The process of neurogenesis, which involves the creation of various neuron types, has been extensively studied in neuroscience. However, our understanding of its genetic and biological foundations in humans remains incomplete, particularly for immature neurons resulting from adult hippocampal neurogenesis known as immature dentate granule cells (imGCs), which are crucial for the brain's ability to adapt throughout adulthood.
A collaborative research effort involving the University of Pennsylvania, the Chinese Academy of Sciences, and other institutions recently conducted a study aimed at enhancing our understanding of imGC development and examining if their origins in humans differ from those in other species. The findings published in Nature Neuroscience indicate that although similar biological processes affect these cells in the brains of mice, pigs, monkeys, and humans, gene expression patterns in human imGCs are significantly different.
Nature Neuroscience"ImGCs produced through adult hippocampal neurogenesis are critical for brain plasticity, learning, memory, and hold promise for regenerative medicine," noted Yi Zhou, the paper's first author, in an interview with Medical Xpress.
"However, we have limited knowledge about the molecular characteristics of imGCs in humans and macaques, as most studies have depended on mice models, leading to inconsistencies in identifying and characterizing imGCs in primates."
A key objective of Zhou's study was to identify unique molecular traits and gene expression patterns specific to human imGCs. The research focused on four mammalian species — mice, pigs, monkeys, and humans.
"Our goal was to accurately identify imGCs using published single-cell RNA sequencing (scRNA-seq) data and conduct a systematic comparison of the molecular landscapes across species to uncover evolutionary changes and features unique to humans," Zhou explained. "Given potential interspecies variations, we avoided using mouse-derived markers to annotate imGCs in human and macaque scRNA-seq datasets."
In previous work, Zhou and his team developed a machine learning technique for identifying human imGCs with remarkable success. However, characterizing these cells in macaques had been challenging, with earlier efforts producing inconsistent results.
The new study employed a machine learning-based approach to classify hippocampal cells using an algorithm trained on high-confidence imGCs, identified in young macaques where such cells are abundant (expressing classical markers like DCX and PROX1 but not mature counterparts like CALB1).
Nature Neuroscience"Our new classifier allowed us to identify transcriptome-wide immature neuronal traits of macaque imGCs with consistent criteria across datasets," Zhou said. "We then conducted a cross-species analysis comparing imGCs and their mature counterparts in humans, macaques, pigs, and mice using all available scRNA-seq data at the time."
The researchers found that gene expression richness differs significantly among species in imGCs more than in mature granule cells. Despite this, the underlying biological processes governing development appear similar across all studied species.
"We also identified several gene families enriched in human imGCs compared to mature granule cells, not seen in macaques, pigs, or mice," Zhou mentioned.
"In particular, we found enrichment of the ATP6 gene family encoding proton-transporting vacuolar-type ATPase subtypes. Developing a model using human pluripotent stem cells, we demonstrated that vacuolar-type ATPase critically regulates imGC neurite outgrowth and neuronal network activity in vitro."
In summary, the researchers suggest that while the fundamental biological processes driving imGC development are consistent across species, gene regulation varies significantly. These differences could play a crucial role in cellular adaptation and brain function.
"Our results underscore the importance of independent molecular and functional analyses of adult neurogenesis across species and highlight the value of human cell-based models for understanding human imGCs," Zhou said.
This study may inspire further research comparing neurogenesis processes and imGC development across different species, potentially leading to new therapeutic approaches targeting specific neuron genesis in the hippocampus.
"Due to sequencing depth limitations, our analysis focused on highly expressed genes, leaving unexplored whether low-expression genes enriched in imGCs exhibit cross-species similarities or differences," Zhou noted.
"Moreover, we didn't consider species-specific genomic features or isoform usage. Future research with larger sample sizes and deeper sequencing could reduce variability and enable further study of different data modalities of imGCs across sexes, developmental stages, and disease states."
Currently, the team's focus has been on imGCs that are not yet fully developed. In future studies, Zhou and colleagues aim to investigate other brain cell types in adult mammals, such as quiescent and active neural stem cells.