ArticleAging cell2026
3D Culture Reverses Limbal Niche Cell Replicative Aging via FOSL1 Upregulation.
Article in Aging cell, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Limbal niche cells (LNCs) serve as essential regulators of limbal microenvironmental homeostasis and corneal epithelial wound repair, representing a promising therapeutic resource for limbal stem cell deficiency (LSCD). However, their clinical application is constrained by replicative aging during in vitro expansion. In this study, we investigated whether a three-dimensional (3D) Matrigel-based culture system could modulate replicative aging in LNCs. Compared with conventional two-dimensional (2D) culture, 3D-cultured LNCs restored stemness marker expression and enhanced proliferative capacity. Concurrently, these cells displayed reduced senescence-associated β-galactosidase (SA-β-gal) activity and decreased expression of senescence-associated proteins, including p16, p21, p53, and γ-H2AX. Single-cell RNA sequencing (scRNA-seq) analysis revealed prominent upregulation of FOS-like antigen 1 (FOSL1). FOSL1 is a component of the AP-1 transcription factor family and participates in cell proliferation and stress adaptation. Functional assays using an in vitro replicative aging model showed that FOSL1 knockdown in early-passage (P4) LNCs accelerated senescence, whereas FOSL1 overexpression in late-passage (P11) LNCs attenuated senescence. Mechanistically, FOSL1 knockdown induced mitochondrial dysfunction characterized by elevated levels of mitochondrial superoxide and cellular reactive oxygen species (ROS), as well as a decrease in mitochondrial membrane potential, while FOSL1 overexpression preserved mitochondrial integrity and function. Collectively, our findings demonstrate that 3D culture reverses LNC replicative aging through FOSL1-mediated enhancement of mitochondrial function, providing a microenvironment-based strategy to counteract replicative aging in adult stem cells for corneal regenerative therapy.
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