Nails are highly keratinized skin appendages that exhibit continuous growth under physiological conditions and full regeneration upon removal. These mini-organs are maintained by two autonomous populations of skin stem cells. The fast-cycling, highly proliferative stem cells of the nail matrix (nail stem cells (NSCs)) predominantly replenish the nail plate. Furthermore, the slow-cycling population of the nail proximal fold (nail proximal fold stem cells (NPFSCs)) displays bifunctional properties by contributing to the peri-nail epidermis under the normal homeostasis and the nail structure upon injury. Here, we discuss nail mini-organ stem cells’ location and their role in skin and nail homeostasis and regeneration, emphasizing their importance to orchestrate the whole digit tip regeneration. Such endogenous regeneration capabilities are observed in rodents and primates. However, they are limited to the region adjacent to the nail’s proximal area, indicating the crucial role of nail mini-organ stem cells in digit restoration. Further, we explore the molecular characteristics of nail mini-organ stem cells and the critical role of the bone morphogenetic protein (BMP) and Wnt signaling pathways in homeostatic nail growth and digit restoration. Finally, we investigate the latest accomplishments in stimulating regenerative responses in regeneration-incompetent injuries. These pioneer results might open up new opportunities to overcome amputated mammalian digits and limbs’ regenerative failures in the future.

The loss of fur during human evolution has long mystified scientists and the public ^1–5 . Reduced hair density coincides with acquisition of epidermal rete ridges, the developmental timing and molecular mechanisms of which are poorly understood despite their prominence in humans ^1,6–9 . Examination of human and pig skin development has shown that rete ridges form through a mechanism independent from those of hair follicles ^10,11 and sweat glands ^3,4,12–15 by establishing interconnected epidermal invaginations. Here we document the occurrence of rete ridges across Mammalia, including in grizzly bears and dolphins, and show that neonatal pig wounds can regenerate them de novo. Multispecies spatiotemporal transcriptomics identifies significant signalling interactions between epidermal and dermal cells during rete ridge morphogenesis, particularly through bone morphogenetic proteins (BMP). We also demonstrate that mouse fingerpad skin forms rete ridges and functionally requires epidermal BMP signalling. We propose that evolution of rete ridges in mammalian skin involved replacement of the molecular program for formation of discrete microscopic appendages, including hair follicles and sweat glands, with a distinct program for the interconnected appendage network. Broad epidermal activation of BMP is required for the development of rete ridge networks organized around underlying dermal pockets. Understanding rete ridge mechanisms may enable development of therapeutic approaches to regenerate epidermal appendages lost during wounding or disease in humans.

Introduction Noroviruses are the leading cause of acute gastroenteritis in all age groups, but illness is more severe and causes excess mortality in the elderly, particularly those in long-term care. The total burden of norovirus disease in the elderly in the UK is poorly defined; no current surveillance programmes systematically or accurately quantify norovirus infection in those living in care homes. The aim of this study is to evaluate an enhanced surveillance system for acute gastroenteritis among the elderly in care homes. Methods and analysis We will conduct this prospective cohort study in care homes in North West England; residents and staff at study care homes will be asked to participate. We will prospectively enrol a cohort of participants in an enhanced surveillance system to capture the incidence of acute gastroenteritis and use multiplex PCR to detect pathogens. We will sample symptomatic and non-symptomatic participants to understand characteristics of norovirus disease and susceptibility to infection. We will generate novel data on transmission dynamics by collecting data on the pattern of interactions within care homes using electronic proximity sensors. Comparisons of outbreak and non-outbreak periods will be used to quantify the impact of norovirus outbreaks on care homes. Ethics and dissemination The study has been approved by the North West–Greater Manchester South NHS Research Ethics Committee (REC Reference: 16/NW/0541). Study outputs will be disseminated through scientific conferences and peer-reviewed publications. This study will provide detailed insight on the burden and aetiology of acute gastroenteritis in care homes, in addition to generating novel data on transmission dynamics and risks. The study will identify areas for improving infection control practice and allow more accurate modelling of the introduction of interventions such as vaccination.

Skin and its appendages form an integrated system of ectodermal mini-organs that rely on Wnt signaling for lifelong homeostasis and regeneration; yet, the pathway operates in a highly organ-specific manner in each compartment. In interfollicular epidermis, the Wnt activity is spatially graded, thus maintaining the balance between basal progenitor proliferation and terminal differentiation. The hair follicle is governed by an intrinsic oscillator based on cross-regulation between Wnt and BMP signaling, providing a cell-autonomous layer of control over hair cycle dynamics. Finally, the nail organ is characterized by the spatial compartmentalization of Wnt activity, with a distal matrix activation zone supported by specialized mesenchymal niche cells that sustain continuous nail plate growth and coordinate the digit tip regeneration. Understanding these divergent regulatory architectures provides a conceptual framework for targeted regenerative strategies aimed at enhancing repair in skin and its appendages. Therefore, in this review, we synthesize recent molecular studies on Wnt signaling in the adult skin, hair follicles, and nail mini-organs, highlighting appendage-specific features that underlie their distinct regenerative capacities. We further discuss how dysregulated Wnt signaling contributes to skin, hair, and nail pathologies such as alopecia, chronic wounds, excessive scarring, skin cancer, and nail deformations, and summarize the emerging strategies that target Wnt pathway to therapeutically enhance hair regrowth, wound repair, cancer treatment, and digit tip regeneration.

Ectodermal dysplasia comprises a group of hereditary disorders affecting the development of the skin and its appendages. Among the more than 150 characterised forms of ectodermal dysplasia, hypohidrotic ectodermal dysplasia is the most prevalent in children. Hypohidrotic ectodermal dysplasia is marked by reduced sweating, sparse hair, a limited number of conical-shaped teeth, and brittle nails. The condition results from mutations in genes involved in the EDA-EDAR-EDARADD-NF-κB signalling pathway, which is crucial for early epithelial-mesenchymal communication during the formation of skin appendages. The Wnt/β-catenin pathway also plays a vital role in the development of hair follicles, teeth, and other ectodermal structures. In this article, publicly available single-cell gene expression data from a mouse model were re-analysed to investigate the expression profiles of genes from both the EDA-EDAR and WNT pathways. Wnt10b, Dkk4 and Edar were confirmed to be expressed in epidermal keratinocytes, particularly in Fgf20-positive early placode-forming cells. Furthermore, correlated expression of Edaradd and NF-κB was observed during early appendage formation, while Eda ligand expression was detected in Dkk1-positive mesenchymal progenitor cells, transiently amplifying to become the first dermal condensate and subsequently dermal papilla cells. These findings further support previous observations that EDA-A1 signalling through EDAR-EDARADD and NF-κB enhances WNT pathway activity, creating a mutually reinforcing network. Disruption of this feedback loop between the EDA-EDAR and WNT pathways give rise to the characteristic phenotypes of hypohidrotic ectodermal dysplasia observed in children. Early restoration of the EDA-EDAR and WNT signalling pathways may offer a promising therapeutic strategy for rescuing skin appendage development and thus reducing the effects of ectodermal dysplasias in the future.

Objectives To estimate the incidence of gastroenteritis in individuals in care homes. Design Prospective cohort study. Setting Five participating care homes in North West England, UK. Participants Residents and staff present at the five study care homes between 15 August 2017 and 30 May 2019 (n=268). Outcome measures We calculated incidence rates for all gastroenteritis cases per 1000 person-years at risk and per 1000 bed-days at risk. We also calculated the incidence rate of gastroenteritis outbreaks per 100 care homes per year. Results In total 45 cases were reported during the surveillance period, equating to 133.7 cases per 1000 person-years at risk. In residents the incidence rate was 0.62 cases per 1000 bed-days. We observed seven outbreaks in all care homes included in surveillance, a rate of 76.4 outbreaks per 100 care homes per year. 15 stool samples were tested; three were positive for norovirus, no other pathogens were detected. Conclusions We found that surveillance of infectious gastroenteritis disease in care homes based on outbreaks, the current general approach, detected a majority of cases of gastroenteritis. However, if policymakers are to estimate the burden of infectious gastroenteritis in this setting using only routine outbreak surveillance data and not accounting for non-outbreak cases, this study implies that the total burden will be underestimated.