Integrin-Binding Matricellular Protein Fibulin-5 Maintains Epidermal Stem Cell Heterogeneity During Skin Aging

The extracellular matrix (ECM) is crucial in building the extracellular environment and translating extracellular information into biochemical signals that sustain tissue functions. Fibulin-5 (Fbln5) is a multifunctional ECM protein essential for forming elastic fibers and regulating cellular functions by binding to integrins. Although fibulin-5 expression decreases with age in human skin, its functional implications, particularly in epidermal stem cell regulation, remain largely unexplored. Here, we show that the loss of Fbln5 in mice leads to early impairments of epidermal stem cell properties that resemble changes observed during chronological skin aging. Fbln5 deficiency is associated with reduced expression of integrins and other cell junction proteins and decreased YAP activation in epidermal stem cells. Pharmacological inhibition of YAP reduces the fast-cycling stem cell region in mice and downregulates the fast-cycling epidermal stem cell marker SLC1A3 in human primary keratinocytes. At the cellular level, YAP activity and SLC1A3 expression are modulated by cell density, with low-density cultures exhibiting high nuclear YAP and elevated SLC1A3 expression, whereas high-density conditions suppress both. Under high-density conditions, fibulin-5 coating partially restores nuclear YAP localization and increases SLC1A3 expression. Together, these findings suggest that, beyond its structural role in elastic fiber formation, fibulin-5 contributes to the maintenance of epidermal stem cell balance during skin aging by linking extracellular alterations to YAP-dependent intracellular signaling.