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When stem cells from the hair follicle and infundibulum are recruited to the IFE upon injury, they progressively lose their initial identity and are reprogrammed to an IFE fate³⁴. The molecular mechanisms responsible for this plasticity are still incompletely understood. In a comparison of chromatin landscapes of injured IFE and homeostatic HFSCs and IFESCs, the wounded IFE exhibited a hybrid signature between HFSCs and IFESCs, in which the open chromatin regions were enriched for both IFESC (Klf5) and HFSC (Sox9) transcription factors¹². This hybrid stage called ‘lineage infidelity’ seems to ensure proper re-establishment of the epidermal barrier¹². Although this hybrid state is transient during repair, it persists in skin cancer^12, 69.

Differentiated suprabasal epidermal cells are able to revert back to a stem cell state upon wounding^70, 71, a phenomenon also observed in airway epithelium after lineage ablation of basal stem cells⁷². However, lineage tracing and photolabelling of suprabasal IFE cells demonstrated that these cells cannot adopt a basal state again under wound healing conditions^9,10. Contrastingly, a population of Gata6-expressing cells residing in the isthmus, which during homeostatic conditions give rise to the sebaceous duct, can be mobilized during wound healing to migrate toward the injured IFE and revert from a differentiated to a basal stem cell fate⁵⁰. This reversion does not occur immediately after injury, as the suprabasal cells require a few days to access the basal layer and undergo stem cell reprograming⁵⁰. This intriguing observation raises the question of whether other differentiated epidermal cells are also able to revert back to a stem cell state or whether this is a unique property of the Gata6-expressing population. It is possible that the timing of reversion is important and that experiments performed on the tail and ear epidermis induced the labelling of the suprabasal cells too early to observe the reversion^9, 10. Further experiments will be necessary to identify the mechanisms underlying this cellular plasticity and reprogramming of differentiated cells during wound healing. Other cases of dedifferentiation have been previously described in the hair follicle^73, 74. After depilation or laser ablation to induce the loss of bulge HFSCs, hair germ cells⁷³ as well as infundibulum or sebaceous gland cells⁷⁴ are able to repopulate the stem cell niche and establish functional HFSCs. Similarly to skin, cells in the gut epithelium that are committed to terminal differentiation can revert back to a progenitor-like state and contribute to tissue repair following injury^75–77. However, intestinal stem cells are required to ensure tissue repair following ionizing radiation⁷⁸, demonstrating that despite the ability of committed cells to re-assume stemness, regular tissue resident stem cells are essential for repair.

The degree of damage can also influence cellular plasticity. In relatively small wounds, re-epithelialization occurs without reforming hair follicles, whereas de novo hair follicle formation is apparent in large wounds⁸. Lineage tracing confirmed that these de novo hair follicles do not originate from HFSCs but IFE cells⁸. Analogous to hair follicle morphogenesis during embryonic development^79–81, WIHN depends on Wnt signalling as overexpression of Dickkopf Wnt signalling pathway inhibitor 1 (Dkk1), or β-catenin deletion in IFE basal cells prevents de novo hair follicle regeneration⁸. Epidermal deletion of Wntless, a gene required for the secretion of Wnt ligands, suppresses WIHN, suggesting that keratinocyte-derived Wnt is essential⁸². Different mouse strains have different susceptibilities to WIHN^83, 84. Toll like receptor 3 (Tlr3) is increased in mouse strains with enhanced WIHN and dsRNA is a key signal that triggers skin regeneration through Tlr3⁸⁴. Msh homeobox 2 (Msx2) is also crucial for WIHN⁸⁵. Fibroblast growth factor 9 (Fgf9), secreted by γδ T cells, triggers Wnt expression by wound-induced fibroblasts, further amplifying the Wnt signal required for WIHN. These data illustrate the importance of a crosstalk between immune cells, fibroblasts and keratinocytes to enable successful WIHN⁸⁶.

Plasticity upon wound healing is also observed in other skin lineages. In the dermis, myofibroblasts, located close to de novo formed hair follicles, are converted into adipocytes in large wounds⁸⁷. This cell fate conversion depends on BMP signalling originating from newly formed hair follicles that activate the expression of Zfp423, a transcription factor regulating adipocyte development⁸⁷. Cell plasticity has also been described in other epithelia, such as the mammary gland, lung and intestinal epithelium⁸⁸. It will be important to define whether generic mechanisms conserved across different tissues and species control cellular plasticity after lineage ablation and during tissue repair, inflammation or tumorigenesis.