Skin stem cells: rising to the surface

The skin epidermis and its appendages provide a protective barrier that is impermeable to harmful microbes and also prevents dehydration. To perform their functions while being confronted with the physicochemical traumas of the environment, these tissues undergo continual rejuvenation through homeostasis, and, in addition, they must be primed to undergo wound repair in response to injury. The skin's elixir for maintaining tissue homeostasis, regenerating hair, and repairing the epidermis after injury is its stem cells, which reside in the adult hair follicle, sebaceous gland, and epidermis. Stem cells have the remarkable capacity to both self-perpetuate and also give rise to the differentiating cells that constitute one or more tissues. In recent years, scientists have begun to uncover the properties of skin stem cells and unravel the mysteries underlying their remarkable capacity to perform these feats. In this paper, I outline the basic lineages of the skin epithelia and review some of the major findings about mammalian skin epithelial stem cells that have emerged in the past five years

A Breath of Fresh Air in Lung Regeneration

Enhancing the ability of the lungs to regenerate following injury could revolutionize the treatment of a wide range of different diseases. In this issue, Kumar et al. (2011) and Ding et al. (2011) dissect the cellular and molecular mechanisms of murine lung regeneration following injury and provide insights into the basic biology of the organ with implications for development of future therapeutic approaches

Catenins: Keeping Cells from Getting Their Signals Crossed

Adherens junctions have been traditionally viewed as building blocks of tissue architecture. The foundations for this view began to change with the discovery that a central component of AJs, β-catenin, can also function as a transcriptional cofactor in Wnt signaling. In recent years, conventional views have similarly been shaken about the other two major AJ catenins, α-catenin and p120-catenin. Catenins have emerged as molecular sensors that integrate cell-cell junctions and cytoskeletal dynamics with signaling pathways that govern morphogenesis, tissue homeostasis, and even intercellular communication between different cell types within a tissue. These findings reveal novel aspects of AJ function in normal tissues and offer insights into how changes in AJs and their associated proteins and cytoskeletal dynamics impact wound-repair and cancer

Desmoplakin: an unexpected regulator of microtubule organization in the epidermis

Despite their importance in cell shape and polarity generation, the organization of microtubules in differentiated cells and tissues remains relatively unexplored in mammals. We generated transgenic mice in which the epidermis expresses a fluorescently labeled microtubule-binding protein and show that in epidermis and in cultured keratinocytes, microtubules stereotypically reorganize as they differentiate. In basal cells, microtubules form a cytoplasmic network emanating from an apical centrosome. In suprabasal cells, microtubules concentrate at cell–cell junctions. The centrosome retains its ability to nucleate microtubules in differentiated cells, but no longer anchors them. During epidermal differentiation, ninein, which is a centrosomal protein required for microtubule anchoring (Dammermann, A., and A. Merdes. 2002. J. Cell Biol. 159:255–266; Delgehyr, N., J. Sillibourne, and M. Bornens. 2005. J. Cell Sci. 118:1565–1575; Mogensen, M.M., A. Malik, M. Piel, V. Bouckson-Castaing, and M. Bornens. 2000. J. Cell Sci. 113:3013–3023), is lost from the centrosome and is recruited to desmosomes by desmoplakin (DP). Loss of DP prevents accumulation of cortical microtubules in vivo and in vitro. Our work uncovers a differentiation-specific rearrangement of the microtubule cytoskeleton in epidermis, and defines an essential role for DP in the process

Coordinating cytoskeletal tracks to polarize cellular movements

For many years after the discovery of actin filaments and microtubules, it was widely assumed that their polymerization, organization, and functions were largely distinct. However, in recent years it has become increasingly apparent that coordinated interactions between microtubules and filamentous actin are involved in many polarized processes, including cell shape, mitotic spindle orientation, motility, growth cone guidance, and wound healing. In the past few years, significant strides have been made in unraveling the intricacies that govern these intertwined cytoskeletal rearrangements

A developmental conundrum: a stabilized form of β-catenin lacking the transcriptional activation domain triggers features of hair cell fate in epidermal cells and epidermal cell fate in hair follicle cells

Wnt signaling orchestrates morphogenetic processes in which changes in gene expression are associated with dramatic changes in cell organization within developing tissue/organss. Upon signaling, excess β-catenin not utilized at cell–cell junctions becomes stabilized, where it can provide the transcriptional activating domain for Lef/Tcf DNA binding proteins. In skin epithelium, forced stabilization of β-catenin in epidermis promotes hair follicle morphogenesis, whereas conditional removal of β-catenin in hair progenitor cells specifies an epidermal fate. We now report that a single protein, a stabilized version of β-catenin lacking the COOH-terminal transactivation domain, acts in epidermis to promote hair fates and in hair cells to promote epidermal fate. This reveals fundamental differences in ways that epidermal and hair cells naturally respond to β-catenin signaling. In exploring the phenotype, we uncovered mechanistic insights into the complexities of Lef1/Tcf/β-catenin signaling. Importantly, how a cell will respond to the transgene product, where it will be localized, and whether it can lead to activation of endogenous β-catenin/Tcf/Lef complexes is specifically tailored to skin stem cells, their particular lineage and their relative stage of differentiation. Finally, by varying the level of β-catenin signaling during a cell fate program, the skin cell appears to be pliable, switching fates multiple times

Specific MicroRNAs Are Preferentially Expressed by Skin Stem Cells To Balance Self-Renewal and Early Lineage Commitment

SummaryIncreasing evidence suggests that microRNAs may play important roles in regulating self-renewal and differentiation in mammalian stem cells (SCs). Here, we explore this issue in skin. We first characterize microRNA expression profiles of skin SCs versus their committed proliferative progenies and identify a microRNA subset associating with “stemness.” Of these, miR-125b is dramatically downregulated in early SC progeny. We engineer an inducible mice system and show that when miR-125b is sustained in SC progenies, tissue balance is reversibly skewed toward stemness at the expense of epidermal, oil-gland, and HF differentiation. Using gain- and loss-of-function in vitro, we further implicate miR-125b as a repressor of SC differentiation. In vivo, transcripts repressed upon miR-125b induction are enriched >700% for predicted miR-125b targets normally downregulated upon SC-lineage commitment. We verify some of these miR-125b targets, and show that Blimp1 and VDR in particular can account for many tissue imbalances we see when miR-125b is deregulated

Actin Cable Dynamics and Rho/Rock Orchestrate a Polarized Cytoskeletal Architecture in the Early Steps of Assembling a Stratified Epithelium

AbstractTo enable stratification and barrier function, the epidermis must permit self-renewal while maintaining adhesive connections. By generating K14-GFP-actin mice to monitor actin dynamics in cultured primary keratinocytes, we uncovered a role for the actin cytoskeleton in establishing cellular organization. During epidermal sheet formation, a polarized network of nascent intercellular junctions and radial actin cables assemble in the apical plane of the monolayer. These actin fibers anchor to a central actin-myosin network, creating a tension-based plane of cytoskeleton across the apical surface of the sheet. Movement of the sheet surface relative to its base expands the zone of intercellular overlap, catalyzing new sites for nascent intercellular junctions. This polarized cytoskeleton is dependent upon α-catenin, Rho, and Rock, and its regulation may be important for wound healing and/or stratification, where coordinated tissue movements are involved

Sticky Business Orchestrating Cellular Signals at Adherens Junctions

AbstractCohesive sheets of epithelial cells are a fundamental feature of multicellular organisms and are largely a product of the varied functions of adherens junctions. These junctions and their cytoskeletal associations contribute heavily to the distinct shapes, polarity, spatially oriented mitotic spindle planes, and cellular movements of developing tissues. Deciphering the underlying mechanisms that govern these conserved cellular rearrangements is a prerequisite to understanding vertebrate morphogenesis