Cell migration is an integral part of re-epithelialization during skin wound healing, a complex process involving molecular controls that are still largely unknown. Here we identify a novel role for Tcf3, an essential transcription factor regulating embryonic and adult skin stem cell functions, as a key effector of epidermal wound repair. We show that Tcf3 is upregulated in skin wounds and that Tcf3 overexpression accelerates keratinocyte migration and skin wound healing. We also identify Stat3 as an upstream regulator of Tcf3. We show that the pro-migration effects of Tcf3 are non-cell autonomous and occur independently of its ability to interact with β-catenin. Finally, we identify lipocalin-2 as the key secreted factor downstream of Tcf3 that promotes cell migration in vitro and wound healing in vivo. Our findings provide new insights into the molecular controls of wound-associated cell migration and identify potential therapeutic targets for the treatment of defective wound repair.

SUMMARYHair follicles cyclically degenerate and regenerate throughout adult life and require regular stem cell activation to drive the cycle. In the resting phase of the hair cycle, hair follicle stem cells are maintained in a quiescent state until they receive signals to proliferate. We found that the forkhead transcription factor Foxp1 is crucial for maintaining the quiescence of hair follicle stem cells. Loss of Foxp1 in skin epithelial cells leads to precocious stem cell activation, resulting in drastic shortening of the quiescent phase of the hair cycle. Conversely, overexpression of Foxp1 in keratinocytes prevents cell proliferation by promoting cell cycle arrest. Finally, through both gain-and loss-of-function studies, we identify fibroblast growth factor 18 (Fgf18) as the key downstream target of Foxp1. We show that exogenously supplied FGF18 can prevent the hair follicle stem cells of Foxp1 null mice from being prematurely activated. As Fgf18 controls the length of the quiescent phase and is a key downstream target of Foxp1, our data strongly suggest that Foxp1 regulates the quiescent stem cell state in the hair follicle stem cell niche by controlling Fgf18 expression.

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The Lef/Tcf-family transcription factor Tcf3 has important roles in development, stem cell function and malignancy. Previous gain-and loss-of-function studies have suggested that Tcf3 is a mediator of selfrenewal and an undifferentiated state in stem and progenitor cells in skin, but little is known of its role in other postnatal tissues. Here, we explore the distribution and behavior of Tcf3-expressing cells in several adult tissues using a novel Tcf3-CreER knock-in mouse model. By lineage tracing in dorsal skin, we verify that Tcf3-expressing cells in the hair follicle bulge are self-renewing stem cells with multilineage potential. We then demonstrate, for the first time, the presence of Tcf3-expressing cells in the basal layer of several other stratified epithelia, including the paw skin, tongue and esophagus. By lineage tracing, we demonstrate that the Tcf3-expressing population in these tissues includes persistent stem cells, transient progenitors and cells undergoing active differentiation. Our observations here suggest that the role of Tcf3 in cell-fate decision is more complex than previously appreciated and is highly dependent on cellular context.

Adoptive immunotherapy is an appealing approach to cancer treatment, with the potential for more precise targeting and reduced toxicity. While early clinical trial data using adoptive T cells against post-transplant virus-associated hematologic malignancies, lymphoma and melanoma have been promising, treating other solid tumors has proven to be more challenging. Adoptive lymphocytes have been genetically modified in many ways to improve activity and circumvent tumor evasion, including transfer of transgenic T-cell receptors and chimeric antigen receptors to redirect T cell and natural killer cell antigen specificity. Gene transfer may also allow expression of homeostatic cytokines or their receptors to overcome the lack of stimulatory signals or expression of dominant-negative receptors for inhibitory cytokines to compensate for an immunosuppressive tumor milieu. In addition, suicide genes can install a 'safety switch' on adoptively transferred cells to allow ablation if necessary. Although further refinement and validation are necessary, these genetic modification strategies offer hope for significant improvements in cancer immunotherapy.