Hair follicle and interfollicular epidermal stem cells make varying contributions to wound regeneration

Abstract

Upon wounding, multiple stem cell populations in the hair follicle (HF) and interfollicular epidermis (IFE) converge at the site of injury. Although these cells can contribute permanently to the regenerating epithelium, it remains unclear whether these contributions vary among cells originating from diverse compartments in the skin. By comparing the fates of several keratinocyte lineages, we observed here an initial decrease in both HF-and IFE-derived cells within the transient acanthotic layers of the regenerating epithelium. At the same time, the relative abundance of early-arriving IFE-derived cells specifically in the wound basal layer declined as later-arriving HF-derived cells entered the site of injury. Although laggard bulge-derived cells were typically constrained at the regenerative periphery, these cells persisted in the wound basal layer. Finally, suppressing Notch enabled IFE-derived cells to out-compete HF-derived cells. Taken together, these findings indicate that IFE-, HF-and bulge-derived cells make distinct contributions to regeneration over time. Furthermore, we speculate that extrinsic, non-genetic factors such as spatial constraint, distance from the wound, and basal versus suprabasal position may largely determine whether a cell ultimately persists.

The battle of the bulge: re‐evaluating hair follicle stem cells in wound repair

“…Several recent studies have suggested that a bulge contribution is not seen until much later in wound repair (Fig. a) . Thus, the kinetics of when exactly bulge cells proliferate and migrate in response to injury stimuli could account for some (but certainly not all) of the conflicting data.…”

“…For example, we extensively profiled the HF response to injury from 0 hours to 3 days postinjury, which we would consider the early response window . However, other studies may consider day 10 postinjury an early wound time‐point, with 50 days considered “late” . In addition, the size of wound employed will alter the time to re‐epithelialize, which might also determine whether bulge cells become incorporated or not (discussed later) (Fig.…”

“…It is likely that differences in wound type (abrasion, incision, excision) and size strongly influence which HF populations are activated to respond to injury. For example, studies reporting no bulge cell contribution to epidermal repair generate full‐thickness wounds excisional between 2.5 and 6 mm diameter. Full‐thickness wounds would result in the complete amputation of HFs within the wound itself, while leaving mostly intact follicles at the wound periphery.…”

“…In directly injured HFs, a rapid bulge activation is seen, which may be designed initially to restore the appendage, although it is unclear whether different levels of HF damage elicit different speeds of bulge response …”

“…For many decades, the capacity of the hair follicle (HF) to directly contribute to skin repair has been appreciated (s1–s4), although recent advances in transgenic mouse technology have heralded an explosion of research in this area (s5–s9) . The HF bulge (see Fig.…”