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

Abstract

Stem cells are of great interest to the scientific community due to their potential role in regenerative and rejuvenative medicine. However, their role in the aging process and carcinogenesis remains unclear. Because DNA replication in stem cells may contribute to the background mutation rate and thereby to cancer, reducing proliferation and establishing a relatively quiescent stem cell compartment has been hypothesized to limit DNA replication-associated mutagenesis. On the other hand, as the main function of stem cells is to provide daughter cells to build and maintain tissues, the idea of a quiescent stem cell compartment appears counterintuitive. Intriguing observations in mice have led to the idea of separated stem cell compartments that consist of cells with different proliferative activity. Some epithelia of short-lived rodents appear to lack quiescent stem cells. Comparing stem cells of different species and different organs (comparative stem cell biology) may allow us to elucidate the evolutionary pressures such as the balance between cancer and longevity that govern stem cell biology (evolutionary stem cell biology). The oral mucosa and its stem cells are an exciting model system to explore the characteristics of quiescent stem cells that have eluded biologists for decades.

Fig. 1

Organizational shift in squamous epithelia of small short-lived (mouse) to long-lived mammals (human): the establishment of a quiescent basal cell layer overlaid by a proliferative parabasal cell layer

Fig. 2

Model how catastrophic events such as cytotoxic treatments trigger the activation of the quiescent stem cell layer similar to observations made in mouse colon and the HSC system

Fig. 3

Expression of cell cycle regulators, proliferation markers and CDK inhibitors in human squamous epithelia. Images courtesy of The Human Protein Atlas available from www.proteinatlas.org

Fig. 4

The potential role of DREAM complex components in oral stem cell quiescence. On the basis of the data on the DREAM complex, the hypothesis can be stated that the core components of the G0-maintaining and -inducing DREAM complex, such as RBL2 and E2F4 are expressed in the quiescent basal cell layer of the oral mucosa. However, currently there are no data supporting this hypothesis. However, RB1 and the machinery that phosphorylates RB1 are present in para- and suprabasal cells but absent in the basal cells (see also Fig. 3). On the other hand, MYBL2 may be expressed broadly in the squamous epithelium of the esophagus but with a tendency to higher expression in basal cells, an expression pattern that does not fit the proliferative state of the cells

Fig. 5

Model of mTOR signaling in the oral mucosa based on expression data of key targets of mTOR activity (S6K1/2, RPS6, EIF4B, TFE3, EIF4E, EIF4G) and putative regulators of mTOR (DEPTOR, PML, DDIT3). Therefore, the cell layers with the highest mTOR activity may be parabasal and especially suprabasal differentiated cells. Some expression data for these proteins are summarized in the Supplementary Fig. S2

Fig. 6

Defining markers of quiescent stem cells. a Comparison of three datasets representing analyses of basal cells of squamous epithelia (human esophagus: Owen et al., mouse oral mucosa: Jones et al., human squamous epithelia ANDL/HPA.) The majority of genes in each dataset shows no overlap with the other two datasets. b Similarly, when comparing datasets on human epidermal stem cells, there is little overlap between publications (WATT;^, KAUR; MATIC)