Enhance wound healing in oral epithelia

Oral epithelia display a remarkable capacity for renewal and regeneration. They turnover roughly twice as rapidly as the epidermis, and heal more quickly than skin, and without scarring. Yet little is known about the stem cells that maintain the oral epithelia, where they reside, and how they respond to injury. In the epidermis, conflicting views have emerged of how stem cells are functionally organized. In one model, the epidermis is thought to be maintained by a homogenous pool of equipotent “committed progenitors.” An alternative view proposes that the epidermis is hierarchically organized, with rare quiescent “reserve” stem cells that respond primarily to injury and “active” stem cells that maintain the epidermis during homeostasis. There is also strong evidence that populations of cells located within the junctional zone of the hair follicle also populate the epidermis during wound repair. However, the differences in both proliferative and regenerative capacity between epidermis and oral epithelia suggest that different stratified epithelia may be maintained by stem cells with quite different properties.

Oral Stem Cells

Division orientation and oral stem cells

Regardless of the model, there does seem to be agreement that in most regions of the epidermis, the perpendicular divisions that are common during development seem to be exceptionally rare in the adult. However, many planar divisions appear to be operationally asymmetric, as live-imaging has revealed that one daughter cell frequently delaminates and differentiates following division. These studies suggest that the spindle orientation machinery may operate differently during homeostasis than during development. While we know that LGN-dependent oriented cell divisions play important and diverse roles during oral epithelial development (Byrd et al, Development 2016), much less is known about division orientation in adult tissues.

Characterizing oral stem cells

Reserve stem cells are more quiescent than active stem cells. Thus, differences in proliferation rates can be used to identify so-called “label-retaining cells” which cycle infrequently. To determine whether proliferative heterogeneity exists within the oral epithelia, we have adopted an unbiased genetic-label retention strategy developed by the Tumbar lab (Tumbar lab @ Cornell) [need Figure of TRE-H2B-GFP system, which I can provide]. We have found that many regions of oral epithelia seem to dilute label relatively quickly and uniformly, analogous to dorsal epidermis, while other regions, including dorsal tongue, show pockets of label-retaining cells. Most interesting to us, however, is the hard palate region. The hard palate contains a unique topology that seems ideally suited to harbor stem cell niches. It contains numerous large ridges called rugae, and within these rugae are embedded smaller folds of tissue called rete ridges. Our label-retention experiments have shown that more quiescent cells—we term them “infrequently dividing cells” or IDCs—reside in distinct regions between rugae, often at the base of rete ridges. Interestingly, in the adult palate, in contrast to adult epidermis, perpendicular divisions are frequent. Moreover, while FDCs expand predominantly through perpendicular asymmetric divisions, IDCs more often divide symmetrically.

 

Ongoing questions being addressed in current studies include:

How do IDCs and FDCs respond to injury?

Does the mechanical stress on palatal epithelium caused by mastication influence cell turnover rates?

What are the transcriptional profiles associated with IDCs and FDCs and how do these compare to other stratified epithelial stem cell populations?

What happens to palatal stem cells if we disrupt their niche?