How and Why the Circadian Clock Regulates Proliferation of Adult Epithelial Stem Cells

Abstract

First described in the early 20 th century, diurnal oscillations in stem cell proliferation exist in multiple internal epithelia, including in the gastrointestinal track, and in the epidermis. In the mouse epidermis, 3- to 4-fold more stem cells are in S-phase during the night than during the day. Work that is more recent showed that an intact circadian clock intrinsic to keratinocytes is required for these oscillations in epidermal stem cell proliferation. The circadian clock also regulates DNA excision repair and DNA-damage in epidermal stem cells in response to ultraviolet B radiation. During skin inflammation, epidermal stem cell proliferation is increased and diurnal oscillations are suspended. Here we discuss possible reasons for the evolution of this stem cell phenomenon. We argue that the circadian clock coordinates intermediary metabolism and the cell cycle in epidermal stem cells to minimize accumulation of DNA damage from metabolism-generated reactive oxygen species. Circadian disruption, common in modern society, leads to asynchrony between metabolism and the cell cycle, and we speculate this will lead to oxidative DNA damage, dysfunction of epidermal stem cells, and skin aging.

Keratinocytes Exposed to Blue or Red Light: Proteomic Characterization Showed Cytoplasmic Thioredoxin Reductase 1 and Aldo-Keto Reductase Family 1 Member C3 Triggered Expression

“…In these cells, G 2 /M cell cycle arrest was induced, and the apoptotic rate increased. At the same time, high-irradiance blue light decreased the expression levels of the BMAL1 and PER2 clock genes in the HaCaT cells, suggesting a circadian rhythm dysregulation [34][35][36]. High-irradiance red light did not induce cell death and did not alter the clock gene expression levels.…”

“Time Is out of Joint” in Pluripotent Stem Cells: How and Why

“…Studies in recent years have revealed the essential role for biological clocks in regulating stem cell circadian homeostasis [4][5][6][7][8][9]. Importantly, although a molecular circadian clock resides in almost all cells in in vivo and in vitro cultures, cells such as germline, zygote, and pluripotent stem cells (PSCs) show no discernible circadian rhythms of clock gene expression [10][11][12].…”

Interplay of Light, Melatonin, and Circadian Genes in Skin Pigmentation Regulation

“…The skin can transmit light information to directly impact the circadian rhythm and proliferation of the epidermis. Light generally decreases proliferation: Light decreases epidermal stem cell numbers in S-phase of the cell cycle during the day compared to the night [10], reduces proliferation of cultured human melanocytes [11,12], and inhibits proliferation of pigmented cells in fish [13]. Opsins such as Opn3, Opn4 (Melanopsin), and Opn5 function as light sensors in mammalian pigment cells to regulate both pigment synthesis/intracellular movement [4,5,6] and melanocyte proliferation [14,15].…”