Divergent HIF isoform association is linked to hypoxia responses in Mesenchymal stromal cells and human dermal fibroblasts

Abstract

Abstract Hypoxia is a fundamental microenvironmental signal that shapes stromal cell behavior in tissue repair, fibrosis, and regenerative medicine. Mesenchymal stromal cells (MSCs) and fibroblasts share overlapping phenotypic features under standard culture conditions, yet whether they engage equivalent adaptive programs under hypoxic stress remains unclear. Here, we performed comparative transcriptomic analyses to define and contrast hypoxia responses in MSCs and human dermal fibroblasts (HDFs). Both cell types mounted robust hypoxia-responsive programs; however, MSCs exhibited substantially broader transcriptomic remodeling, with two- to four-fold more differentially expressed genes than HDFs. Although a conserved subset of hypoxia-responsive genes was shared, most regulated transcripts were cell-type-specific, indicating distinct adaptive architectures. Pathway and co-expression analyses further revealed divergent HIF-associated signaling structure: MSC responses were more strongly aligned with HIF1A-centered regulatory networks, whereas HDF responses showed relatively stronger HIF2A/HIF3A-associated organization. Despite overlapping baseline stromal marker profiles, hypoxia induced pronounced and non-overlapping surface-marker remodeling in the two cell types, linking regulatory divergence to phenotypic state changes. Collectively, these findings demonstrate that hypoxia does not simply amplify a common stromal program, but instead exposes latent cell-type-specific strategies of adaptation. MSCs undergo broader and more plastic remodeling, whereas fibroblasts adopt a comparatively restrained but distinct regulatory state. These results refine the interpretation of stromal identity under stress conditions and have implications for regenerative medicine, fibrosis biology, and cell manufacturing.

The authors' abstract, as published at the source. Scientific Reports, 2026 · DOI ↗