Widespread sex dimorphism across single-cell transcriptomes of adult African turquoise killifish tissues.

The African turquoise killifish (Nothobranchius furzeri), the shortest-lived vertebrate that can be bred in captivity, is an emerging model organism for aging research. Here, we describe a multitissue, single-cell gene expression atlas of female and male blood, kidney, liver, and spleen. We annotate 22 cell types, define marker genes, and infer differentiation trajectories. We find pervasive sex-dimorphic gene expression across cell types. Sex-dimorphic genes tend to be linked to lipid metabolism, consistent with clear differences in lipid storage in female vs. male turquoise killifish livers. We use machine learning to predict sex using single-cell gene expression and identify potential markers for molecular sex identity. As a proof of principle, we show that our atlas can be used to deconvolute existing bulk RNA sequencing (RNA-seq) data to obtain accurate estimates of cell type proportions. This atlas can be a resource to the community that could be leveraged to develop cell-type-specific expression in transgenic animals.

Widespread sex-dimorphism across single-cell transcriptomes of adult African turquoise killifish tissues.

The African turquoise killifish (Nothobranchius furzeri), the shortest-lived vertebrate that can be bred in captivity, is an emerging model organism to study vertebrate aging. Here we describe the first multi-tissue, single-cell gene expression atlas of female and male turquoise killifish tissues comprising immune and metabolic cells from the blood, kidney, liver, and spleen. We were able to annotate 22 distinct cell types, define associated marker genes, and infer differentiation trajectories. Using this dataset, we found pervasive sex-dimorphic gene expression across cell types, especially in the liver. Sex-dimorphic genes tended to be involved in processes related to lipid metabolism, and indeed, we observed clear differences in lipid storage in female vs. male turquoise killifish livers. Importantly, we use machine-learning to predict sex using single-cell gene expression in our atlas and identify potential transcriptional markers for molecular sex identity in this species. As proof-of-principle, we show that our atlas can be used to deconvolute existing liver bulk RNA-seq data in this species to obtain accurate estimates of cell type proportions across biological conditions. We believe that this single-cell atlas can be a resource to the community that could notably be leveraged to identify cell type-specific genes for cell type-specific expression in transgenic animals.

Transplanted Human Neural Progenitor Cells Attenuate Motor Dysfunction and Lengthen Longevity in a Rat Model of Ataxia.

The spastic Han Wistar (sHW) rat serves as a model for human ataxia presenting symptoms of motor deterioration, weight loss, shortened lifespan, and Purkinje neuron loss. Past studies revealed that human neural progenitor cells (NPCs) improved ataxic symptoms at 20 d posttransplantation in sHW rats. In this study, we investigated the fate and longer-term effectiveness of these transplanted NPCs. Rats were placed into four treatment groups: an untreated normal control group (n = 10), an untreated mutant rat control (n = 10), a mutant group that received an injection of dead NPCs (n = 9), and a mutant group that received live NPCs (n = 10). Bilateral cerebellar injections containing 500,000 of either live or dead NPCs were performed on mutant sHW rats at 40 d of age. Motor activity for all mutant rats started to decline in open field testing around day 35. However, at day 45, the live NPC-treated mutants exhibited significant improvements in open field activity. Similar improvements were observed during rotarod testing and weight gain through the completion of the experiments (100 d). Immunohistochemistry revealed few surviving human NPCs in the cerebella of 80- and 100-d-old NPC-treated mutants; while cresyl violet staining revealed that live NPC-treated mutants had significantly more surviving Purkinje neurons compared to mutants that were untreated or received dead NPCs. Direct stereotactic implantation of NPCs alleviated the symptoms of ataxia, acting as a neuroprotectant, supporting future clinical applications of these NPCs in the areas of ataxia as well as other neurodegenerative diseases.