Self-renewing tissues like the mammalian epidermis and its appendages go through cycles of proliferation, terminal differentiation and apoptosis. To maintain tissue integrity and stem cell (SC) function, these diverse processes need to sustain constant environmental assaults, including UV radiation. In the mammalian epidermis, multiple SC compartments have been identified, including SCs in the basal layer of the interfollicular epidermis and the hair follicle bulge. Bulge SCs are the primary cellular source for hair follicle renewal. Previous work has shown that bulge SCs are equipped with specific surveillance mechanisms protecting them against accumulation of DNA damage and unwanted cell loss to maintain tissue integrity and HF regeneration throughout lifetime. Importantly, protection of hair follicle SCs against DNA damage-induced apoptosis was shown to correlate with high levels of the anti-apoptotic protein Bcl-2 in bulge SCs. Here we show that suprabasal bulge SCs (CD34+/Itg6Low), located between the old and the new hair follicle, are particularly dependent on Bcl-2 mediated protection. Thus, revealing heterogeneity in the control of bulge SC survival which is required to maintain hair follicle regeneration. Our data suggest that loss of cell-matrix adhesion in suprabasal bulge SCs correlates with an increased pro-apoptotic signature, rendering suprabasal bulge SCs more prone to apoptosis and therefore more dependent on Bcl-2 mediated protection. Bcl-2 is also known as a potent proto-oncogene associated with different types of cancer. Using our previously established mutant Lef1 mouse model for oncogenic stress and SC-driven tumorigenesis we could show that Bcl-2 expression is reduced in the SC compartment but highly expressed in the tumors. Moreover, overexpression of Bcl-2 in mutant Lef1 mice resulted in an increase of tumor incidence and frequency, suggesting survival and selection of Bcl-2 expressing SCs as cells of origin for tumor formation. In summary our data reveal a dual role for Bcl-2 for epidermal regeneration and cancer. During HF regeneration, Bcl-2 is selectively protecting suprabasal bulge SCs from apoptosis while upon oncogenic stress, Bcl-2 is preventing cell death of potential tumor-inducing SCs, thereby promoting tumor formation.

The dual role of stem cell-specific Bcl-2 function for epidermal regeneration and cancer