{"doi":"10.1002/ctm2.1196","title":"Special properties of adult neurogenesis in the human hippocampus: Implications for its clinical applications","abstract":"Adult neurogenesis, the process of generating functional neurons from neural progenitors (Figure 1A), occurs throughout the lifetime in the hippocampus of almost all mammals examined, including humans.1, 2 Adult hippocampal neurogenesis plays critical roles in learning and memory, cognition, and affective behaviours, whereas its dysfunction has been associated with many neurological and psychiatric disorders, such as Alzheimer's disease (Figure 1B).1, 2 Studies in rodents have revealed distinct molecular, cellular, physiological, and neuronal circuitry properties of immature neurons (imNs) generated during adult neurogenesis compared to their mature counterparts (mNs), which are considered the foundation for the functional role of adult hippocampal neurogenesis.2 Limited knowledge of imNs in adult humans represents a major roadblock to harness their potential in clinical applications for brain disorders and regenerative medicine. There are contradictory reports on the existence and abundance of newly generated neurons in the adult human hippocampus, mostly based on immunohistological analysis of one or two pre-defined markers known in rodents.3, 4 Several single-cell/single-nucleus RNA sequencing (scRNA-seq) analyses surveying the human hippocampus of different age groups did not identify a distinct imN cluster, including in the prenatal human hippocampus (summarized in Zhou et al.5). This is in sharp contrast to the clear sub-clustering of immature progeny identified in the adult mouse hippocampal scRNA-seq dataset,6 suggesting fundamental differences between species. Some studies7 performed correlation analysis by comparing human cells in their datasets to mouse imNs,6 assuming large transcriptomic resemblances between imNs of humans and mice. In our recent study,5 we leveraged the whole transcriptome scRNA-seq to comprehensively characterize human imNs using a machine learning-based analytic approach. We trained a classifier using our human infant hippocampus dataset and then used it to identify imNs in the human hippocampus across the lifespan. We found not only conserved immature features but also significant species differences between imNs in humans and mice in gene expression and temporal dynamics across ages (Figure 1C). We also performed immunohistological analysis of neuronal progenitor cells and developed an ex vivo culture system of human hippocampal surgical tissue to demonstrate the capacity for adult human hippocampal neurogenesis.5 Our results support continuous hippocampal neurogenesis in humans and suggest a model for retaining a large pool of imNs in the adult human hippocampus by low-frequency de novo generation of neural progenitors and prolonged maturation of imNs (Figure 1A,C).5 Significant species differences revealed in our study5 (Figure 1C), and others8, 9 highlight limitations of using classic models, such as mice, to fully recapitulate features of human brain development or disorders, or to predict the impact of therapeutic treatment on human diseases. Not only did we observe substantial variance in imN-enriched molecular signatures, we also found cell dynamics regarding transcriptomic shifts associated with age and potentially prolonged maturation in human imNs.5 Such cross-species differences in various aspects have been widely observed in other brain regions (e.g., the developing neocortex) in humans in comparison with other species, such as mice and non-human primates.8, 9 Therefore, direct analyses of human brain tissue or human-based model systems are critical to examine mechanisms, pathologies, treatment strategies, and functions of human biological processes and diseases, including adult human neurogenesis. In recent years, procurement of high-quality human brain specimens and advances in human pluripotent stem cell (hPSC)-based model systems provide unprecedented opportunities to directly examine human brain development and diseases to understand their underlying cellular and molecular me","journal":"Clinical and Translational Medicine","year":2023,"id":352290,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9534,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":227203,"name":"Yijing Su","orcid":"0000-0002-4146-0068","position":1,"is_corresponding":false},{"id":21533,"name":"Guo‐li Ming","orcid":"0000-0002-2517-6075","position":2,"is_corresponding":false},{"id":123278,"name":"Hongjun Song","orcid":"0000-0002-8720-5310","position":3,"is_corresponding":false},{"id":527293,"name":"Yi Zhou","orcid":"0000-0001-6500-8554","position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-19T01:12:50.107998Z","pmid":"36740454","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}