Finding the hematopoietic stem cell niche in the placenta

The origin of definitive hematopoiesis poses a fundamental biological question. In this issue of Developmental Cell, two groups have independently found a novel hematopoietic stem cell (HSC) niche in the extraembryonic placenta, in addition to previously identified alternative locations of hematopoiesis at different developmental stages.     

Finding paradise: cues directing the migration of the waterfall climbing Hawaiian gobioid Sicyopterus stimpsoni

A series of waterfall-climbing trials were conducted to identify cues that direct the climbing of juvenile Sicyopterus stimpsoni. In the first experiment, whether climbing juveniles preferentially ascend water sources with conspecifics or whether the presence of just stream water is sufficient to attract fish to ascend a climbing path were assessed. In the second experiment, whether climbing juveniles create a trail of mucus that facilitates the ability of conspecifics to follow their lead was determined. The results indicate that juvenile S. stimpsoni are less likely to climb in waters devoid of organic cues but are strongly attracted to stream water with or without the odour of conspecifics. Once climbing, performance did not differ for juveniles climbing in differing water choices, suggesting an all-or-nothing commitment once climbing commences. Climbing S. stimpsoni did produce a mucous trail while climbing that was associated with a mucous gland that dramatically increases in size just prior to juveniles gaining the ability to climb. The trail was not followed closely by subsequent juveniles traversing the same channel, however, suggesting only weak trail-following in waterfall climbing S. stimpsoni. Previous genetic studies suggest that juvenile S. stimpsoni do not home to natal streams in the face of strong near-shore oceanic currents. Instead, these fish appear primarily to rely on cues that suggest the presence of organic growth in streams, a factor that may indicate suitable habitat in an ever-changing stream environment but which may also be vulnerable to interference through human activity.     

Multivectorial abnormal cell migration in the NOD mouse thymus

We previously described a fibronectin/VLA-5-dependent impairment of NOD thymocyte migration, correlated with partial thymocyte arrest within thymic perivascular spaces. Yet, NOD thymocytes still emigrate, suggesting the involvement of other cell migration-related alterations. In this context, the aim of this work was to study the role of extracellular matrix ligands, alone or in combination with the chemokine CXCL12, in NOD thymocyte migration. Intrathymic contents of CXCL12, fibronectin, and laminin were evaluated by immunohistochemistry while the expression of corresponding receptors was ascertained by flow cytometry. Thymocyte migration was measured using Transwell chambers and transendothelial migration was evaluated in the same system, but using an endothelial cell monolayer within the chambers. NOD thymocytes express much lower VLA-5 than C57BL/6 thymocytes. This defect was particularly severe in CD4(+) thymocytes expressing Foxp3, thus in keeping with the arrest of Foxp3(+) cells within the NOD giant perivascular spaces. We observed an enhancement in CXCL12, laminin, and fibronectin deposition and colocalization in the NOD thymus. Furthermore, we detected altered expression of the CXCL12 receptor CXCR4 and the laminin receptor VLA-6, as well as enhanced migratory capacity of NOD thymocytes toward these molecules, combined or alone. Moreover, transendothelial migration of NOD thymocytes was diminished in the presence of exogenous fibronectin. Our data unravel the existence of multiple cell migration-related abnormalities in NOD thymocytes, comprising both down- and up-regulation of specific responses. Although remaining to be experimentally demonstrated, these events may have consequences on the appearance of autoimmunity in NOD mice.     

Stem cell researchers find their niche

The EuroSTELLS Workshop ;Stem Cell Niches', organised by Anna Bigas, Ernest Arenas and Pasqualino Loi, took place in January 2008 in Barcelona, Spain. The goal of the conference was to promote scientific collaboration and synergy between stem cell researchers worldwide and those in the EuroSTELLS consortia (an initiative of the European Science Foundation EUROCORES Programme), and to stimulate discussion of the latest results in the field of stem cell niches.     

Stromal cell networks regulate thymocyte migration and dendritic cell behavior in the thymus

After entry into thymus, T cell progenitors migrate in the cortex and the medulla while completing their education. Recent reports have documented the dynamic and tortuous behavior of thymocytes. However, other than chemokines and/or segregated thymic substrates, the factors contributing to the dynamic patterns of thymocyte movement are poorly characterized. By combining confocal and dynamic two-photon microscopy, we demonstrate that thymocytes continuously migrate on thymic stromal cell networks. In addition to constituting "roads" for thymocytes, we observed that these networks also provide a scaffold on which dendritic cells attach themselves. These results highlight the central role of stromal microanatomy in orchestrating the multiple cellular interactions necessary for T cell migration/development within the thymus.     

EphB receptors coordinate migration and proliferation in the intestinal stem cell niche

More than 10(10) cells are generated every day in the human intestine. Wnt proteins are key regulators of proliferation and are known endogenous mitogens for intestinal progenitor cells. The positioning of cells within the stem cell niche in the intestinal epithelium is controlled by B subclass ephrins through their interaction with EphB receptors. We report that EphB receptors, in addition to directing cell migration, regulate proliferation in the intestine. EphB signaling promotes cell-cycle reentry of progenitor cells and accounts for approximately 50% of the mitogenic activity in the adult mouse small intestine and colon. These data establish EphB receptors as key coordinators of migration and proliferation in the intestinal stem cell niche.     

Integrin activation by chemokines: relevance to inflammatory adhesion cascade during T cell migration

The adhesive function of integrins is regulated through cytoplasmic signaling induced by several stimuli, whose process is designated "inside-out signaling". A large number of leukocytes are rapidly recruited to the sites of inflammation where they form an essential component of the response to infection, injury, autoimmune disorders, allergy, tumor invasion, atherosclerosis and so on. The recruitment of leukocytes into tissue is regulated by a sequence of interactions between the circulating leukocytes and the endothelial cells. Leukocyte integrins play a pivotal role in leukocyte adhesion to endothelial cells. During the process, the activation of integrins by various chemoattractants, especially chemokines, is essential for integrin-mediated adhesion in which a signal transduced to the leukocyte converts the functionally inactive integrin to an active adhesive configuration. We have proposed that H-Ras-sensitive activation of phosphoinositide 3 (PI 3)-kinase and subsequent profilin-mediated actin polymerization, can be involved in chemokine-induced integrin-dependent adhesion of T cells. The present review documents the relevance of cytoplasmic signaling and cytoskeletal assembly to integrin-mediated adhesion induced by chemoattractants including chemokines during inflammatory processes. In contrast, various adhesion molecules are known to transduce extracellular information into cytoplasm, which leads to T cell activation and cytokine production from the cells, designated "outside-in signaling". Such a bi-directional "cross-talking" among adhesion molecules and cytokines is most relevant to inflammatory processes by augmenting immune cell migration from circulation into inflamed tissue such as rheumatoid arthritis, tumor invasion, Beh?et's disease and atherosclerosis.     

Partial migration: niche shift versus sexual maturation in fishes

Summary Many fish populations have both resident and migratory individuals. Migrants usually grow larger and have higher reproductive potential but lower survival than resident conspecifics. The decision about migration versus residence probably depends on the individual growth rate, or a physiological process like metabolic rate which is correlated with growth rate. Fish usually mature as their somatic growth levels off, where energetic costs of maintenance approach energetic intake. After maturation, growth also stagnates because of resource allocation to reproduction. Instead of maturation, however, fish may move to an alternative feeding habitat and their fitness may thereby be increased. When doing so, maturity is usually delayed, either to the new asymptotic length, or sooner, if that gives higher expected fitness. Females often dominate among migrants and males among residents. The reason is probably that females maximize their fitness by growing larger, because their reproductive success generally increases exponentially with body size. Males, on the other hand, may maximize fitness by alternative life histories, e.g. fighting versus sneaking, as in many salmonid species where small residents are the sneakers and large migrants the fighters. Partial migration appears to be partly developmental, depending on environmental conditions, and partly genetic, inherited as a quantitative trait influenced by a number of genes.     

Regulation of human natural killer cell migration and proliferation by the exodus subfamily of CC chemokines

Natural killer (NK) cells play an important role in innate and adaptive immune responses to obligate intracellular pathogens. Nevertheless, the regulation of NK cell trafficking and migration to inflammatory sites is poorly understood. Exodus-1/MIP-3alpha/LARC, Exodus-2/6Ckine/SLC, and Exodus-3/MIP-3beta/ELC/CKbeta-11 are CC chemokines that share a unique aspartate-cysteine-cysteine-leucine motif near their amino terminus and preferentially stimulate the migration of T lymphocytes. The effects of Exodus chemokines on human NK cells were examined. Exodus-1, -2, and -3 did not induce detectable chemotaxis of resting peripheral blood NK cells. In contrast, Exodus-2 and -3 stimulated migration of polyclonal activated peripheral blood NK cells in a dose-dependent fashion. Exodus-2 and -3 also induced dose-dependent chemotaxis of NKL, an IL-2-dependent human NK cell line. Results of modified checkerboard assays indicate that migration of NKL cells in response to Exodus-2 and -3 represents true chemotaxis and not simply chemokinesis. Exodus-1, -2, and -3 did not induce NK cell proliferation in the absence of other stimuli. Nevertheless, Exodus-2 and -3 significantly augmented IL-2-induced proliferation of normal human CD56(dim) NK cells. In contrast, Exodus-1, -2, and -3 did not affect the cytolytic activity of resting or activated peripheral blood NK cells. Expression of message for CCR7, a shared receptor for Exodus-2 and -3, was detected in activated polyclonal NK cells and NKL cells but not resting NK cells. Taken together, these results indicate that Exodus-2 and -3 can participate in the recruitment and proliferation of activated NK cells. Exodus-2 and -3 may regulate interactions between T cells and NK cells that are crucial for the generation of optimal immune responses.     

Selection events in directing B cell development

Homeostasis in the B cell compartment (as well as in T cells) is controlled by tightly regulated selection events. Throughout their life span, B cells are subjected to selection signals determining not only developmental progression, but also maturation and survival. It is now clear that most of these signals require the expression of B cell antigen receptor (or preB receptor) with functional signaling capacity. The administration of numerous mutations into the mouse germline enabled us to identify several checkpoints along the B cell developmental pathway, and provided us with powerful experimental tools to probe for selection events regulating developmental progression. In here, we will discuss recent studies in this field.     

A homing receptor-bearing cortical thymocyte subset: implications for thymus cell migration and the nature of cortisone-resistant thymocytes

The thymus exports a selected subset of virgin T lymphocytes to the peripheral lymphoid organs. The mature phenotype of these thymus emigrants is similar to that of medullary thymocytes and has been cited as supporting a medullary rather than cortical exit site. Using the monoclonal antibody MEL-14, we identify a 1%-3% subpopulation of thymocytes that expresses high levels of a receptor molecule involved in lymphocyte homing to peripheral lymph nodes. We present evidence that these rare MEL-14hi thymocytes are predominantly of mature phenotype and represent the major source of thymus emigrants. Surprisingly, MEL-14hi thymocytes are exclusively cortical in location, although their mature phenotype may allow them to masquerade as medullary cells in conventional studies. We also demonstrate that unlike medullary thymocytes, many cortisone-resistant thymocytes (CRT) are MEL-14hi. Thus, in contrast to current dogma, CRT do not represent a sample of medullary thymocytes as they are found in situ and their level of immunocompetence does not necessarily reflect that of the medullary population. Our findings refute the hypothesis that phenotypically and functionally mature cells are restricted to the medulla, and support our proposition that most thymus emigrants are derived from the MEL-14hi cortical subset.     

Rap-GEF signaling controls stem cell anchoring to their niche through regulating DE-cadherin-mediated cell adhesion in the Drosophila testis

Stem cells will undergo self-renewal to produce new stem cells if they are maintained in their niches. The regulatory mechanisms that recruit and maintain stem cells in their niches are not well understood. In Drosophila testes, a group of 12 nondividing somatic cells, called the hub, identifies the stem cell niche by producing the growth factor Unpaired (Upd). Here, we show that Rap-GEF/Rap signaling controls stem cell anchoring to the niche through regulating DE-cadherin-mediated cell adhesion. Loss of function of a Drosophila Rap-GEF (Gef26) results in loss of both germline and somatic stem cells. The Gef26 mutation specifically impairs adherens junctions at the hub-stem cell interface, which results in the stem cells "drifting away" from the niche and losing stem cell identity. Thus, the Rap signaling/E-cadherin pathway may represent one mechanism that regulates polarized niche formation and stem cell anchoring.     

T cell differentiation in the thymus

T lymphocytes arise in the thymus and seed to peripheral lymphoid organs as fully functional cells at the time of exit. In humans, the thymus begins to function very early in ontogeny and releases large numbers of T cells before the time of birth. However, the vast majority of developing thymocytes (>95%) die within the thymus as a result of stringent selection processes. Positive selection imposes self-MHC-restriction on thymocytes and dictates the MHC-restricted repertoire of post-thymic T cells. Negative selection results in deletion of autoreactive cells. Both types of selection depend on cell to cell contracts and on the presence of appropriate growth factors which are still largely undetermined. Cell to cell contacts occur between developing thymocytes and cells of the thymic microenvironment (accessory cells), and are mediated by several receptor/ligand interactions which subserve the function of establishing and stabilizing these contacts. Besides MHC-TCR interactions, adhesion molecules are important for thymocyte maturation, selection and activation, and for the export and peripheral homing of mature T cells produced in the thymus. Here we describe a novel integrin involved in thymocyte-thymic epithelial cell interactions.     

Socializing with the neighbors: stem cells and their niche

The potential of stem cells in regenerative medicine relies upon removing them from their natural habitat, propagating them in culture, and placing them into a foreign tissue environment. To do so, it is essential to understand how stem cells interact with their microenvironment, the so-called stem cell niche, to establish and maintain their properties. In this review, we examine adult stem cell niches and their impact on stem cell biology.