Role of Krox20 Transcription Factor and Krox20+ Stem Cells in Epithelial Tissue Development and Homeostasis

Abstract

Resident stem cells (SCs) within tissues are important for normal homeostasis maintenance and wound repair. This is mediated by the ability of SCs to properly self-renew, maintain their identity, and differentiate. Epidermal SCs occupy exclusive niches, priming them for giving rise to specific portions of the of the interfollicular epidermis (IFE) and hair follicle (HF). During homeostasis, the bulge SCs generate the lower portion of the HF, while isthmus, junctional zone, and infundibular SCs give rise to the upper HF and IFE. Beyond their unique cell fate, these cells are also capable of generating other portions of the epidermis, but only during pathological conditions (e.g., wounding). In this study, we report a newly identified infundibular SCs, marked by transcription factor Krox20. While Krox20-expessing cells are limited to the infundibular niche, lineage tracing analysis shows that these cells differentiate to generate both the entire HF and the IFE during homeostasis. Notably, previously identified epidermal SCs are derived and continually replenished from Krox20 lineage cells. The ablation of K14-derived Krox20-expressing cells results in deformed HF structure and the lack of a hair shaft, as well as abnormal differentiation and stratification of the IFE. Taken together, these results highlight Krox20-expressing cells as epidermal SCs, crucial for HF and IFE homeostasis and maintenance. Notably, this study represents the first description of a SC population which give rise to both the HF and the IFE during homeostasis, representing a paradigm shift in the current understanding of epidermal SCs differentiation. To evaluate the role of the Krox20 protein in these cells, we ablated Krox20 expression in K14-derived epithelial cells, and found that this resulted in spontaneous hair loss, correlated with aberrant HF structure and epidermal differentiation. Interestingly, these mice also serendipitously developed squamous metaplasia of the ocular surface, resulting from the loss of Meibomian glands (MGs). Expression analyses showed that Krox20-expressing cells constitute stem/progenitor cells that are restricted to the ductal region of the MG, but differentiate to give rise to the entire MG structure. Overall, this study identifies Krox20 as a marker of resident SCs that are essential to continually replenish epithelial-derived tissues (e.g., the epidermis and the MG), with Krox20 expression playing an important role in the function of these cells