Associate Professor The Chinese University of Hong Kong the Chinese University of Hong Kong, Hong Kong
Abstract: Adult stem cells, such as mesenchymal stem cells (MSCs) and neural stem cells (NSCs), are essential for maintaining tissue homeostasis and promoting regeneration. However, aging significantly impairs the function of adult stem cells, characterized by reduced responsiveness to tissue injury, disrupted proliferative potential, and diminished functional capacity. These age-associated changes ultimately compromise cell replacement and tissue regeneration in older organisms.
In this study, we identify two H3K9 demethylases, KDM3A and KDM4C, as key regulators of heterochromatin reorganization during MSC senescence. Our findings reveal that KDM3A and KDM4C transcriptionally activate condensin components NCAPD2 and NCAPG2, which are critical for maintaining proper chromosome organization. MSCs derived from Kdm3a−/− mice exhibit defective chromosome architecture, heightened DNA damage responses, and accelerated bone aging.
Furthermore, our recent work highlights the critical role of KDM3A in NSCs. Loss of Kdm3a, either globally or specifically in NSCs, impairs hippocampal neurogenesis and results in persistent deficits in learning and memory throughout adulthood in mice. In vitro, Kdm3a deficiency reduces proliferation and neuronal differentiation while promoting glial differentiation in NSCs. Mechanistically, we show that KDM3A localizes to both the nucleus and cytoplasm of NSCs, where it regulates the Wnt/β-Catenin signaling pathway via dual mechanisms.
These findings underscore the pivotal roles of KDM3A and KDM4C in maintaining adult stem cell function during aging and provide new insights into their contributions to tissue regeneration and age-related decline.
Funding Source: The work is supported by NSFC (82472409), Guangdong Province Basic and Applied Basic Research Fund (2024A1515012929). This work is also supported by Hong Kong University Grants Committee (GRF 14111519, GRF14116622, GRF14112223) .
