Association of TGFβ signaling with the maintenance of a quiescent stem cell niche in human oral mucosa

Abstract

A dogma in squamous epithelial biology is that proliferation occurs in the basal cell layer. Notable exceptions are squamous epithelia of the human oral cavity, esophagus, ectocervix, and vagina. In these human epithelia, proliferation is rare in the basal cell layer, and the vast majority of cells positive for Ki67 and other proliferation markers are found in para- and suprabasal cell layers. This unique human feature of a generally quiescent basal cell layer overlaid by highly proliferative cells offers the rare opportunity to study the molecular features of undifferentiated, quiescent, putative stem cells in their natural context. Here, we show that the quiescent human oral mucosa basal cell layer expresses putative markers of stemness, while para- and suprabasal cells are characterized by cell cycle genes. We identified a TGFβ signature in this quiescent basal cell layer. In in vitro organotypic cultures, human keratinocytes could be induced to express markers of these quiescent basal cells when TGFβ signaling is activated. The study suggests that the separation of basal cell layer and proliferation in human oral mucosa may function to accommodate high proliferation rates and the protection of a quiescent reserve stem cell pool. Psoriasis, an epidermal inflammatory hyperproliferative disease, exhibits features of a quiescent basal cell layer mimicking normal oral mucosa. Our data indicate that structural changes in the organization of epithelial proliferation could contribute to longevity and carcinogenesis.

Divide and conquer: two stem cell populations in squamous epithelia, reserves and the active duty forces

“…19,20 This deviation of the basal cell proliferation dogma is not only true for ectocervix and vagina, but also for the oral cavity, the esophagus and the anus (Fig. 1 21 ). Even in the human epidermis the situation is not as clear cut as the dogma states, and a substantial number of replicating cells can actually be found in suprabasal cell layers 21,22 and has been debated for nearly 100 years.…”

“…1 21 ). Even in the human epidermis the situation is not as clear cut as the dogma states, and a substantial number of replicating cells can actually be found in suprabasal cell layers 21,22 and has been debated for nearly 100 years. 23–25 In the human oral mucosa, these proliferating and undifferentiated non-basal cells are frequently associated with the parabasal cell layer, and one interpretation of this organization is that the stem cell compartment is divided in a basal quiescent and a parabasal active compartment similar to what has been outlined for the stem cell compartments of the intestines, the hair follicle and the hematopoietic system.…”

“…The first limitation is serious as basal cells are quiescent and only a few percent of basal cells are Ki67-positive. 21,22,28 If few cells are going through S-phase during the labeling period, few cells can incorporate the label, and few of these normally quiescent stem cells will be detected subsequently. In the human squamous epithelium of the cervix, it has been estimated that a basal stem cell replicates every 33 days, 20 and therefore a labeling period of at least 33 days would be necessary.…”

In focus in HCB

“…Thus, to address these questions, Beckmann et al (2016) used quantitative RT-PCR and immunofluorescence to assess the presence of Cx43 in undifferentiated HCBiPS2 cells, and freeze-fracture replica immunogold labeling (FRIL) to ultrastructurally investigate gap junction Stem cells figure prominently in two articles featured in the current issue. Andl et al (2016) investigated the unique cell proliferation situation presented by human oral mucosa. Unlike epidermal stratified squamous epithelia where a proliferative basal cell layer is overlain by successively differentiated cell layers, the human oral mucosa contains a quiescent basal cell layer, with proliferation mostly restricted to parabasal and suprabasal cell layers.…”

“…Unlike epidermal stratified squamous epithelia where a proliferative basal cell layer is overlain by successively differentiated cell layers, the human oral mucosa contains a quiescent basal cell layer, with proliferation mostly restricted to parabasal and suprabasal cell layers. Andl et al (2016) have now addressed the important and intriguing question relating to the function of such a quiescent basal cell layer. They performed an immunohistochemical and in situ hybridization characterization of the basal cell layer on sections from tissues embedded in paraffin, as well as in a human organotypic cell culture model of oral mucosal tissue.…”