John A Cornelius, Megana Shivakumar, Taeyun Kim, Orlando Cervantes, Raj P Kapur, Hazel Huang, Hong Zhao, Briana M Del Rosario, Amanda Li, Richard J Li, Sidney Sun, Andrew E Vo, Gygeria Manuel, Akshaj Bharadwaj, Jeff Munson, Miranda Li, Edmunda Li, Sophia Chima, Austyn Orvis, Michelle Coleman, Alexandra Christodolou, Melissa R Berg, Britni C Curtis, Brenna A Menz, Jin Dai, Inah D Golez, Solomon N Wangari, Stephen A McCartney, Kristen Noble, Pilar Flores-Espinoza, Addy Cecilia Helguera-Repetto, Andrea Olmos-Ortiz, Monica Selena Fonseca-Perez, Chris English, Audrey Baldessari, Nardhy Gomez-Lopez, Rebecca Hodge, Lakshmi Rajagopal, Kristina M Adams Waldorf
Single-cell populations from the third-trimester nonhuman primate fetal brain are highly similar to those in the human fetus at the level of major lineages. This late-gestation single-cell atlas of the periventricular proliferative zone provides a unique reference for progenitor, neuronal, glial, vascular, and immune cell states during a critical window of primate neurodevelopment, enabling mechanistic interrogation of how inflammatory, infectious, or hypoxic insults disrupt vulnerable neurogenic niches.
BACKGROUND: The fetal brain undergoes rapid cellular and structural changes in late gestation, when waves of neurogenesis and gliogenesis shape cortical circuitry. The ventricular zone (VZ), subventricular zone (SVZ), periventricular white matter (PVWM), and deep white matter (DWM) are enriched in neuroprogenitor cells, newborn neurons, and interneurons, which are regions challenging to study in the third-trimester human fetal brain. The nonhuman primate (NHP) provides a powerful translational model to overcome this limitation, given its close similarity to human neurodevelopmental trajectories. The study objective was to construct a single-cell RNA-Seq (scRNA-Seq) atlas of the late-gestation fetal brain of the pigtail macaque (Macaca nemestrina), focusing on cells in the periventricular proliferative zone.
METHODS: A sample of the lateral ventricular wall, subventricular zone, and overlying white/gray matter was dissociated into single cells and processed through 10X Genomics sequencing, SoupX removal of ambient RNA, empty droplet removal, doublet exclusion, and Seurat's pipeline which consists of aggregation, unsupervised clustering, and cluster annotation to create a single-cell RNA-Seq (scRNA-Seq) atlas. We also investigated developmental trajectories using scVelo and CellRank2.
RESULTS: This analysis captured diverse populations of neuroprogenitors, newborn neurons, developing lineages of excitatory and inhibitory neurons, oligodendrocytes, astrocytes, epithelial and vascular cells.
CONCLUSIONS: Single-cell populations from the third-trimester nonhuman primate fetal brain are highly similar to those in the human fetus at the level of major lineages. This late-gestation single-cell atlas of the periventricular proliferative zone provides a unique reference for progenitor, neuronal, glial, vascular, and immune cell states during a critical window of primate neurodevelopment, enabling mechanistic interrogation of how inflammatory, infectious, or hypoxic insults disrupt vulnerable neurogenic niches.