Combined Metallomics/Transcriptomics Profiling Reveals a Major Role for Metals in Wound Repair.

Holly N Wilkinson,Barbara-Ann Guinn,Matthew J Hardman

doi:10.3389/fcell.2021.788596

Holly N Wilkinson, Barbara-Ann Guinn + Show 1 more

Open Access

https://doi.org/10.3389/fcell.2021.788596

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Abstract

Endogenous metals are required for all life, orchestrating the action of diverse cellular processes that are crucial for tissue function. The dynamic wound healing response is underpinned by a plethora of such cellular behaviours, occurring in a time-dependent manner. However, the importance of endogenous metals for cutaneous repair remains largely unexplored. Here we combine ICP-MS with tissue-level RNA-sequencing to reveal profound changes in a number of metals, and corresponding metal-regulated genes, across temporal healing in mice. Wound calcium, magnesium, iron, copper and manganese are elevated at 7 days post-wounding, while magnesium, iron, aluminium, manganese and cobalt increase at 14 days post-wounding. At the level of transcription, wound-induced pathways are independently highly enriched for metal-regulated genes, and vice versa. Moreover, specific metals are linked to distinct wound-induced biological processes and converge on key transcriptional regulators in mice and humans. Finally, we reveal a potential role for one newly identified transcriptional regulator, TNF, in calcium-induced epidermal differentiation. Together, these data highlight potential new and diverse roles for metals in cutaneous wound repair, paving the way for further studies to elucidate the contribution of metals to cellular processes in the repair of skin and other tissues.

Highlights

Skin is the first barrier to noxious environmental onslaught and as such, must be repaired quickly and efficiently when damaged
We show for the first time that temporal alterations in the wound metallome correlate with both metaland injury-linked transcriptional changes across normal murine skin repair
Tissue concentrations of eight skin-relevant metal elements were compared between unwounded skin (D0) and wounds at days 1, 3, 7 and 14 (D1, D3, D7 and D14) postwounding (PW; Figure 1; absolute values provided in Supplementary Table S2)

Summary

Introduction

Skin is the first barrier to noxious environmental onslaught and as such, must be repaired quickly and efficiently when damaged. This wound healing process involves a cascade of cellular signalling events that actuate functional responses to confer tissue repair (Wilkinson and Hardman, 2020). These events are grouped into characteristic wound healing stages (haemostasis, inflammation, proliferation and extracellular matrix remodelling) that are tightly controlled but remain highly dynamic and often overlap (Greaves et al, 2013).

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