WOUND HEALING: Better understanding of its cellular dynamics

4 distinct cell states in normal skin that change gene expression during healing.
This work by the University of California – Irvine which deciphers the evolution of gene expression and the differentiation trajectories of epidermal cells during the healing of a skin wound. This experimental research, carried out in mice and published in the journal Cell Reports, allows in particular to better understand the delay in healing and the chronicity of wounds in diabetic patients.

The Californian team brings the first complete picture of the main changes that occur in skin cells when they prepare and then start the healing process. This work thus provides new data on the problems of wound healing encountered with various pathological conditions, including diabetes. “This is the first full decryption of the main changes in cellular heterogeneity from cutaneous homeostasis to scarring” explains the main author, Dr Xing Dai, professor of biological chemistry and dermatology at the UCI School of Medicine .

 These 4 transcription states differ in their metabolic preferences and follow a “hierarchical” model during the process of re-epithelialization of the wound.
4 epidermal basal cell states in homeostatic skin

In the event of cutaneous injury, the skin must modify its cellular dynamics to trigger and allow efficient healing and rapid restoration of the protective barrier. We know that wound healing is a precisely regulated process consisting of several distinct overlapping stages (inflammation, re-epithelialization and scar remodeling). These 3 stages require coordinated actions of the different types of cells, epidermal, dermal, immune and endothelial. Re-epithelialization is allowed by the migration and proliferation of epidermal cells at the periphery of the wound. However, there remains an uncertainty on the model of migration of epidermal cells during reepithelialization of the wound: 2 models are discussed:

the basal cells first migrate into the wound bed and convert unidirectionally into suprabasal cells,
the peripheral epidermal cells of the wound crawl so that the suprabasal cells migrate and become basal cells.
Recent imaging studies have already defined distinct areas of epidermal cellular activity in the wound area:

a migratory zone around the banks of the wound where the basal and suprabasal cells move towards the center of the wound;
an intermediate and mixed zone of coordinated migration and proliferation;
a hyperproliferative area- furthest from the edges of the wound.
However, the exact number of distinct transcription states for the epidermal wound cells during healing is unknown. Here, the researchers are sequencing single-cell RNA from normal or injured mouse skin cells and identifying four distinct cell states in normal skin that change gene expression during healing.

4 distinct transcription states are highlighted with this research, in the epidermal basal layer in a homeostasis or stable state of the skin. Using unicellular RNA sequencing techniques coupled with fluorescence imaging, the team identifies 3 non-proliferative basal cell states in homeostatic skin and 1 proliferative state. These 4 states differ in their metabolic preferences and follow a “hierarchical” model during the process of re-epithelialization of the wound, the process by which the skin and mucous membranes replace the damaged superficial epithelial cells in the event of a wound. In addition, these 4 states appear spatially distributed over the surface of the wound.

The identification of these 4 states contributes to a better understanding of specific cell dynamics at the unicellular and tissue scale and the genetics of wound healing. The study provides a comprehensive perspective on epidermal cell dynamics and transition states during homeostasis and healing.

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