Epidermal stem cells are retained in vivo throughout skin aging

In healthy individuals, skin integrity is maintained by epidermal stem cells which self-renew and generate daughter cells that undergo terminal differentiation. It is currently unknown whether epidermal stem cells influence or are affected by skin aging. We therefore compared young and aged skin stem cell abundance, organization, and proliferation. We discovered that despite age-associated differences in epidermal proliferation, dermal thickness, follicle patterning, and immune cell abundance, epidermal stem cells were maintained at normal levels throughout life. These findings, coupled with observed dermal gene expression changes, suggest that epidermal stem cells themselves are intrinsically aging resistant and that local environmental or systemic factors modulate skin aging

Mechanistic overlap between chronic lung injury and cancer:ERS Lung Science Conference 2017 report

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Clinical and health economic evaluation of a post-stroke arrhythmia monitoring service

Atrial fibrillation (AF) is a major cause of recurrent stroke and transient ischaemic attack (TIA) in the UK. As many patients can have asymptomatic paroxysmal AF, prolonged arrhythmia monitoring is advised in selected patients following a stroke or TIA. This service evaluation assessed the clinical and potential health economic impact of prolonged arrhythmia monitoring post-stroke using R-TEST monitoring devices.This was a prospective, case-controlled, service evaluation in a single health board in the North of Scotland. Patients were included if they had a recent stroke or TIA, were in sinus rhythm, and did not have another indication for, or contraindication to, oral anticoagulation. A health economic model was developed to estimate the clinical and economic value delivered by the R-TEST monitoring. Approval to use anonymised patient data in this service evaluation was obtained.During the evaluation period, 100 consecutive patients were included. The average age was 70 ± 11 years, 46% were female. Stroke was the presenting complaint in 83% of patients with the other 17% having had a TIA. AF was detected in seven of 83 (8.4%) patients who had had a stroke and one of 17 (5.9%) patients with a TIA. Health economic modelling predicted that adoption of R-TEST monitoring has a high probability of demonstrating both clinical and economic benefits.In conclusion, developing a post-stroke arrhythmia monitoring service using R-TEST devices is feasible, effective at detecting AF, and represents a probable clinical and economic benefi

Human embryonic lung epithelial tips are multipotent progenitors that can be expanded in vitro as long-term self-renewing organoids.

The embryonic mouse lung is a widely used substitute for human lung development. For example, attempts to differentiate human pluripotent stem cells to lung epithelium rely on passing through progenitor states that have only been described in mouse. The tip epithelium of the branching mouse lung is a multipotent progenitor pool that self-renews and produces differentiating descendants. We hypothesized that the human distal tip epithelium is an analogous progenitor population and tested this by examining morphology, gene expression and in vitro self-renewal and differentiation capacity of human tips. These experiments confirm that human and mouse tips are analogous and identify signalling pathways that are sufficient for long-term self-renewal of human tips as differentiation-competent organoids. Moreover, we identify mouse-human differences, including markers that define progenitor states and signalling requirements for long-term self-renewal. Our organoid system provides a genetically-tractable tool that will allow these human-specific features of lung development to be investigated

Phenotypic Analysis of Stem Cell Microenvironments Within the Conducting Airway Epithelium

The elucidation of mechanisms for epithelial maintenance and renewal after injury are central to understanding aspects of normal airway diversity and the pathobiology of lung diseases including asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and cancer. Due to the low steady state turnover of the airway epithelium, it has been proposed that epithelial remodeling following chronic lung injury or disease may be the result of aberrant epithelial stem cell activation. Previous results indicated that intrapulmonary conducting airways contain rare populations of stem cells that localized to neuroepithelial body (NEB) microenvironments, and that these cells are activated following injury involving depletion of airway Clara cells. These airway cells were uniquely pollutant resistant, exhibited robust mitotic and differentiation potential, and exhibited the molecular property of Clara cell secretory protein (CCSP) expression. Despite this recent progress, many aspects of airway stem cell maintenance, initiation, and regulation remain elusive. Studies presented in this dissertation were undertaken (1) to investigate the existence of alternate, regionally distinct airway stem cell populations, (2) to elucidate mechanisms of airway stem cell pollutant resistance, and (3) to identify signaling pathways associated with stem cell-associated repair. Results of these studies demonstrate the existence of unique, NEB microenvironment-independent CCSP expressing stem cells restricted to airway bronchoalveolar duct junction (BADJ) microenvironments. Results also identify likely mechanisms of CCSP expressing stem cell pollutant resistance that include reduced levels of Cytochrome P450 expression and robust drug / pollutant efflux systems. Finally, results of these studies indicate that activation of the b-catenin signaling pathway and definitive downstream target genes occurs within NEB and BADJ microenvironments during airway regeneration. Together, these findings demonstrate that regionally distinct, pollutant resistant airway stem cell populations are responsible for the maintenance of appropriate epithelial diversity and facilitate renewal processes after injury. Furthermore, these studies support the notion that b-catenin signaling and downstream target gene activation are important mediators of stem cell-associated epithelial renewal

Epithelial cell migration as a potential therapeutic target in early lung cancer

Lung cancer is the most lethal cancer type worldwide, with the majority of patients presenting with advanced stage disease. Targeting early stage disease pathogenesis would allow dramatic improvements in lung cancer patient survival. Recently, cell migration has been shown to be an integral process in early lung cancer ontogeny, with preinvasive lung cancer cells shown to migrate across normal epithelium prior to developing into invasive disease. TP53 mutations are the most abundant mutations in human nonsmall cell lung cancers and have been shown to increase cell migration via regulation of Rho-GTPase protein activity. In this review, we explore the possibility of targeting TP53-mediated Rho-GTPase activity in early lung cancer and the opportunities for translating this preclinical research into effective therapies for early stage lung cancer patients

Epidermal Cadm1 expression promotes autoimmune alopecia via enhanced T cell adhesion and cytotoxicity

Autoimmune alopecia is characterized by an extensive epidermal T cell infiltrate that mediates hair follicle destruction. We have investigated the role of cell adhesion molecule 1 (Cadm1; Necl2) in this disease. Cadm1 is expressed by epidermal cells and mediates heterotypic adhesion to lymphocytes expressing class 1-restricted T cell-associated molecule (CRTAM). Using a murine autoimmune alopecia model, we observed an increase in early-activated cytotoxic (CD8-restricted, CRTAM-expressing) T cells, which preferentially associated with hair follicle keratinocytes expressing Cadm1. Coculture with Cadm1-transduced MHC-matched APCs stimulated alopecic lymph node cells to release IL-2 and IFN-gamma. Overexpression of Cadm1 in cultured human keratinocytes did not promote cytokine secretion, but led to increased adhesion of alopecic cytotoxic T cells and enhanced T cell cytotoxicity in an MHC-independent manner. Epidermal overexpression of Cadm1 in transgenic mice led to increased autoimmune alopecia susceptibility relative to nontransgenic littermate controls. Our findings reveal that Cadm1 expression in the hair follicle plays a role in autoimmune alopecia. The Journal of Immunology, 2012, 188: 1514-1522

Necl2 regulates epidermal adhesion and wound repair

Differential expression of cell adhesion molecules regulates stem cell location, self-renewal and lineage selection under steady state conditions and during tissue repair. We show that the intercellular adhesion protein nectin-like molecule 2 (Necl2) is highly expressed in bulge stem cells of adult human and mouse hair follicles. Overexpression of Necl2 in cultured human keratinocytes led to upregulation of calcium/calmodulin-associated Ser/Thr kinase (CASK), increased calcium-independent intercellular adhesion, and inhibition of cell motility and in vitro wound healing. Although the rate of cell proliferation was reduced, terminal differentiation was unaffected. To assess the role of Necl2 in vivo, we examined the epidermis of Necl2-null mice and developed transgenic mice that expressed Necl2 in the basal layer of murine epidermis. Necl2 overexpression led to a reduction in S-phase cells and an increase in quiescent cells retaining DNA label in the bulge. Although epidermal homeostasis appeared normal in both transgenic and knockout mice, wound healing was markedly delayed. Necl2 overexpression resulted in reduced proliferation and increased levels of CASK and E-cadherin at the leading edge of healing wounds, consistent with its effects in culture. Our results demonstrate that Necl2 is involved in regulating epidermal stem cell quiescence and location