DEFINING HUMAN SKIN: MECHANISMS OF EPIDERMAL RETE RIDGES, APICAL RIDGES, AND THERMOREGULATION

Sean Thompson

Human skin has long been appreciated through an evolutionary lens for its loss of fur, characterized by a reduction in hair follicles, alongside the acquisition of additional specialized mini-organs, like sweat glands, rete ridges, and fingerprint ridges. However, during skin aging, disease, or wound healing, these mini-organs can become disrupted or even entirely lost. Commonly referred to as epidermal appendages, these mini-organs form from the outermost layer of skin, the epidermis, during development and collectively contribute to many essential functions of human skin, such as enabling a thick epidermal barrier, supporting cutaneous thermoregulation, and establishing unique skin surface texture patterns. First, we unraveled the evolutionary developmental phenomena and molecular mechanisms supporting rete ridge formation in human and human-like skin. Using a combination of comparative developmental approaches, single-cell and spatial transcriptomics, and functional in vivo validation of essential mechanisms underlying rete ridge formation, we determined that rete ridges are a distinct type of epidermal appendage that forms an interconnected, three-dimensional structural architecture along the basal epidermis. Furthermore, rete ridges evolved in the body skin of animals with reduced hair density and support a thicker, armor-like epidermis. Furthermore, we characterized human-like rete ridge development in pig skin and mouse fingerpads of mice, enabling future studies to more tractably probe mechanisms of rete ridge development and disease than is possible with humans. Using these models, we demonstrated rete ridges form through a distinct molecular mechanism from other epidermal appendages, requiring broad epidermal BMP signaling but not LEF1/WNT nor EDA/EDAR signaling. Additionally, we implicate a vascularized dermal niche, which we named the dermal pocket, and demonstrate that epidermal-dermal signaling is also required for rete ridge formation. Next, we uncover evolutionary and functional relationships between hair coverage in mice and North American grizzly bears which demonstrated that the primary function of hair coverage is to inhibit heat dissipation through skin. We further characterize porcine cutaneous heat dissipation during neonatal nursing behavior and during regenerative neonatal wound healing, with human-relevant implications for skin’s thermoregulatory functions during homeostatic or wound healing conditions. Finally, we characterize apical ridges, the main structural feature in body skin of humans and other terrestrial mammals which endows skin with its surface texture. We demonstrate that apical ridges are influenced by, but do not absolutely require, epidermal LEF1/WNT and EDA/EDAR signaling, begin forming prior to hair follicles and other epidermal appendages, and exhibit regional nuances between body, palmoplantar, and digital skin in humans and other mammals. In digital skin, LEF1/WNT and BMP signaling regulate apical ridge or transverse ridge (volar apical ridge-like topographic features) size. Critically, we demonstrate that disrupting epidermal differentiation flattens apical ridges, suggesting that a combination of multiple epidermal-dermal signaling and cellular processes may combine during the formation of skin topography. Collectively, this body of work illuminates several distinct yet defining aspects of human skin anatomy and function which have been critically understudied or overlooked in recent decades. The evolutionary, developmental, and functional insights generated by these studies will improve biomedical research models, from animal models to skin organoids, and will also inform clinical and therapeutic efforts to improve human skin health and maintenance during disease, aging, and regenerative wound repair.

DEFINING HUMAN SKIN: MECHANISMS OF EPIDERMAL RETE RIDGES, APICAL RIDGES, AND THERMOREGULATION

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