https://www.cell.com/cell/pdf/S0092-8674(06)01344-4.pdf

Wnt/beta-catenin signaling in development and disease.

Many adult regenerative cells divide infrequently but have high proliferative capacity. We developed a strategy to fluorescently label slow-cycling cells in a cell type-specific fashion. We used this method to purify the label-retaining cells (LRCs) that mark the skin stem cell (SC) niche. We found that these cells rarely divide within their niche but change properties abruptly when stimulated to exit. We determined their transcriptional profile, which, when compared to progeny and other SCs, defines the niche. Many of the >100 messenger RNAs preferentially expressed in the niche encode surface receptors and secreted proteins, enabling LRCs to signal and respond to their environment.

/pdf/defining-the-epithelial-stem-cell-niche-in-skin-2l3fc78omk.pdf

Defining the epithelial stem cell niche in skin.

Socializing with the Neighbors: Stem Cells and Their Niche

Evidence accumulated over the past decade shows that long non-coding RNAs (lncRNAs) are widely expressed and have key roles in gene regulation. Recent studies have begun to unravel how the biogenesis of lncRNAs is distinct from that of mRNAs and is linked with their specific subcellular localizations and functions. Depending on their localization and their specific interactions with DNA, RNA and proteins, lncRNAs can modulate chromatin function, regulate the assembly and function of membraneless nuclear bodies, alter the stability and translation of cytoplasmic mRNAs and interfere with signalling pathways. Many of these functions ultimately affect gene expression in diverse biological and physiopathological contexts, such as in neuronal disorders, immune responses and cancer. Tissue-specific and condition-specific expression patterns suggest that lncRNAs are potential biomarkers and provide a rationale to target them clinically. In this Review, we discuss the mechanisms of lncRNA biogenesis, localization and functions in transcriptional, post-transcriptional and other modes of gene regulation, and their potential therapeutic applications.

/pdf/gene-regulation-by-long-non-coding-rnas-and-its-biological-25d7y97amp.pdf

Gene regulation by long non-coding RNAs and its biological functions.

Sleep-induced apnea and disordered breathing refers to intermittent, cyclical cessations or reductions of airflow, with or without obstructions of the upper airway (OSA). In the presence of an anat...

Pathophysiology of Sleep Apnea

Tissue stem cells form the cellular base for organ homeostasis and repair. Stem cells have the unusual ability to renew themselves over the lifetime of the organ while producing daughter cells that differentiate into one or multiple lineages. Difficult to identify and characterize in any tissue, these cells are nonetheless hotly pursued because they hold the potential promise of therapeutic reprogramming to grow human tissue in vitro, for the treatment of human disease. The mammalian skin epithelium exhibits remarkable turnover, punctuated by periods of even more rapid production after injury due to burn or wounding. The stem cells responsible for supplying this tissue with cellular substrate are not yet easily distinguishable from neighboring cells. However, in recent years a significant body of work has begun to characterize the skin epithelial stem cells, both in tissue culture and in mouse and human skin. Some epithelial cells cultured from skin exhibit prodigious proliferative potential; in fact, for >20 years now, cultured human skin has been used as a source of new skin to engraft onto damaged areas of burn patients, representing one of the first therapeutic uses of stem cells. Cell fate choices, including both self-renewal and differentiation, are crucial biological features of stem cells that are still poorly understood. Skin epithelial stem cells represent a ripe target for research into the fundamental mechanisms underlying these important processes.

https://www.pnas.org/content/pnas/100/suppl_1/11830.full.pdf

Stem cells of the skin epithelium.

The hair coat, which keeps most mammals warm, dry and protected from harmful elements, requires a constant supply of new hairs throughout the lifetime of the animal. To produce new hairs, existing follicles undergo cycles of growth (anagen), regression (catagen) and rest (telogen). During each

The hair cycle

Human disease results from loss of organ function. Whether the tissue failure results from infarction, infection, trauma, or congenital malfunction, the ideal treatment would be regrowth of a new organ or tissue to replace that which is lost or injured. Stem cell research holds the promise of developing such treatments for many life-threatening and debilitating diseases. Stem cells come in two basic types, unrestricted and restricted. Embryonic stem cells are totipotent, able to differentiate into all cell types characteristic of the species they are taken from. Adult stem cells are thought to be more restricted in their potential, functioning as the body’s natural source of cells for tissue homeostasis and repair. Although it seems unlikely that adult stem cells harvested from one tissue might be reprogrammed to take on the characteristics of a different cell type, several tantalizing results have encouraged researchers to consider this possibility. Before scientists can begin to define the limits of adult stem cell plasticity, they need to understand the signals that instruct multipotent cells to self-renew and differentiate within the lineages of their resident tissues. Skin is an excellent model system in which to explore these fundamental mechanisms, because skin keratinocytes are easily accessible and are one of the few adult stem cell types that can be maintained and propagated in vitro. These cells have already been engrafted long term to replace damaged epidermis on burn patients. Now skin biologists have begun to identify some of the key steps involved in generating a functional tissue from multipotent stem cells. The totipotency of embryonic stem (ES) cells, coupled with their ability to respond to morphogenic signals and differentiate into any desired cell fate, makes them an attractive starting place for cell replacement therapies. If stem cells derived from adult human tissues offer similar promise, this would circumvent many of the ethical and technical issues that cloud the ES cell field (Ferrari et al. 1998; Gussoni et al. 1999; Krause et al. 2001; Peterson 2002). In the past few years, researchers have claimed that mouse brain stem cells injected into irradiated recipient mice contribute to the recovering hematopoietic system (Bjornson et al. 1999), and conversely, some transplanted bone marrow stem cells reportedly differentiate into brain cells (Mezey et al. 2000). Even in human, female cancer patients receiving bone marrow transplants from male donors were found to have differentiated cells with male chromosomes in their cerebella, leading scientists to posit that transdifferentiation of donor hematopoietic stem cells may occur in brain tissue (Weimann et al. 2003). Although enticing, the seemingly extraordinary plasticity of adult stem cells has been met by critics who suggest that the reported transdifferentiation events may have arisen from fusion of stem cells with existing differentiated cells, or from injections of heterogeneous populations of incompletely characterized stem cells, rather than true reprogramming (Terada et al. 2002; Wagers et al. 2002; Ying et al. 2002). Advocates counter that tissue injury, which is present in clinical situations requiring treatment, increases the rate at which bone-marrow-derived stem cells transdifferentiate into other cell types such as muscle and neurons (Jiang et al. 2002; LaBarge and Blau 2002). As the controversy over stem cell plasticity continues, the potential for cell fusion or deregulated transdifferentiation raises other concerns, as cancerous cells may derive from somatic stem cells (Reya et al. 2001). The contention in the adult stem cell field reflects how little is known in a rapidly moving field whose potential impact on clinical medicine is high. A major challenge over the next decade will be to identify the molecular signals that regulate stem cell self-renewal, proliferation, and differentiation. Unless responding to injury, most adult stem cells typically divide infrequently to maintain homeostasis within their resident tissues. As a stem cell daughter commits to differentiate, it first enters a transient state of rapid proliferation (Fig. 1A). Following several cycles of division, the transiently amplifying cells withdraw from the cell cycle and execute a terminal differentiation program (Potten et al. 1979). Stem cell progeny differentiate in response to similar external and intrinsic signals experienced by their multipotent embryonic counterparts. Adult stem cells reside in specific niches. Corresponding author. E-MAIL fuchs@rockefeller.edu; FAX (212) 327-7954. Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/ gad.1086903.

/pdf/stem-cells-in-the-skin-waste-not-wnt-not-4kdld0e8p1.pdf

Stem cells in the skin: waste not, Wnt not.

Rationale and Objectives: Although many clinical physiology and epidemiology studies show an association between obstructive sleep apnea (OSA) and markers of insulin resistance, no causal pathway has been established. The purpose of the current study was to determine if the intermittent hypoxia (IH) stimulus that characterizes OSA causes insulin resistance in the absence of obesity. Furthermore, we assessed the impact of IH on specific metabolic function in liver and muscle. Finally, we examined the potential mechanistic role of the autonomic nervous system (ANS) in mediating insulin resistance in response to IH.Methods and Results: Hyperinsulinemic euglycemic clamps were conducted and whole-body insulin sensitivity, hepatic glucose output, and muscle-specific glucose utilization assessed in conscious, chronically instrumented adult male C57BL/6J mice exposed to (1) IH (achieving a nadir of FiO2 = 5–6% at 60 cycles/h for 9 h), (2) intermittent air as a control, (3) IH with ANS blockade (hexamethonium), or...

/pdf/intermittent-hypoxia-causes-insulin-resistance-in-lean-mice-3cxi7runxi.pdf

Intermittent Hypoxia Causes Insulin Resistance in Lean Mice Independent of Autonomic Activity

Developing new techniques to induce β-cells to replicate is a major goal in diabetes research. Endogenous β-cells replicate in response to metabolic changes, such as obesity and pregnancy, which increase insulin requirement. Mouse genetic models promise to reveal the pathways responsible for compensatory β-cell replication. However, no simple, short-term, physiological replication stimulus exists to test mouse models for compensatory replication. Here, we present a new tool to induce β-cell replication in living mice. Four-day glucose infusion is well tolerated by mice as measured by hemodynamics, body weight, organ weight, food intake, and corticosterone level. Mild sustained hyperglycemia and hyperinsulinemia induce a robust and significant fivefold increase in β-cell replication. Glucose-induced β-cell replication is dose and time dependent. β-Cell mass, islet number, β-cell size, and β-cell death are not altered by glucose infusion over this time frame. Glucose infusion increases both the total protein abundance and nuclear localization of cyclin D2 in islets, which has not been previously reported. Thus, we have developed a new model to study the regulation of compensatory β-cell replication, and we describe important novel characteristics of mouse β-cell responses to glucose in the living pancreas.

https://diabetes.diabetesjournals.org/content/diabetes/56/7/1792.full.pdf

Laura C. Alonso

Papers

Stem cells of the skin epithelium.

The hair cycle

Stem cells in the skin: waste not, Wnt not.

Intermittent Hypoxia Causes Insulin Resistance in Lean Mice Independent of Autonomic Activity

Glucose Infusion in Mice: A New Model to Induce β-Cell Replication