Ontogeny of Skin Stem Cells and Molecular Underpinnings

Abstract

Skin stem cells (SCs) play a pivotal role in supporting tissue homeostasis. Several types of SCs are responsible for maintaining and regenerating skin tissue. These include bulge SCs and others residing in the interfollicular epidermis, infundibulum, isthmus, sebaceous glands, and sweat glands. The emergence of skin SCs commences during embryogenesis, where multipotent SCs arise from various precursor populations. These early events set the foundation for the diverse pool of SCs that will reside in the adult skin, ready to respond to tissue repair and regeneration demands. A network of molecular cues regulates skin SC behavior, balancing quiescence, self-renewal, and differentiation. The disruption of this delicate equilibrium can lead to SC exhaustion, impaired wound healing, and pathological conditions such as skin cancer. The present review explores the intricate mechanisms governing the development, activation, and differentiation of skin SCs, shedding light on the molecular signaling pathways that drive their fate decisions and skin homeostasis. Unraveling the complexities of these molecular drivers not only enhances our fundamental knowledge of skin biology but also holds promise for developing novel strategies to modulate skin SC fate for regenerative medicine applications, ultimately benefiting patients with skin disorders and injuries.

Keywords: epidermis; hair follicle; homeostasis; molecular cues; ontogeny; sebaceous glands; signaling; skin; stem cells; sweat glands.

Figure 1

Molecular cues orchestrating the maintenance, proliferation, and differentiation of interfollicular epidermal stem cells (IFESCs). IFESCs are located in the basal layer of the epidermis. Created with BioRender.com.

Figure 2

Molecular regulators governing the transition between quiescence and the activation of hair follicle stem cells (HFSCs). Specifically, green-colored signals activate HFSCs, whereas red-colored cues preserve HFSC quiescence. HFSCs include bulge SCs (green cells) as well as hair germ SCs (orange cells). Created with BioRender.com.

Figure 3

Molecular cues governing the differentiation of sebaceous gland stem cells (SGSCs). Green-colored signals guide SGSC fate towards differentiated sebaceous gland cells, while red-colored signals hinder sebaceous gland generation. The molecular mechanisms responsible for regulating the properties of stem cells located in the infundibulum and isthmus regions have yet to be fully elucidated. Created with BioRender.com.

Figure 4

Molecular identity and regulators of sweat gland stem cells (SwGSCs). Green-colored signals guide SCs towards differentiated sweat gland cells, while red-colored signals hinder sweat gland formation. Epidermal SCs, located proximal to the sweat duct, exhibit high levels of K14. Basal SCs, located along the SwD, express α6-integrin. Luminal SCs are characterized by the markers K19, K18, K15, and CD29. Myoepithelial SCs are identified by K14 and K5. Other populations of SwGSCs include those expressing LGR5, LGR6, BMP1, and NESTIN. Created with BioRender.com.