programs [ 15 ]. The programming generates 2 compartments with different neurochemical signatures refer to as striosome and matrix, which fully intermingled the direct pathway MSNs and indirect pathway MSNs [ 15 ]. Recently, a method to generate an organoid resembling the striatum has been reported [ 16 ]. To date, human corticogenesis has been well characterized in human cortical organoids (hCOs), [ 17 ] whereas the similar developmental dynamics in hStrOs are not well illustrated; consequently, this lack of understanding limits its application in disease modeling and targeted manipulation. Therefore, detailed and systemic phenotyping of developing organoids is necessary to enhance the repertoire of phenotypic assays available for hStrOs.

Pluripotent stem cell-based central nervous system (CNS) models have rapidly evolved since the advent of neural rosette formation from human embryonic stem cells (hESCs) [ 1 ]. Techniques to derive a targeted neuron from human pluripotent stem cells (hPSCs) are sophisticated [ 2 – 5 ]. Based on 2-dimensional (2D) differentiation methods, various protocols have been published to construct 3-dimensional (3D) brain organoids through guided and unguided methods [ 6 – 9 ], which are self-organized and partially recapitulate the neuronal activities of the human brain. Brain organoid technology provides unique opportunities to anatomically and spatially characterize the development of the human brain. The flexibility of organoids provides more chances to study complex neural systems; for example, fused organoids have been used to describe neuronal projections and migration between multiple brain regions [ 9 – 11 ].

Results

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[1] Url: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001868

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