Abstract
The dopaminergic system has key roles in human physiology and is implicated in a broad range of neurological and neuropsychiatric conditions that are increasingly investigated using induced pluripotent stem cell-derived midbrain models. To determine the similarity of such models to human systems, we undertook single cell and spatial profiling of first and second trimester fetal midbrain and compared it to in vitro midbrain models. Our initial histological analysis of second trimester fetal midbrain revealed structural complexity already similar to that of adult tissue, although this similarity did not fully extend to transcriptional activity. Moreover, we show that in vitro models recapitulate the transcriptional activity of late first trimester fetal midbrain, while 3D models replicate the spatial organization and cellular microenvironments of first and second trimester fetal midbrain. Understanding the extent of human tissue recapitulation in midbrain laboratory models is essential to justify their use as biological proxies.
Competing Interest Statement
M.A.K. is a founder of, and consultant to Bloomsbury Genetic Therapies. She has received honoraria from PTC for sponsored symposia and provided consultancy. All other authors declare no conflict of interest.
Data availability
Raw FASTQ files for both single-cell and spatial transcriptomics will be deposited in Gene Expression Omnibus (GEO). Four supplemental data files will be made available in a Zenodo repository, detailed as follows:
Data S1-S2: VCF files with donor genotypes to deconvolute pooled scRNA-seq data.
Data S3: Single-cell data generated in our study (RDS object: Seurat object with counts and metadata).
Data S4: Integrated datasets (RDS object: Seurat object with counts and metadata).
