Tcf3 expression marks both stem and progenitor cells in multiple epithelia

Abstract

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.

Somatic stem cell heterogeneity: diversity in the blood, skin and intestinal stem cell compartments

“…Specifically, these studies used bulge and hair germ-specific inducible K15 –CrePR transgenic mice 61 , and K19 –CreER 54,72 , Lgr5 –CreER 59,72 , Gli1 –CreER 73 and Tcf3 –CreER 74 knock-in mice (see the activity of these promoter s in FIG. 2).…”

“…Although lineage tracing is a very powerful tool for identifying stem cell populations in the skin, it relies on cell-type- and temporal-specific induction of Cre recombinases and therefore produces slightly different results depending on the timing of the labelling 74,78 . Collectively however, the results that have been obtained using this approach strongly support the concept of stem cell heterogeneity in the hair follicle, in which several distinct pools of stem cells regenerate one or more parts of the hair follicle.…”

“…Similarly, laser ablation of hair germ cells induces bulge cells to reconstitute the hair germ and give rise to new hair growth 79 . Following wounding by removal of a full‑thickness piece of skin (that is, including the dermis as well as the epidermis), the majority of the re-epithelialized portion of the IFE is derived from the neighbouring basal cells of the IFE 71 , although cells from discrete compartments of the hair follicle have also been found to contribute to the regeneration and repair of the IFE 58,63,69,72–74,81 .…”

Hair follicle and interfollicular epidermal stem cells make varying contributions to wound regeneration

“…7,8 Consequently, stem cells that do not ordinarily encounter one another during homeostasis, such as those of the HF bulge and the basal layer of the IFE, are suddenly brought into contact when they converge at the wounded area. 8 Although multiple reports have documented the overall persistence of different HF stem cell-derived sub-populations following wound healing, [9][10][11][12][13][14][15][16] few have quantitated the specific ability of these cells to populate the permanent, basal layer of the regenerating epithelium over time. This layer is likely to be significant, since IFE stem cells are found exclusively in the basal layer, whereas their differentiated progeny stratify into the overlying suprabasal layers of the skin and are eventually sloughed off.…”

Monitoring Wnt/β-Catenin Signaling in Skin

“…Whereas the stratified epidermis self-renews continuously, hair follicles undergo periodic degeneration and regeneration, depending on signals from a specific dermal niche, the dermal papilla [2]. In response to wounding, stem cells from both the stratified epidermis and hair follicles contribute to repair of the epidermis [3–9]. …”