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The Roles of the Lrig1- and Lgr6-Positive Stem Cells in the Skin and the Functions of the Molecular Markers That Define Them

  • Author(s): Huang, Yaohui Phillips
  • Advisor(s): Klein, Ophir
  • et al.
Abstract

The adult mouse skin is made up of many separate cell compartments, each of which contains its own resident stem cell population(s) that acts to maintain it. The hair follicle, in particular, is a rich vein of stem cells - several distinct populations, with different lineage potentials, reside there and these have to communicate with one another to coordinate their actions during normal homeostasis and in times of tissue regeneration.

In this dissertation, I describe the roles of two different stem cell populations in the hair follicle, and the functions of molecular markers that define them. First, Lrig1 is a marker of stem cells in the junctional zone of the hair follicle. By gene expression network analysis of normal mouse skin, we placed Lrig1 within a network, including Krt79 and Efnb2, involved in homeostasis of the hair follicle infundibulum. Lineage tracing showed that Lrig1-positive cells maintain a discrete infundibulum cell compartment, and that single cells from this compartment migrate into the epidermis during normal homeostasis and also downward in anagen follicles. This process is accelerated by treatment with 12-O-tetradecanoylphorbol-13-acetate, which stimulates both epidermal proliferation and follicle growth. Activation of mutant Hras or Kras in Lrig1-positive cells leads to distinct phenotypes - the former leads to wavy hair while the latter gives rise to oily skin. Both Hras and Kras activation can cause wound-dependent papilloma development, but Lrig1-positive cells are not common cells-of-origin of chemically induced tumours. Rather than acting as a stem cell reservoir, we propose that Lrig1-positive cells may play a facilitating role during tissue regeneration and tumour development.

Second, Lgr6 marks stem cells in the central isthmus of the hair follicle just above the bulge. By expression analysis of a panel of skin cell lines, we demonstrate that Lgr6, and not Lgr5, is a cutaneous squamous cancer stem cell marker. In vitro knockdown of Lgr6 in squamous tumour cell lines leads to increased growth, while in vivo Lgr6 knockdown causes elevated proliferation in the epidermis along with increased epidermal lineage tracing from the Lgr6-positive stem cells. Finally, Lgr6 deficiency results in reduced latency to papilloma development during skin chemical carcinogenesis. We propose that Lgr6 positively regulates Wnt signalling in epidermal cells and acts to restrain commitment of skin stem cell towards the epidermal lineage during normal homeostasis and tumour development.

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