Deciphering cell-autonomous and non-autonomous mechanisms of cell death function in skin regeneration

• Applicant: Privatdozentin Dr. Catherin Niemann
• Subject Area: Dermatology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 507956072

The balance between proliferation, differentiation and cell death shapes organ development and is crucial for tissue function and homeostasis throughout life. In mammalian skin, regulated cell death constitutes not only an important cellular response mechanism preventing tissue damage by environmental challenges and injury, but also plays a fundamental role during tissue remodelling, e.g. the hair regeneration cycle. In particular, the regression phase (catagen) of the hair follicle (HF) regeneration cycle strictly depends on coordinated cell death modalities. Previous work, including our own data, indicate that cell death is important for controlling the size and composition of the HF bulge stem cell (SC) compartment. This is of particular relevance, given that SCs not only drive epithelial regeneration and repair, they have also been identified as cell-of-origin for different types of skin cancer and thus have a tremendous impact on the initiation and progression of skin diseases. In this context, our work recently identified the anti-apoptotic factor Bcl-2 as a main mediator protecting a subpopulation of HF SCs against premature cell loss. Further, we showed that SC-specific Bcl-2 expression governs the process of tumour initiation in vivo.This proposal aims to mechanistically dissect cell-autonomous and cell-non-autonomous cell death functions driving the complex process of tissue regeneration during the hair cycle and tissue repair. To this end, we have generated a mouse model overexpressing Bcl-2 within the skin epithelium (Bcl-2EOE mice) and demonstrated a Bcl-2-dependent highly specific block of cell death during catagen. Remarkably, mice protected from catagen-related cell death still show HF retraction. However, elevated keratinocyte survival results in an enlargement of the HF bulge consisting of a heterogenous SC pool. Worth mentioning, Bcl-2EOE mice show major defects in the hair regeneration cycle and tissue architecture. Based on our data, we will specifically address the following questions: Which HF cell population is normally undergoing cell death during catagen and thus is surviving in Bcl-2EOE mice? How does the composition of the SC bulge compartment mechanistically accommodate hair growth? Given that bulge SC are the main cellular source feeding into tissue repair, we will address whether changes in the bulge SC composition impair wound healing responses and tissue repair mechanisms. Using Bcl-2EOE, we will find out how catagen-related cell death impacts on the molecular crosstalk between dying keratinocytes and the surrounding fibroblasts, immune and fat cells and elucidate what the consequences of blocked keratinocyte death for tissue remodelling are. Our systematic analysis will lead to a better understanding of the mechanistic underpinnings of cell death modalities required for normal tissue homeostasis, maintenance, regeneration and repair.

• DFG Programme: Research Grants