Arthur D. Lander

What does the concept of the stem cell niche really mean today

Lander et al. BMC Biology 2012, 10:19 http://www.biomedcentral.com/1741-7007/10/19 FORUM Open Access What does the concept of the stem cell niche really mean today? Arthur D Lander, Judith Kimble, Hans Clevers, Elaine Fuchs, Didier Montarras, Margaret Buckingham, Anne L Calof, Andreas Trumpp and Thordur Oskarsson The richness of niche-ness – an introduction Arthur D Lander Ideas about stem cells, and how they behave, have been undergoing a lot of change in recent years, thanks to developments in visualizing, monitoring, and manipulating cells and tissues. Curious to find out what impact these changes are having on one of the most enduring and widely accepted metaphors in stem cell biology – the idea of the stem cell niche – BMC Biology asked researchers working on a variety of systems to write about their current conception of what a stem cell niche really is. The answers presented below suggest that the detailed mechanisms underlying niche function are extremely varied. Niches may be composed of cells, or cells together with extracellular structures such as the extracellular matrix (ECM). They may be sources of secreted or cell surface factors – including members of the Notch, Wnt, fibroblast growth factor (FGF), epidermal growth factor (EGF), transforming growth factor (TGF)-β, stem cell factor (SCF), and chemokine families – that control stem cell renewal, maintenance, or survival. They may consist of just a single cell type, or a whole host of interacting cells. They may derive from cells outside the stem cell’s lineage, or they may derive primarily from the stem cell’s own descendents. In general, there seems to be much more consensus about the fact that stem cells invariably need niches than about the specific mechanisms by which niches do their jobs. Why should a stem cell need a special environment? This is a pertinent question, given that none of the elementary processes that stem cells rely upon – growing, dividing, differentiating – are unique to stem cells. We can easily imagine three classes of answers: One possibility is that there are demands placed on stem cells that necessitate special support for viability. For example, the need, imposed by cellular immortality, to minimize the accumulation of genetic damage, may drive stem cells to adopt a peculiar metabolic state that Correspondence: bmcbiologyeditorial@biomedcentral.com might force them to rely upon other cells nearby for sustenance. This ‘nutritive’ function of the niche remains a formal possibility, but in most systems few experimental data in support of it have so far emerged. A second possibility is that niches are agents of feedback control. Recent studies tell us that stem cell pools are not slavishly maintained at a constant size by fixed, asymmetric divisions, but are usually capable of expanding or contracting and, even under homeostatic conditions, may face large stochastic fluctuations. The varied growth factors and cell surface molecules produced by niche cells may share the common goal of controlling stem cell pools. If this is the case, then the niche might best be thought of not simply as an environment conducive to stem cell functioning, but as an apparatus for communicating information about the state of a tissue back to the stem cells that maintain it. An important question to address would then be how niches obtain and relay such information. A third possibility is that niches are instruments of coordination among tissue compartments. Some of the best evidence for this view comes from work on the hair follicle niche, described below by Elaine Fuchs. There, stem and progenitor cells responsible for maintenance of epidermis, pigmentation, hair, and connective and adipose tissue all interact in close proximity. A need to achieve tight coordination among these different cell populations may be the overriding reason for complex organization of this niche. The possibility that other niches may also be hubs of inter-lineage coordination is certainly an idea worth investigating. The C. elegans distal tip cell and the concept of a stem cell niche Judith Kimble Schofield originally hypothesized the existence of a microenvironment required for maintenance of stem cells and coined the term stem cell niche [1] (Figure 1a, left). The first example of such a stem cell niche was the mesenchymal ‘distal tip cell’ (DTC) in Caenorhabditis

Free Extracellular Diffusion Creates the Dpp Morphogen Gradient of the Drosophila Wing Disc

BACKGROUNDnHow morphogen gradients form has long been a subject of controversy. The strongest support for the view that morphogens do not simply spread by free diffusion has come from a variety of studies of the Decapentaplegic (Dpp) gradient of the Drosophila larval wing disc.nnnRESULTSnIn the present study, we initially show how the failure, in such studies, to consider the coupling of transport to receptor-mediated uptake and degradation has led to estimates of transport rates that are orders of magnitude too low, lending unwarranted support to a variety of hypothetical mechanisms, such as planar transcytosis and restricted extracellular diffusion. Using several independent dynamic methods, we obtain data that are inconsistent with such models and show directly that Dpp transport occurs by simple, rapid diffusion in the extracellular space. We discuss the implications of these findings for other morphogen systems in which complex transport mechanisms have been proposed.nnnCONCLUSIONSnWe believe that these findings resolve a major, longstanding question about morphogen gradient formation and provide a solid framework for interpreting experimental observations of morphogen gradient dynamics.

Organ-Level Quorum Sensing Directs Regeneration in Hair Stem Cell Populations

Coordinated organ behavior is crucial for an effective response to environmental stimuli. By studying regeneration of hair follicles in response to patterned hair plucking, we demonstrate that organ-level quorum sensing allows coordinated responses to skin injury. Plucking hair at different densities leads to a regeneration of up to five times more neighboring, unplucked resting hairs, indicating activation of a collective decision-making process. Through data modeling, the range of the quorum signal was estimated to be on the order of 1 mm, greater than expected for a diffusible molecular cue. Molecular and genetic analysis uncovered a two-step mechanism, where release of CCL2 from injured hairs leads to recruitment of TNF-α-secreting macrophages, which accumulate and signal to both plucked and unplucked follicles. By coupling immune response with regeneration, this mechanism allows skin to respond predictively to distress, disregarding mild injury, while meeting stronger injury with full-scale cooperative activation of stem cells.

How cells know where they are.

Development, regeneration, and even day-to-day physiology require plant and animal cells to make decisions based on their locations. The principles by which cells may do this are deceptively straightforward. But when reliability needs to be high—as often occurs during development—successful strategies tend to be anything but simple. Increasingly, the challenge facing biologists is to relate the diverse diffusible molecules, control circuits, and gene regulatory networks that help cells know where they are to the varied, sometimes stringent, constraints imposed by the need for real-world precision and accuracy.

Dynamics and precision in retinoic acid morphogen gradients

Retinoic acid (RA) regulates many cellular behaviors during embryonic development and adult homeostasis. Like other morphogens, RA forms gradients through the use of localized sources and sinks, feedback, and interactions with other signals; this has been particularly well studied in the context of hindbrain segmentation in vertebrate embryos. Yet, as a small lipophilic molecule derived from a dietary source-vitamin A-RA differs markedly from better-studied polypeptide morphogens in its mechanisms of transport, signaling, and removal. Computational models suggest that the distinctive features of RA gradients make them particularly robust to large perturbations. Such features include combined positive and negative feedback effects via intracellular fatty acid binding proteins and RA-degrading enzymes. Here, we discuss how these features, together with feedback interactions among RA target genes, help enable RA to specify multiple, accurate pattern elements in the developing hindbrain, despite operating in an environment of high cellular and biochemical uncertainty and noise.

Multispecies model of cell lineages and feedback control in solid tumors

We develop a multispecies continuum model to simulate the spatiotemporal dynamics of cell lineages in solid tumors. The model accounts for protein signaling factors produced by cells in lineages, and nutrients supplied by the microenvironment. Together, these regulate the rates of proliferation, self-renewal and differentiation of cells within the lineages, and control cell population sizes and distributions. Terminally differentiated cells release proteins (e.g., from the TGFβ superfamily) that feedback upon less differentiated cells in the lineage both to promote differentiation and decrease rates of proliferation (and self-renewal). Stem cells release a short-range factor that promotes self-renewal (e.g., representative of Wnt signaling factors), as well as a long-range inhibitor of this factor (e.g., representative of Wnt inhibitors such as Dkk and SFRPs). We find that the progression of the tumors and their response to treatment is controlled by the spatiotemporal dynamics of the signaling processes. The model predicts the development of spatiotemporal heterogeneous distributions of the feedback factors (Wnt, Dkk and TGFβ) and tumor cell populations with clusters of stem cells appearing at the tumor boundary, consistent with recent experiments. The nonlinear coupling between the heterogeneous expressions of growth factors and the heterogeneous distributions of cell populations at different lineage stages tends to create asymmetry in tumor shape that may sufficiently alter otherwise homeostatic feedback so as to favor escape from growth control. This occurs in a setting of invasive fingering, and enhanced aggressiveness after standard therapeutic interventions. We find, however, that combination therapy involving differentiation promoters and radiotherapy is very effective in eradicating such a tumor.

A reaction-diffusion mechanism influences cell lineage progression as a basis for formation, regeneration, and stability of intestinal crypts

BackgroundColon crypts, a single sheet of epithelia cells, consist of a periodic pattern of stem cells, transit-amplifying cells, and terminally differentiated cells that constantly renew and turnover. Experimental evidence suggests that Wnt signaling promotes and regulates stem cell division, differentiation, and possible cell migrations while intestinal BMP signaling inhibits stem cell self-renewal and repression in crypt formation. As more molecular details on Wnt and BMP in crypts are being discovered, little is still known about how complex interactions among Wnt, BMP, and different types of cells, and surrounding environments may lead to de novo formation of multiple crypts or how such interactions affect regeneration and stability of crypts.ResultsWe present a mathematical model that contains Wnt and BMP, a cell lineage, and their feedback regulations to study formation, regeneration, and stability of multiple crypts. The computational explorations and linear stability analysis of the model suggest a reaction–diffusion mechanism, which exhibits a short-range activation of Wnt plus a long-range inhibition with modulation of BMP signals in a growing tissue of cell lineage, can account for spontaneous formation of multiple crypts with the spatial and temporal pattern observed in experiments. Through this mechanism, the model can recapitulate some distinctive and important experimental findings such as crypt regeneration and crypt multiplication. BMP is important in maintaining stability of crypts and loss of BMP usually leads to crypt multiplication with a fingering pattern.ConclusionsThe study provides a mechanism for de novo formation of multiple intestinal crypts and demonstrates a synergetic role of Wnt and BMP in regeneration and stability of intestinal crypts. The proposed model presents a robust framework for studying spatial and temporal dynamics of cell lineages in growing tissues driven by multiple signaling molecules.

The Protective Role of Symmetric Stem Cell Division on the Accumulation of Heritable Damage

Stem cell divisions are either asymmetric—in which one daughter cell remains a stem cell and one does not—or symmetric, in which both daughter cells adopt the same fate, either stem or non-stem. Recent studies show that in many tissues operating under homeostatic conditions stem cell division patterns are strongly biased toward the symmetric outcome, raising the question of whether symmetry confers some benefit. Here, we show that symmetry, via extinction of damaged stem-cell clones, reduces the lifetime risk of accumulating phenotypically silent heritable damage (mutations or aberrant epigenetic changes) in individual stem cells. This effect is greatest in rapidly cycling tissues subject to accelerating rates of damage accumulation over time, a scenario that describes the progression of many cancers. A decrease in the rate of cellular damage accumulation may be an important factor favoring symmetric patterns of stem cell division.

Reduction of Nipbl impairs cohesin loading locally and affects transcription but not cohesion-dependent functions in a mouse model of Cornelia de Lange Syndrome

Cornelia de Lange Syndrome (CdLS) is a genetic disorder linked to mutations in cohesin and its regulators. To date, it is unclear which function of cohesin is more relevant to the pathology of the syndrome. A mouse heterozygous for the gene encoding the cohesin loader Nipbl recapitulates many features of CdLS. We have carefully examined Nipbl deficient cells and here report that they have robust cohesion all along the chromosome. DNA replication, DNA repair and chromosome segregation are carried out efficiently in these cells. While bulk cohesin loading is unperturbed, binding to certain promoters such as the Protocadherin genes in brain is notably affected and alters gene expression. These results provide further support for the idea that developmental defects in CdLS are caused by deregulated transcription and not by malfunction of cohesion-related processes.

Cell lineage branching as a strategy for proliferative control

BackgroundHow tissue and organ sizes are specified is one of the great unsolved mysteries in biology. Experiments and mathematical modeling implicate feedback control of cell lineage progression, but a broad understanding of what lineage feedback accomplishes is lacking.ResultsBy exploring the possible effects of various biologically relevant disturbances on the dynamic and steady state behaviors of stem cell lineages, we find that the simplest and most frequently studied form of lineage feedback - which we term renewal control - suffers from several serious drawbacks. These reflect fundamental performance limits dictated by universal conservation-type laws, and are independent of parameter choice. Here we show that introducing lineage branches can circumvent all such limitations, permitting effective attenuation of a wide range of perturbations. The type of feedback that achieves such performance - which we term fate control - involves promotion of lineage branching at the expense of both renewal and (primary) differentiation. We discuss the evidence that feedback of just this type occurs in vivo, and plays a role in tissue growth control.ConclusionsRegulated lineage branching is an effective strategy for dealing with disturbances in stem cell systems. The existence of this strategy provides a dynamics-based justification for feedback control of cell fate in vivo.See commentary article: http://dx.doi.org/10.1186/s12915-015-0123-7.