Bifunctional ectodermal stem cells around the nail display dual fate homeostasis and adaptive wounding response toward nail regeneration

Abstract

Regulation of adult stem cells (SCs) is fundamental for organ maintenance and tissue regeneration. On the body surface, different ectodermal organs exhibit distinctive modes of regeneration and the dynamics of their SC homeostasis remain to be unraveled. A slow cycling characteristic has been used to identify SCs in hair follicles and sweat glands; however, whether a quiescent population exists in continuously growing nails remains unknown. Using an in vivo label retaining cells (LRCs) system, we detected an unreported population of quiescent cells within the basal layer of the nail proximal fold, organized in a ring-like configuration around the nail root. These nail LRCs express the hair stem cell marker, keratin 15 (K15), and lineage tracing show that these K15-derived cells can contribute to both the nail structure and peri-nail epidermis, and more toward the latter. Thus, this stem cell population is bifunctional. Upon nail plucking injury, the homeostasis is tilted with these SCs dominantly delivering progeny to the nail matrix and differentiated nail plate, demonstrating their plasticity to adapt to wounding stimuli. Moreover, in vivo engraftment experiments established that transplanted nail LRCs can actively participate in functional nail regeneration. Transcriptional profiling of isolated nail LRCs revealed bone morphogenetic protein signaling favors nail differentiation over epidermal fate. Taken together, we have found a previously unidentified ring-configured population of bifunctional SCs, located at the interface between the nail appendage organ and adjacent epidermis, which physiologically display coordinated homeostatic dynamics but are capable of rediverting stem cell flow in response to injury.

Exploring the biology of the nail: An intriguing but less-investigated skin appendage

“…3A) [37]. In agreement with this, a recent study using the LRC technique identified nail stem cells within the basal layer of the PNF, organized in a ring-like configuration around the nail root [38].…”

“…By contrast, in alopecia areata, which is regarded as a T cell-mediated autoimmune disease, it was suggested that IP collapse in the anagen hair bulb may be induced by upregulation of interferon-gamma, triggers of which include infection and psychoemotional stress [45]. [38] (mouse), proximal NM [24] (mouse), distal NM [23] (mouse). (B) Immune privilege (IP) in the hair follicle and the nail unit.…”

Lgr6 marks nail stem cells and is required for digit tip regeneration

“…Instead, they found label-retaining cells within the proximal nail fold that give rise to the eponychium during homeostatic conditions. They also showed that, during long-term growth or wounding/regenerative conditions, these cells have a binary potential and can differentiate into the nail plate, thus leading to the conclusion that the proximal nail fold harbors nail stem cells (35). Although these data are seemingly in conflict with both the preexisting literature as well as the data we present in this article, the differences in experimental markers and timing of pulses/ analyses can rectify most of the discrepancies.…”

“…We confirm that the nail matrix gives rise to the nail plate, and in addition, we show that Lgr6 is a molecular marker specific to the nail stem cells. Interestingly, Leung et al recently performed a Keratin5 TetOff ;TreH2BGFP pulse-chase experiment to identify label-retaining cells in the digit tip and did not find a presumptive stem cell population within the nail matrix (35). Instead, they found label-retaining cells within the proximal nail fold that give rise to the eponychium during homeostatic conditions.…”

“…A similar differential response has been revealed within the digit tip such that the Keratin5/15-marked label-retaining cells within the proximal nail fold serve as the stem cell pool for the eponychium, and only after long term quiescent growth do they give rise to occasional cells in the nail plate. However, upon mechanical ablation of the nail, these stem cells significantly increase their contribution to the nail plate (35), implying an inherent plasticity to this stem cell population during tissue stress. Taken in the context of the Lgr6 −/− experiments in this article, this finding suggests that, upon wounding of the nail matrix/plate, the eponychium stem cells may be capable of regenerating the nail matrix or specifically generating Lgr6-expressing nail stem cells; however, if this is the cellular hierarchy, in our experiments, these cells were insufficient to rescue the Lgr6 −/− phenotype.…”