Summary: Maintenance of adult tissues depends on sustained activity of resident stem cell populations, yet the mechanisms that regulate stem cell self-renewal during homeostasis remain largely unknown. Using an imaging and tracking approach that captures all epidermal stem cell activity in large regions of living mice, we show that self-renewal is locally coordinated with epidermal differentiation, with a lag time of one to two days. In both homeostasis and upon experimental perturbation, we find that differentiation of a single stem cell is followed by division of a direct neighbor, but not vice versa. Finally, we show that exit from the stem cell compartment is sufficient to drive neighboring stem cell self-renewal. Together, these findings establish that epidermal stem cell self-renewal is not the constitutive driver of homeostasis. Instead it is precisely tuned to tissue demand and responds directly to neighbor cell differentiation.

Cells in healthy tissues acquire mutations with surprising frequency. Many of these mutations are associated with abnormal cellular behaviours such as differentiation defects and hyperproliferation, yet fail to produce macroscopically detectable phenotypes1–3. It is currently unclear how the tissue remains phenotypically normal, despite the presence of these mutant cells. Here we use intravital imaging to track the fate of mouse skin epithelium burdened with varying numbers of activated Wnt/β-catenin stem cells. We show that all resulting growths that deform the skin tissue architecture regress, irrespective of their size. Wild-type cells are required for the active elimination of mutant cells from the tissue, while utilizing both endogenous and ectopic cellular behaviours to dismantle the aberrant structures. After regression, the remaining structures are either completely eliminated or converted into functional skin appendages in a niche-dependent manner. Furthermore, tissue aberrancies generated from oncogenic Hras, and even mutation-independent deformations to the tissue, can also be corrected, indicating that this tolerance phenomenon reflects a conserved principle in the skin. This study reveals an unanticipated plasticity of the adult skin epithelium when faced with mutational and non-mutational insult, and elucidates the dynamic cellular behaviours used for its return to a homeostatic state.

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Adult stem cells across diverse organs self-renew and differentiate to maintain tissue homeostasis. How stem cells receive input to preserve tissue structure and function largely relies on their communication with surrounding cellular and non-cellular elements. As such, how tissues are organized and patterned not only reflects organ function but also inherently hardwires networks of communication between stem cells and their environment to direct tissue homeostasis and injury repair. This review highlights how different methods of stem cell communication reflect the unique organization and function of diverse tissues.

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Mutations associated with tumor development in certain tissues can be nontumorigenic in others, yet the mechanisms underlying these different outcomes remains poorly understood. To address this, we targeted an activating Hras mutation to hair follicle stem cells and discovered that Hras mutant cells outcompete wild-type neighbors yet are integrated into clinically normal skin hair follicles. In contrast, targeting the Hras mutation to the upper noncycling region of the skin epithelium leads to benign outgrowths. Follicular Hras mutant cells autonomously and nonautonomously enhance regeneration, which directs mutant cells into continuous tissue cycling to promote integration rather than aberrancy. This follicular tolerance is maintained under additional challenges that promote tumorigenesis in the epidermis, including aging, injury, and a secondary mutation. Thus, the hair follicle possesses a unique, enhanced capacity to integrate and contain Hras mutant cells within both homeostatic and perturbed tissue, demonstrating that in the skin, multiple, distinct mechanisms exist to suppress oncogenic growth.

The Drosophila ovarian germline stem cells (GSCs) constantly experience self-renewal and differentiation, ensuring the female fertility throughout life. The balance between GSC self-renewal and differentiation is exquisitely regulated by the stem cell niche, the stem cells themselves and systemic factors. Increasing evidence has shown that the GSC regulation also involves epigenetic mechanisms including chromatin remodeling and histone modification. Here, we find that dBre1, an E3 ubiquitin ligase, functions in controlling GSC self-renewal and germ cell differentiation via distinct mechanisms. Removal or knock down of dBre1 function in the germline or somatic niche cell lineage leads to a gradual GSC loss and disruption of H3K4 trimethylation in the Drosophila ovary. Further studies suggest that the defective GSC maintenance is attributable to compromised BMP signaling emitted from the stem cell niche and impaired adhesion of GSCs to their niche. On the other hand, dBre1-RNAi expression in escort cells causes a loss of H3K4 trimethylation and accumulation of spectrosome-containing single germ cells in the germarium. Reducing dpp or dally levels suppresses the germ cell differentiation defects, indicating that dBre1 limits BMP signaling activities for the differentiation control. Strikingly, all phenotypes observed in dBre1 mutant ovaries can be mimicked by RNAi-based reduced expression of dSet1, a Drosophila H3K4 trimethylase. Moreover, genetic studies favor that dBre1 interacts with dSet1 in controlling GSC maintenance and germ cell differentiation. Taken together, we identify a dBre1/dSet1-dependent pathway for the H3K4 methylation involved in the cell fate regulation in the Drosophila ovary.

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