A time to heal: microRNA and circadian dynamics in cutaneous wound repair

Abstract

Many biological systems have evolved circadian rhythms based on the daily cycles of daylight and darkness on Earth. Such rhythms are synchronised or entrained to 24-h cycles, predominantly by light, and disruption of the normal circadian rhythms has been linked to elevation of multiple health risks. The skin serves as a protective barrier to prevent microbial infection and maintain homoeostasis of the underlying tissue and the whole organism. However, in chronic non-healing wounds such as diabetic foot ulcers (DFUs), pressure sores, venous and arterial ulcers, a variety of factors conspire to prevent wound repair. On the other hand, keloids and hypertrophic scars arise from overactive repair mechanisms that fail to cease in a timely fashion, leading to excessive production of extracellular matrix (ECM) components such as such as collagen. Recent years have seen huge increases in our understanding of the functions of microRNAs (miRNAs) in wound repair. Concomitantly, there has been growing recognition of miRNA roles in circadian processes, either as regulators or targets of clock activity or direct responders to external circadian stimuli. In addition, miRNAs are now known to function as intercellular signalling mediators through extracellular vesicles (EVs). In this review, we explore the intersection of mechanisms by which circadian and miRNA responses interact with each other in relation to wound repair in the skin, using keratinocytes, macrophages and fibroblasts as exemplars. We highlight areas for further investigation to support the development of translational insights to support circadian medicine in the context of these cells.

The Cardiac Circadian Clock

“…A detailed review of the function of all these cell type–specific clocks is beyond the scope of this paper; the reader is instead referred to relatively recent published literature. 23 , 44 , 47 , 48 , 49 Here, we provide detail regarding how cell- and animal-based studies, in combination with state-of-the-art hypothesis-testing and hypothesis-generating strategies, have yielded considerable insight into the physiologic role of the cardiomyocyte circadian clock.…”

Potential effects of shift work on skin autoimmune diseases

“…Previous studies showed a sleep-wake cycle-dependent hematopoietic release of granulocytes and monocytes and subsequent traffic of these cells to various tissues (110,(354)(355)(356). Although rhythmic leukocyte homing to skin seems to be neglectable in the steady state (355), indirect evidence indicates that there is a circadian regulation of immune cell traffic to the skin upon wounding and upon microbial or antigenic challenges (357)(358)(359)(360)(361)(362). Likewise, tissue-resident innate immune cells like dendritic cells (363,364), mast cells (317,365,366) or macrophages (367)(368)(369) show circadian regulation that impacts cutaneous responses to antigens and allergens, respectively.…”

Current Perspective on the Role of the Circadian Clock and Extracellular Matrix in Chronic Lung Diseases

“…A potential ECM modulator is the circadian clock. Regulation of the ECM components by circadian clock genes and related processes have been demonstrated in various tissues including the nervous, squamous epithelium, connective/cartilage, liver, kidney, and cardiac muscle [41][42][43][44][45][46][47][48][49][50]. Circadian regulation of the ECM has been minimally studied in the lung, but analyzing similar processes and structures in different tissues could be a starting point for future investigations.…”

“…Furthermore, recent findings suggest that EVs and the protein cargo they carry may be circadian-regulated [51,52]. In the squamous epithelium, recent evidence suggests that microRNAs function as intercellular communicators for wound repair processes through transportation via extracellular vesicles [43]. Although various tissues throughout the body differ functionally, many molecular and intercellular processes are maintained universally.…”