Mammalian skin research represents the convergence of three complementary disciplines: cell biology, mouse genetics, and dermatology. The skin provides a paradigm for current research in cell ...adhesion, inflammation, and tissue stem cells. Here, I discuss recent insights into the cell biology of skin. Single-cell analysis has revealed that human epidermal stem cells are heterogeneous and differentiate in response to multiple extrinsic signals. Live-cell imaging, optogenetics, and cell ablation experiments show skin cells to be remarkably dynamic. High-throughput, genome-wide approaches have yielded unprecedented insights into the circuitry that controls epidermal stem cell fate. Last, integrative biological analysis of human skin disorders has revealed unexpected functions for elements of the skin that were previously considered purely structural.
Skin architecture and function depend on diverse populations of epidermal cells and dermal fibroblasts. Reciprocal communication between the epidermis and dermis plays a key role in skin development, ...homeostasis and repair. While several stem cell populations have been identified in the epidermis with distinct locations and functions, it is now recognised that there is additional heterogeneity within the mesenchymal cells of the dermis. Here, we discuss recent insights into how these distinct cell populations are maintained and coordinated during development, homeostasis, and wound healing. We highlight the importance of the local environment, or niche, in cellular plasticity. We also discuss new mechanisms that have been identified as influencing wound repair and cancer progression.
Different epidermal and dermal cell populations not only contribute to tissue homeostasis but also to wound repair and underlie tumour heterogeneity and progression.
Skin cellular behaviour and fate are regulated by interactions at the level of single cells, termed microniches, as well as on higher scales.
Individual niche components and transcription factors can be identified that significantly affect stem cell maintenance and behaviour.
Cell population-specific mechanisms regulate cellular plasticity and behaviour during wound repair and tumour development.
Epidermal stem cell plasticity is achieved by a loss of lineage specificity during wound healing, and may become permanent in skin cancer.
Lineage tracing is the identification of all progeny of a single cell. Although its origins date back to developmental biology of invertebrates in the 19th century, lineage tracing is now an ...essential tool for studying stem cell properties in adult mammalian tissues. Lineage tracing provides a powerful means of understanding tissue development, homeostasis, and disease, especially when it is combined with experimental manipulation of signals regulating cell-fate decisions. Recently, the combination of inducible recombinases, multicolor reporter constructs, and live-cell imaging has provided unprecedented insights into stem cell biology. Here we discuss the different experimental strategies currently available for lineage tracing, their associated caveats, and new opportunities to integrate lineage tracing with the monitoring of intracellular signaling pathways.
Central to the classical hematopoietic stem cell (HSC) paradigm is the concept that the maintenance of blood cell numbers is exclusively executed by a discrete physical entity: the transplantable ...HSC. The HSC paradigm has served as a stereotypic template in stem cell biology, yet the search for rare, hardwired professional stem cells has remained futile in most other tissues. In a more open approach, the focus on the search for stem cells as a physical entity may need to be replaced by the search for stem cell function, operationally defined as the ability of an organ to replace lost cells. The nature of such a cell may be different under steady state conditions and during tissue repair. We discuss emerging examples including the renewal strategies of the skin, gut epithelium, liver, lung, and mammary gland in comparison with those of the hematopoietic system. While certain key housekeeping and developmental signaling pathways are shared between different stem cell systems, there may be no general, deeper principles underlying the renewal mechanisms of the various individual tissues.
The field of regenerative medicine holds considerable promise for treating diseases that are currently intractable. Although many researchers are adopting the strategy of cell transplantation for ...tissue repair, an alternative approach to therapy is to manipulate the stem cell microenvironment, or niche, to facilitate repair by endogenous stem cells. The niche is highly dynamic, with multiple opportunities for intervention. These include administration of small molecules, biologics or biomaterials that target specific aspects of the niche, such as cell-cell and cell-extracellular matrix interactions, to stimulate expansion or differentiation of stem cells, or to cause reversion of differentiated cells to stem cells. Nevertheless, there are several challenges in targeting the niche therapeutically, not least that of achieving specificity of delivery and responses. We envisage that successful treatments in regenerative medicine will involve different combinations of factors to target stem cells and niche cells, applied at different times to effect recovery according to the dynamics of stem cell-niche interactions.
Fibroblasts synthesize the extracellular matrix of connective tissue and play an essential role in maintaining the structural integrity of most tissues. Researchers have long suspected that ...fibroblasts exhibit functional specialization according to their organ of origin, body site, and spatial location. In recent years, a number of approaches have revealed the existence of fibroblast subtypes in mice. Here, we discuss fibroblast heterogeneity with a focus on the mammalian dermis, which has proven an accessible and tractable system for the dissection of these relationships. We begin by considering differences in fibroblast identity according to anatomical site of origin. Subsequently, we discuss new results relating to the existence of multiple fibroblast subtypes within the mouse dermis. We consider the developmental origin of fibroblasts and how this influences heterogeneity and lineage restriction. We discuss the mechanisms by which fibroblast heterogeneity arises, including intrinsic specification by transcriptional regulatory networks and epigenetic factors in combination with extrinsic effects of the spatial context within tissue. Finally, we discuss how fibroblast heterogeneity may provide insights into pathological states including wound healing, fibrotic diseases, and aging. Our evolving understanding suggests that ex vivo expansion or in vivo inhibition of specific fibroblast subtypes may have important therapeutic applications.
Epithelia cover the surfaces and line the cavities of the body. Recent studies have highlighted the existence of multiple stem cell compartments within individual epithelia that exhibit striking ...plasticity in response to tissue damage, transplantation, or tumor development. New knowledge about the composition of the epithelial niche and the transcription factor networks that maintain cell identity has provided new insights into the extrinsic and intrinsic regulation of stem cell behavior. In addition new in vitro tissue substitutes allow better integration of data from human and mouse models.
Donati and Watt review recent evidence supporting the existence of multiple stem cell compartments within individual epithelia and discuss data revealing striking plasticity in the heterogeneous populations in response to tissue damage, transplantation, and tumor development.
A new approach to APCs Watt, Fiona M
EMBO reports,
05/2024, Letnik:
25, Številka:
5
Journal Article
Recenzirano
Odprti dostop
The article processing charges associated with open-access publishing are unaffordable for some scientists. One solution is to break the APC down into its component parts, enabling scientists to ...spread the costs over multiple providers and several years.
The key to reducing errors in science is collaboration between all practitioners—researchers, funders and editors—through a shared motivation to nurture scientists and promote discovery.
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