Given the importance of stem cells to adult tissues, it has long been postulated that stem cells divide infrequently to preserve their long-term proliferation potential and to prevent the acquisition ...of errors during DNA replication. Yet, some stem cells must be able to continually churn out progeny in tissues that rapidly turn over or are subject to sudden injuries or growth spurts. This Review explores the challenges that mammalian stem cells face in balancing the competing demands of proliferation and differentiation in tissues.
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.
The versatility of epithelial stem cells
Stem cells are very important in the maintenance of our bodies' tissues and organs. Blanpain and Fuchs review how different populations of naturally ...lineage-restricted epithelial stem cells and committed progenitors can also display remarkable plasticity. These cells can reacquire long-term self-renewing capacities and multilineage differentiation potential during physiological and regenerative conditions. These abilities depend on whether the stem cell remains within its resident niche or has been mobilized to repair a wound. Such cellular plasticity has implications for regenerative medicine and for cancer.
Science
, this issue p.
10.1126/science.1242281
Tissues rely upon stem cells for homeostasis and repair. Recent studies show that the fate and multilineage potential of epithelial stem cells can change depending on whether a stem cell exists within its resident niche and responds to normal tissue homeostasis, whether it is mobilized to repair a wound, or whether it is taken from its niche and challenged to de novo tissue morphogenesis after transplantation. In this Review, we discuss how different populations of naturally lineage-restricted stem cells and committed progenitors can display remarkable plasticity and reversibility and reacquire long-term self-renewing capacities and multilineage differentiation potential during physiological and regenerative conditions. We also discuss the implications of cellular plasticity for regenerative medicine and for cancer.
Our body has a remarkable ability to remember its past encounters with allergens, pathogens, wounds and irritants, and to react more quickly to the next experience. This accentuated sensitivity also ...helps us to cope with new threats. Despite maintaining a state of readiness and broadened resistance to subsequent pathogens, memories can also be maladaptive, leading to chronic inflammatory disorders and cancers. With the ever-increasing emergence of new pathogens, allergens and pollutants in our world, the urgency to unravel the molecular underpinnings of these phenomena has risen to new heights. Here we reflect on how the field of inflammatory memory has evolved, since 2007, when researchers realized that non-specific memory is contained in the nucleus and propagated at the epigenetic level. We review the flurry of recent discoveries revealing that memory is not just a privilege ofthe immune system but also extends to epithelia of the skin, lung, intestine and pancreas, and to neurons. Although still unfolding, epigenetic memories of inflammation have now been linked to possible brain disorders such as Alzheimer disease, and to an elevated risk of cancer. In this Review, we consider the consequences-good and bad-ofthese epigenetic memories and their implications for human health and disease.
Stem cells (SCs) govern tissue homeostasis and wound repair. They reside within niches, the special microenvironments within tissues that control SC lineage outputs. Upon injury or stress, new ...signals emanating from damaged tissue can divert nearby cells into adopting behaviours that are not part of their homeostatic repertoire. This behaviour, known as SC plasticity, typically resolves as wounds heal. However, in cancer, it can endure. Recent studies have yielded insights into the orchestrators of maintenance and lineage commitment for SCs belonging to three mammalian tissues: the haematopoietic system, the skin epithelium and the intestinal epithelium. We delineate the multifactorial determinants and general principles underlying the remarkable facets of SC plasticity, which lend promise for regenerative medicine and cancer therapeutics.
In studying how stem cells make and maintain tissues, nearly every chapter of a cell biology textbook takes on special interest. The field even allows us to venture where no chapters have yet been ...written. In studying this basic problem, we are continually bombarded by nature's surprises and challenges. Stem cell biology has captured my interest for nearly my entire scientific career. Below, I focus on my laboratory's contributions to this fascinating field, to which so many friends and colleagues have made seminal discoveries equally deserving of this award.
In this Perspective, Elaine Fuchs describes her laboratory's contributions to the field of skin stem cells, giving a historical overview of their first isolation and characterization, the discovery of extrinsic and intrinsic factors regulating skin stem cell states, and their role in skin disease.
Cancer stem cells (CSCs) sustain tumor growth through their ability to self-renew and to generate differentiated progeny. These functions endow CSCs with the potential to initiate secondary tumors ...bearing characteristics similar to those of the parent. Recently the hair follicle stem cell marker CD34 was used to purify a CSC-like cell population from early skin tumors arising from treatment with 7,12-dimethylbenzαanthracene/12-o-tetradecanoylphorbol-13-acetate, which typically generates benign papillomas that occasionally progress to squamous cell carcinomas (SCCs). In the present study, we identify and characterize CSCs purified from malignant SCCs. We show that SCCs contain two highly tumorigenic CSC populations that differ in CD34 levels but are enriched for integrins and coexist at the SCC—stroma interface. Intriguingly, whether CD34lo or CD34hi, α6hiβ1hi populations can initiate secondary tumors by serial limit-dilution transplantation assays, but α6loβ1lo populations cannot. Moreover, secondary tumors generated from a single CSC of either subtype contain both CD34lo and CD34hi α6hiβ1hiCSCs, indicating their nonhierarchical organization. Genomic profiling and hierarchical cluster analysis show that these two CSC subtypes share a molecular signature distinct from either the CD34- epidermal or the CD34hi hair follicle stem cell signature. Although closely related, α6hiβ1hiCD34lo and α6hiβ1hiCD34hi CSCs differ in cell-cycle gene expression and proliferation characteristics. Indeed, proliferation and expansion of α6hiβ1hiCD34hi CSCs is sensitive to whether they can initiate a TGF-β receptor II—mediated response to counterbalance elevated focal adhesion kinase-mediated integrin signaling within the tumor. Overall, the coexistence and interconvertibility of CSCs with differing sensitivities to their microenvironment pose challenges and opportunities for SCC cancer therapies.
Tissue patterning and cellular mechanics Heller, Evan; Fuchs, Elaine
The Journal of cell biology,
2015-Oct-26, 2015-10-26, 20151026, Volume:
211, Issue:
2
Journal Article
Peer reviewed
Open access
In development, cells organize into biological tissues through cell growth, migration, and differentiation. Globally, this process is dictated by a genetically encoded program in which secreted ...morphogens and cell-cell interactions prompt the adoption of unique cell fates. Yet, at its lowest level, development is achieved through the modification of cell-cell adhesion and actomyosin-based contractility, which set the level of tension within cells and dictate how they pack together into tissues. The regulation of tension within individual cells and across large groups of cells is a major driving force of tissue organization and the basis of all cell shape change and cell movement in development.
If Narcissus could have self‐renewed even once on seeing his own reflection, he would have died a happy man. Stem cells, on the other hand, have an enormous capacity for self‐renewal; in other words, ...the ability to replicate and generate more of the same. In adult organisms, stem cells reside in specialized niches within each tissue. They replenish tissue cells that are lost during normal homeostasis, and on injury they repair damaged tissue. The ability of a stem cell to self‐renew is governed by the dynamic interaction between the intrinsic proteins it expresses and the extrinsic signals that it receives from the niche microenvironment. Understanding the mechanisms governing when to proliferate and when to differentiate is vital, not only to normal stem cell biology, but also to ageing and cancer. This review focuses on elucidating conceptually, experimentally and mechanistically, our understanding of adult stem cell self‐renewal. We use skin as a paradigm for discussing many of the salient points about this process, but also draw on the knowledge gained from these and other adult stem cell systems to delineate shared underlying principles, as well as highlight mechanistic distinctions among adult tissue stem cells. By doing so, we pinpoint important questions that still await answers.
When stem cells divide they can either self‐renew to maintain the pool of undifferentiated cells or they can differentiate into specialized cell lineages. This review discusses current concepts and mechanisms of adult stem cell self‐renewal.
Transit-amplifying cells (TACs) are an early intermediate in tissue regeneration. Here, using hair follicles (HFs) as a paradigm, we show that emerging TACs constitute a signaling center that ...orchestrates tissue growth. Whereas primed stem cells (SCs) generate TACs, quiescent SCs only proliferate after TACs form and begin expressing Sonic Hedgehog (SHH). TAC generation is independent of autocrine SHH, but the TAC pool wanes if they can’t produce SHH. We trace this paradox to two direct actions of SHH: promoting quiescent-SC proliferation and regulating dermal factors that stoke TAC expansion. Ingrained within quiescent SCs’ special sensitivity to SHH signaling is their high expression of GAS1. Without sufficient input from quiescent SCs, replenishment of primed SCs for the next hair cycle is compromised, delaying regeneration and eventually leading to regeneration failure. Our findings unveil TACs as transient but indispensable integrators of SC niche components and reveal an intriguing interdependency of primed and quiescent SC populations on tissue regeneration.
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•TACs act as signaling rheostats, balancing stem cell usage with tissue generation•Quiescent SCs proliferate only after primed SCs are stimulated to form the TACs•TACs stimulate quiescent SCs to self-renew and mesenchyme to fuel TAC production•Quiescent SCs are dispensable short term but essential for long-term regeneration
Transit-amplifying cells act as signaling centers during tissue regeneration and temporally coordinate stem cell activity in the hair follicle.
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