Abstract
Tissue injury induces changes in cellular identity, but the underlying molecular mechanisms remain obscure. Here, we show that upon damage in a mouse model, epidermal cells at the wound edge convert to an embryonic-like state, altering particularly the cytoskeletal/extracellular matrix (ECM) components and differentiation program. We show that SOX11 and its closest relative SOX4 dictate embryonic epidermal state, regulating genes involved in epidermal development as well as cytoskeletal/ECM organization. Correspondingly, postnatal induction of SOX11 represses epidermal terminal differentiation while deficiency of Sox11 and Sox4 accelerates differentiation and dramatically impairs cell motility and re-epithelialization. Amongst the embryonic genes reactivated at the wound edge, we identify fascin actin-bundling protein 1 (FSCN1) as a critical direct target of SOX11 and SOX4 regulating cell migration. Our study identifies the reactivated embryonic gene program during wound repair and demonstrates that SOX11 and SOX4 play a central role in this process.
Highlights
Tissue injury induces changes in cellular identity, but the underlying molecular mechanisms remain obscure
In summary, our discovery that adult epidermal cells at the wound edge are converted to express an embryonic gene program suggests that the induction of an embryonic program is critical for wound repair
We show that the wound-induced reactivation of an embryonic program is driven by SOX11 and SOX4 and that the re-epithelialization step of wound repair requires both SOX11 and SOX4
Summary
Tissue injury induces changes in cellular identity, but the underlying molecular mechanisms remain obscure. Injuries disrupting the skin barrier elicit responses from multiple cell types, inducing epidermal cells to migrate to the wound site and regenerate a new epidermis[2]. During this wound-healing process, epidermal cells are reprogrammed to be more plastic in their fate, but the regulation of this process remains poorly defined[3,4]. In addition to its role in embryonic development, SOX11 is induced in adult neuronal and mesenchymal cells upon injury and contributes to nerve regeneration and bone repair[10,11,12,13]. As SOX11 clearly holds a critical role in embryonic development and regeneration[10,11,13,17,19], we postulate that SOX11 might be an important molecular link between the embryonic state and tissue regeneration
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