Wound-Induced Hair Follicle Neogenesis as a Promising Approach for Hair Regeneration.

The mammalian skin contains hair follicles, which are epidermal appendages that undergo periodic cycles and exhibit mini-organ features, such as discrete stem cell compartments and different cellular components. Wound-induced hair follicle neogenesis (WIHN) is the remarkable ability to regenerate hair follicles after large-scale wounding and occurs in several adult mammals. WIHN is comparable to embryonic hair follicle development in its processes. Researchers are beginning to identify the stem cells that, in response to wounding, develop into neogenic hair follicles, as well as to understand the functions of immune cells, mesenchymal cells, and several signaling pathways that are essential for this process. WIHN represents a promising therapeutic approach to the reprogramming of cellular states for promoting hair follicle regeneration and preventing scar formation. In the scope of this review, we investigate the contribution of several cell types and molecular mechanisms to WIHN.

Cell Population Dynamics in Wound-Induced Hair Follicle Neogenesis Model.

Hair follicle (HF) regeneration can be achieved in the center of large full-thickness wounds on mouse backs (wound-induced HF neogenesis model, WIHN). Investigations with this model have allowed for the identification of some of the factors limiting the extent of fibrosis, which creates a permissive environment for the reposition of HF. For WIHN, specific subpopulations of cells rather than cell types are permissive to this process. Detailed information on the cellular composition in WIHN is not available. Here, we provide a description of changes in cell numbers of fibroblasts, HF dermal papilla, endothelial cells, keratinocytes (interfollicular epidermis, HF-infundibulum, HF-isthmus, HF-bulge (basal and suprabasal), HF-hair germ) and immune cells (macrophages, monocytes, dendritic cells, T cells (CD4+, CD8+, CD4+/CD8+, regulatory T cells) and neutrophils) based on flow cytometric analysis. We compared unwounded skin with large wounds (1.5 × 1.5 cm) at different time points after wounding. We found that non-immune dermal cells have the largest share in the skin at all time points studied, and that the number of epidermal cells started increasing nine days after wounding, which precede isthmus cells and bulge cells, mirroring the development of hair follicles. Monocytes and neutrophils represent most myeloid cells in wounds and remain in wounds even beyond the inflammatory phase of wound healing. Macrophages can be identified as inflammatory and alternative cells and are also found in wounds even in the late remodeling phase of wound healing. Lastly, we provide information about T cells in large wounds. Most T cells in the wounds were CD8+ at all time points and expressed γδTCR, which was previously thought to be expressed mainly on CD4+. We also report the existence of double positive CD4/CD8. Our study provides a guide in terms of time points suitable for the further study of cell subpopulations aiming to dissect the cellular heterogeneity in WIHN. Our results might set the base for the comparison of WIHN between control mice and animals manipulated to influence HF neogenesis and the full understanding of the responsible actors allowing for HF regeneration.

Topological Distribution of Wound Stiffness Modulates Wound-Induced Hair Follicle Neogenesis.

In the large full-thickness mouse skin regeneration model, wound-induced hair neogenesis (WIHN) occurs in the wound center. This implies a spatial regulation of hair regeneration. The role of mechanotransduction during tissue regeneration is poorly understood. Here, we created wounds with equal area but different shapes to understand if perturbing mechanical forces change the area and quantity of de novo hair regeneration. Atomic force microscopy of wound stiffness demonstrated a stiffness gradient across the wound with the wound center softer than the margin. Reducing mechanotransduction signals using FAK or myosin II inhibitors significantly increased WIHN and, conversely, enhancing these signals with an actin stabilizer reduced WIHN. Here, α-SMA was downregulated in FAK inhibitor-treated wounds and lowered wound stiffness. Wound center epithelial cells exhibited a spherical morphology relative to wound margin cells. Differential gene expression analysis of FAK inhibitor-treated wound RNAseq data showed that cytoskeleton-, integrin-, and matrix-associated genes were downregulated, while hair follicular neogenesis, cell proliferation, and cell signaling genes were upregulated. Immunohistochemistry staining showed that FAK inhibition increased pSTAT3 nuclear staining in the regenerative wound center, implying enhanced signaling for hair follicular neogenesis. These findings suggest that controlling wound stiffness modulates tissue regeneration encompassing epithelial competence, tissue patterning, and regeneration during wound healing.

[Wound-induced hair follicle neogenesis: a new perspective on hair follicles regeneration in adult mammals].

OBJECTIVE: To explore the research progress of the cell sources and related signaling pathways of the wound-induced hair follicle neogenesis (WIHN) in recent years. METHODS: The literature related to WIHN in recent years was reviewed, and the cell sources and molecular mechanism were summarized and discussed. RESULTS: Current research shows that WIHN is a rare regeneration phenomenon in the skin of adult mammals, with multiple cell origins, both hair follicle stem cells and epithelial stem cells around the wound. Its molecular mechanism is complicated, which is regulated by many signaling pathways. Besides, the process is closely related to the immune response, the immunocytes and their related cytokines provide suitable conditions for this process. CONCLUSION: There are still many unsolved problems on the cellular origins and molecular mechanisms of the WIHN. Further study on the mechanisms will enhance the understanding of adult mammals' hair follicle regeneration and may provide new strategy for functional healing of the human skin.

Wound Induced Hair Neogenesis - A Novel Paradigm for Studying Regeneration and Aging.

Hair follicles are the signature dermal appendage of mammals. They can be thought of as mini-organs with defined polarity, distinct constituent cell types, dedicated neurovascular supply, and specific stem cell compartments. Strikingly, some mammals show a capacity for adult hair follicle regeneration in a phenomenon known as wound-induced hair neogenesis (WIHN). In WIHN functional hair follicles reemerge during healing of large cutaneous wounds, and they can be counted to provide an index of regeneration. While age-related decline in hair follicle number and cycling are widely appreciated in normal physiology, it is less clear whether hair follicle regeneration also diminishes with age. WIHN provides an extraordinary quantitative system to address questions of mammalian regeneration and aging. Here we review cellular and molecular underpinnings of WIHN, explore known age-related changes to these elements, and present unanswered questions for future exploration.

Distinct Regulatory Programs Control the Latent Regenerative Potential of Dermal Fibroblasts during Wound Healing.

Dermal fibroblasts exhibit considerable heterogeneity during homeostasis and in response to injury. Defining lineage origins of reparative fibroblasts and regulatory programs that drive fibrosis or, conversely, promote regeneration will be essential for improving healing outcomes. Using complementary fate-mapping approaches, we show that hair follicle mesenchymal progenitors make limited contributions to wound repair. In contrast, extrafollicular progenitors marked by the quiescence-associated factor Hic1 generated the bulk of reparative fibroblasts and exhibited functional divergence, mediating regeneration in the center of the wound neodermis and scar formation in the periphery. Single-cell RNA-seq revealed unique transcriptional, regulatory, and epithelial-mesenchymal crosstalk signatures that enabled mesenchymal competence for regeneration. Integration with scATAC-seq highlighted changes in chromatin accessibility within regeneration-associated loci. Finally, pharmacological modulation of RUNX1 and retinoic acid signaling or genetic deletion of Hic1 within wound-activated fibroblasts was sufficient to modulate healing outcomes, suggesting that reparative fibroblasts have latent but modifiable regenerative capacity.

Embryonic-like regenerative phenomenon: wound-induced hair follicle neogenesis.

Wound-induced hair follicle neogenesis (WIHN) is a regenerative phenomenon that occurs widely in the skin of adult mammalians. A fully functional follicle can regenerate in the center of a full-thickness wound with a large enough size. The cellular origin of this process is similar to embryonic process. Many growth and development-related pathways are involved in WIHN. Studying WIHN can deeply explore the mechanism of biological growth, development and regeneration, and can identify new treatments for hair-related disorders. Our review aims to enlighten future study by summarizing the clinical manifestation of WIHN, as well as the cellular and molecular mechanism of WIHN in recent studies.

Wound-induced hair follicle neogenesis: a new perspective on hair follicles regeneration in adult mammals / 中国修复重建外科杂志

Objective: To explore the research progress of the cell sources and related signaling pathways of the wound-induced hair follicle neogenesis (WIHN) in recent years. Methods: The literature related to WIHN in recent years was reviewed, and the cell sources and molecular mechanism were summarized and discussed. Results: Current research shows that WIHN is a rare regeneration phenomenon in the skin of adult mammals, with multiple cell origins, both hair follicle stem cells and epithelial stem cells around the wound. Its molecular mechanism is complicated, which is regulated by many signaling pathways. Besides, the process is closely related to the immune response, the immunocytes and their related cytokines provide suitable conditions for this process. Conclusion: There are still many unsolved problems on the cellular origins and molecular mechanisms of the WIHN. Further study on the mechanisms will enhance the understanding of adult mammals' hair follicle regeneration and may provide new strategy for functional healing of the human skin.