Merkel cells and Merkel cell carcinoma
The skin epithelium is an essential barrier that protects the body from the environment, helps to maintain temperature and keep water within the body, and performs sensory functions. These activities are largely provided by the epidermis, hair follicles, and specialized cells, including Merkel cells, which respectively serve protective barrier functions, provide thermoprotection, and are involved in mechanosensation. These mechanosensory cells are innervated by afferent neurons and are responsible for the tactile discrimination of the shape and texture of objects. Functional studies in mutant mice, in which Merkel cells were not formed, have demonstrated that the animals were unable to discriminate between different textures when performing behavioral tasks.
Specification of Merkel cells during development
Most of our knowledge about Merkel cells comes from studies focused on the murine back skin, where these cells are found in specialized structures called touch domes which are located exclusively around primary hair follicles (Figure 1). Recently, we discovered that a subset of SOX9 expressing cells located inside of developing hair follicles are Merkel cell progenitors that give rise to Merkel cells at embryonic day (E) 14.5. We also found that fibroblast growth factor receptor 2 (FGFR2) plays an essential function in Merkel cell specification in the back skin, as loss of Fgfr2 leads to drastic decreases in the number of Merkel cells. While the specification of Merkel cells during embryogenesis is well studied, how these cells were maintained and regenerated in adulthood are still largely understudied.
In the lab, we sought to determine whether Merkel cells are renewable during mouse lifespan. We aim to uncover which cell populations contribute to Merkel cells regeneration and also which factors affect this process during normal homeostasis and upon wound healing.
Merkel cell carcinoma (MCC)
Merkel cell carcinoma (MCC) is one of the most aggressive and deadly forms of skin cancer. Although MCC tumors are rare, their incidence has tripled in recent years. Current MCC treatments involve surgery and chemotherapy, but the response to these treatments is poor with a 12-month patient survival rate of only 20%. The development of novel therapeutic strategies for the treatment of MCC is thus critical, but it is hampered by the lack of an effective in vivo model for MCC.
Human genomic studies have shown that more than 80% of MCC tumors contain DNA from the Merkel cell polyomavirus (MCV). In vitro studies show that the expression of MCV’s small T antigen (sT-Ag) leads to the transformation of human cells, whereas ablation of sT-Ag from MCC cell lines inhibits their proliferation. MCV also expresses a large T antigen (LT-Ag), the function and necessity of which remains a topic of debate. However, testing the in vivo relevance of MCV oncogenes for MCC formation has proven difficult. While Merkel cells have been shown to originate from embryonic epidermal stem cells, the expression of MCV oncogenes in these cells results in squamous cell carcinoma rather than MCC. Although this confirms the tumorigenic potential of MCV oncogenes, it also demonstrates that this cell population is not competent to produce MCC.
There has been debate as to whether all epidermal progenitors can give rise to Merkel cells or if there is a specific population of cells called Merkel cell progenitors with this potential. We aim to dissect the developmental program controlling Merkel cell formation and identify these progenitor populations. Uncovering these mechanisms is of major importance not only for the characterization of the Merkel cell lineage, but also for testing the potential of these cells to form MCC when targeted with MCV oncogenes in vivo.