Non-human primates provide a unique way to study the only model in which both developmental and pathological features of the brain in a species phylogenetically close to human. In the past decade, breakthrough advances in single-cell sequencing have enabled the mapping of cell taxonomy and heterogeneity in the developing and adult brain of different mammalian species. Here, we generated single-cell chromatin accessibility (single-cell ATAC) and transcriptomic data of 358,237 cells from three cortical regions of the adult cynomolgus monkey Macaca fascicularis brain. We then integrated this dataset with Stereo-seq (Spatio-Temporal Enhanced Resolution Omics-sequencing) of the corresponding cortical areas to assign topographic information to molecular and regulatory states.

Although the hypothalamus plays a crucial role in the progression of metabolic diseases including obesity and diabetes, the underlying molecular remodeling remains unclear. Here we systematically compared the transcriptomic features of structured hypothalamus at single-cell resolution in obese and diabetic macaques. We found that the infundibular (INF) and the paraventricular nucleus (PVN) were the most susceptible regions to metabolic disruption with the PVN being more sensitive to diabetes. In the INF, obesity displayed reduced synaptic plasticity and energy sensing capability. By contrast, in diabetes there was interactive molecular reprogramming associated with an impaired tanycyte barrier, activated microglia and stimulation of neuronal inflammatory response. Results from Stereo-seq further demonstrate a unique spatial tropism of microglia towards parenchyma relative to the third ventricle. Our data provide an extensive reference resource of distinct molecular changes between obesity and diabetes in the primate hypothalamus, which may facilitate more precise and effective therapies for metabolic disorders.

During mammalian embryogenesis, temporal and spatial regulation of gene expression and cell signaling influences lineage specification, the patterning of tissue progenitors and the morphogenesis of embryo. While the mouse model has been instrumental for our understanding of mammalian development, comparatively little is known about early human and non-human primate gastrulation due to the limitation of technical and ethical. Here, we present a morphological and molecular approach that reveals the systematically morphological changes and comprehensive transcriptional landscape of cell types populating the non-human primate embryos during gastrulation.

Our understanding of human early development is severely hampered by limited access to embryonic tissues. Due to their close evolutionary relationship with humans, non-human primates (NHPs) are often used as surrogates to understand human development but currently suffer from a lack of in vivo datasets, especially from gastrulation to early organogenesis during which the major embryonic cell types are dynamically specified. To fill this gap, we have collected six Carnegie stage (CS) 8-CS11 cynomolgus monkey embryos and performed in-depth transcriptome analyses of 56,636 single cells. Our analyses reveal transcriptomic features of major peri-gastrulation cell types, which help shed light on morphogenetic events including primitive streak (PS) development, somitogenesis, gut tube formation, neural tube patterning, and neural crest regionalization in primates. In addition, comparative analyses with mouse embryos and human embryoids uncover conserved and divergent features of peri-gastrulation development across species, e.g. species-specific dependency on Hippo signaling during presomitic mesoderm differentiation, and provide an initial assessment of relevant stem cell models of human early organogenesis. This comprehensive single-cell transcriptome atlas not only fills the knowledge gap in the NHP research field but also serves as an invaluable resource for understanding human embryogenesis and developmental disorders.