An adult tissue-specific stem cell molecular phenotype is activated in epithelial cancer stem cells and correlated to patient outcome

Recent studies have shown that embryonic stem cell-like molecular phenotypes are commonly activated in human epithelial primary tumors and are linked to adverse patient prognosis. However it remains unclear whether these correlations to outcome are linked to the differentiation status of the human primary tumours1 or represent molecular reminiscences of epithelial cancer stem cells. In addition, while it has been demonstrated that leukemic cancer stem cells re-acquire an embryonic stem cell-like phenotype, the molecular basis of stem cell function in epithelial cancer stem cells has not been investigated. Here we show that a normal adult tissue-specific stem cell molecular phenotype is commonly activated in epithelial cancer stem cells and for the first time provide evidence that enrichment in cancer stem cells-specific molecular signatures are correlated to highly aggressive tumor phenotypes in human epithelial cancers.     

Stem cell function, self-renewal, and behavioral heterogeneity of cells from the adult muscle satellite cell niche

Satellite cells are situated beneath the basal lamina that surrounds each myofiber and function as myogenic precursors for muscle growth and repair. The source of satellite cell renewal is controversial and has been suggested to be a separate circulating or interstitial stem cell population. Here, we transplant single intact myofibers into radiation-ablated muscles and demonstrate that satellite cells are self-sufficient as a source of regeneration. As few as seven satellite cells associated with one transplanted myofiber can generate over 100 new myofibers containing thousands of myonuclei. Moreover, the transplanted satellite cells vigorously self-renew, expanding in number and repopulating the host muscle with new satellite cells. Following experimental injury, these cells proliferate extensively and regenerate large compact clusters of myofibers. Thus, within a normally stable tissue, the satellite cell exhibits archetypal stem cell properties and is competent to form the basal origin of adult muscle regeneration.     

Tissue-specific stem cells: lessons from the skeletal muscle satellite cell

In 1961, the satellite cell was first identified when electron microscopic examination of skeletal muscle demonstrated a cell wedged between the plasma membrane of the muscle fiber and the basement membrane. In recent years it has been conclusively demonstrated that the satellite cell is the primary cellular source for muscle regeneration and is equipped with the potential to self renew, thus functioning as a bona fide skeletal muscle stem cell (MuSC). As we move past the 50(th) anniversary of the satellite cell, we take this opportunity to discuss the current state of the art and dissect the unknowns in the MuSC field.     

The mitochondrial protein OPA1 regulates the quiescent state of adult muscle stem cells

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EphB signaling controls lineage plasticity of adult neural stem cell niche cells

Stem cells remain in specialized niches over the lifespan of the organism in many organs to ensure tissue homeostasis and enable regeneration. How the niche is maintained is not understood, but is probably as important as intrinsic stem cell self-renewal capacity for tissue integrity. We here demonstrate a high degree of phenotypic plasticity of the two main niche cell types, ependymal cells and astrocytes, in the neurogenic lateral ventricle walls in the adult mouse brain. In response to a lesion, astrocytes give rise to ependymal cells and ependymal cells give rise to niche astrocytes. We identify EphB2 forward signaling as a key pathway regulating niche cell plasticity. EphB2 acts downstream of Notch and is required for the maintenance of ependymal cell characteristics, thereby inhibiting the transition from ependymal cell to astrocyte. Our results show that niche cell identity is actively maintained and that niche cells retain a high level of plasticity.     

The satellite cell in male and female, developing and adult mouse muscle: distinct stem cells for growth and regeneration

Satellite cells are myogenic cells found between the basal lamina and the sarcolemma of the muscle fibre. Satellite cells are the source of new myofibres; as such, satellite cell transplantation holds promise as a treatment for muscular dystrophies. We have investigated age and sex differences between mouse satellite cells in vitro and assessed the importance of these factors as mediators of donor cell engraftment in an in vivo model of satellite cell transplantation. We found that satellite cell numbers are increased in growing compared to adult and in male compared to female adult mice. We saw no difference in the expression of the myogenic regulatory factors between male and female mice, but distinct profiles were observed according to developmental stage. We show that, in contrast to adult mice, the majority of satellite cells from two week old mice are proliferating to facilitate myofibre growth; however a small proportion of these cells are quiescent and not contributing to this growth programme. Despite observed changes in satellite cell populations, there is no difference in engraftment efficiency either between satellite cells derived from adult or pre-weaned donor mice, male or female donor cells, or between male and female host muscle environments. We suggest there exist two distinct satellite cell populations: one for muscle growth and maintenance and one for muscle regeneration.     

Gene expression profiling of resting and activated vascular smooth muscle cells by serial analysis of gene expression and clustering analysis

Migration and proliferation of vascular smooth muscle cells (SMCs) are key events in atherosclerosis. However, little is known about alterations in gene expression upon transition of the quiescent, contractile SMC to the proliferative SMC. We performed serial analysis of gene expression (SAGE) of cultured, human SMCs, either grown under resting circumstances or activated with an atherogenic stimulus. Analysis of tags, representing 47,209 and 47,259 mRNAs from a library of resting and activated SMCs, respectively, identified 105 tags induced and 52 tags repressed greater than fivefold. To evaluate the relevance in SMC biology of unmatched, regulated tags, we performed hierarchical clustering analysis, based on their expression profiles in public SAGE databases, and clustered these novel genes in distinct groups. The regulation in SMCs was confirmed by Northern blotting for representative genes of these groups. Plasminogen activator inhibitor-2 has not been associated with atherosclerosis before and was localized to atherosclerotic lesions.     

Stem cell niche: Dynamic neighbor of stem cells

Stem cell niche is a specialized and dynamic microenvironment around the stem cells which plays a critical role in maintaining the stemness properties of stem cells. Over the years, advancement in the research activity has revealed the various important aspects of stem cell niche including cell-cell interaction, cell-extracellular matrix interaction, a large number of soluble signaling factors and various biochemical and biophysical cues (such as oxygen tension, flow, and shear and pore size). Stem cells have the potential to be a powerful tool in regenerative medicine due to their self-renewal property and immense differentiation potential. Recent progresses in in vitro culture conditions of embryonic stem cells, adult stem cells and induced pluripotent stem cells have enabled the researchers to investigate and understand the role of the microenvironment in stem cell properties. The engineered artificial stem cell niche has led to a better execution of stem cells in regenerative medicine. Here we elucidate the key components of stem cell niche and their role in niche engineering and stem cell therapeutics.     

The basement membrane of hair follicle stem cells is a muscle cell niche

The hair follicle bulge in the epidermis associates with the arrector pili muscle (APM) that is responsible for piloerection ("goosebumps"). We show that stem cells in the bulge deposit nephronectin into the underlying basement membrane, thus regulating the adhesion of mesenchymal cells expressing the nephronectin receptor, α8β1 integrin, to the bulge. Nephronectin induces α8 integrin-positive mesenchymal cells to upregulate smooth muscle markers. In nephronectin knockout mice, fewer arrector pili muscles form in the skin, and they attach to the follicle above the bulge, where there is compensatory upregulation of the nephronectin family member EGFL6. Deletion of α8 integrin also abolishes selective APM anchorage to the bulge. Nephronectin is a Wnt target; epidermal β-catenin activation upregulates epidermal nephronectin and dermal α8 integrin expression. Thus, bulge stem cells, via nephronectin expression, create a smooth muscle cell niche and act as tendon cells for the APM. Our results reveal a functional role for basement membrane heterogeneity in tissue patterning. PAPERCLIP:     

Signaling in adult neurogenesis: from stem cell niche to neuronal networks

The mechanisms that determine why neurogenesis is restricted to few regions of the adult brain in mammals, in contrast to its more widespread nature in other vertebrates such as zebrafish, remain to be fully understood. The local environment must provide key signals that instruct stem cell and neurogenic fate, because non-neurogenic progenitors can be instructed towards neurogenesis in this environment. Here, we discuss the recent progress in understanding key factors in the local stem cell niche of the adult mammalian brain, including surprising sources of new signals such as endothelial cells, complement factors and microglia. Moreover, new insights have been gained into how neuronal diversity is instructed in adult neurogenesis, prompting a new view of stem and progenitor cell heterogeneity in the adult mammalian brain.     

Nuclear transfer of adult bone marrow mesenchymal stem cells: developmental totipotency of tissue-specific stem cells from an adult mammal

Recent studies have demonstrated that somatic stem cells have a flexible potential greater than previously expected when they are transplanted into different tissues. On the other hand, recent studies also have revealed that these potentials might occur because of spontaneous cell fusion with recipient cells. The nuclei of somatic cells could have been reprogrammed when they were artificially or spontaneously fused with mouse embryonic stem (ES) cells. The resultant hybrid cells acquired a developmental pluripotency that the original somatic cells did not have but that ES cells did. LaBarge and Blau (Cell 2002; 111:589-601) demonstrated that adult bone marrow-derived cells contributed to muscle tissue in a stepwise biological progression. This means that bone marrow-derived cells became satellite cells of mononucleate muscle stem cells after the first irradiation-induced damage to the mouse, and after the second irradiation-induced damage, multinucleate myofibers appeared from the bone marrow-derived cells. Considered together, the differentiation potential of the somatic stem cell nucleus itself remains unclear. Although the pluripotency of somatic stem cell populations has been evaluated, the developmental totipotency of the nuclei of somatic stem cells, whether or not they fused with other cells, has not been shown, except in only one study concerning fetal neural cells (never in adult stem cells). Here, we showed the developmental totipotency of adult bovine mesenchymal stem cells by nuclear transfer.     

Colonization of the satellite cell niche by skeletal muscle progenitor cells depends on notch signals

Skeletal muscle growth and regeneration rely on myogenic progenitor and satellite cells, the stem cells of postnatal muscle. Elimination of Notch signals during mouse development results in premature differentiation of myogenic progenitors and formation of very small muscle groups. Here we show that this drastic effect is rescued by mutation of the muscle differentiation factor MyoD. However, rescued myogenic progenitors do not assume?a satellite cell position and contribute poorly to myofiber growth. The disrupted homing is due to a deficit in basal lamina assembly around emerging satellite cells and to their impaired adhesion to myofibers. On a molecular level, emerging satellite cells deregulate the expression of basal lamina components and adhesion molecules like integrin α7, collagen XVIIIα1, Megf10, and Mcam. We conclude that Notch signals control homing of satellite cells, stimulating them to?contribute to their own microenvironment and to adhere to myofibers.     

Stem cell review series: aging of the skeletal muscle stem cell niche

Declining stem cell function during aging contributes to impaired tissue function. Muscle-specific stem cells ('satellite cells') are responsible for generating new muscle in response to injury in the adult. However, aged muscle displays a significant reduction in regenerative abilities and an increased susceptibility to age-related pathologies. This review describes components of the satellite cell niche and addresses how age-related changes in these components impinge on satellite cell function. In particular, we review changes in the key niche elements, the myofiber and the basal lamina that are in intimate contact with satellite cells. We address how these elements are influenced by factors secreted by interstitial cells, cells of the immune system, and cells associated with the vasculature, all of which change with age. In addition, we consider more distant sources of influence on the satellite cell niche that change with age, such as neural-mediated trophic factors and electrical activity and systemic factors present in the circulation. A better understanding of the niche elements and their influence on the satellite cell will facilitate the development of therapeutic interventions aimed at improving satellite cell activity and ultimately tissue response to injury in aged individuals.     

Asymmetric self-renewal and commitment of satellite stem cells in muscle

Satellite cells play a central role in mediating the growth and regeneration of skeletal muscle. However, whether satellite cells are stem cells, committed progenitors, or dedifferentiated myoblasts has remained unclear. Using Myf5-Cre and ROSA26-YFP Cre-reporter alleles, we observed that in vivo 10% of sublaminar Pax7-expressing satellite cells have never expressed Myf5. Moreover, we found that Pax7(+)/Myf5(-) satellite cells gave rise to Pax7(+)/Myf5(+) satellite cells through apical-basal oriented divisions that asymmetrically generated a basal Pax7(+)/Myf5(-) and an apical Pax7(+)/Myf5(+) cells. Prospective isolation and transplantation into muscle revealed that whereas Pax7(+)/Myf5(+) cells exhibited precocious differentiation, Pax7(+)/Myf5(-) cells extensively contributed to the satellite cell reservoir throughout the injected muscle. Therefore, we conclude that satellite cells are a heterogeneous population composed of stem cells and committed progenitors. These results provide critical insights into satellite cell biology and open new avenues for therapeutic treatment of neuromuscular diseases.     

盐酸布比卡因、透明质酸酶对大鼠在体肌卫星细胞增殖的影响

目的 :研究盐酸布比卡因和透明质酸酶对成年大鼠肌卫星细胞在体增殖的影响。方法 :免疫组化法 ,H .E染色法 ,光镜和电镜观察。结果 :①正常对照组和生理盐水组肌纤维完整 ,有少量Desmin阳性肌卫星细胞 ,面密度值为 0 .66%± 0 .57%和 2 .48%± 1.13 %。生理盐水组较正常对照组无显著差异 (P >0 .0 5)。②透明质酸酶组肌纤维完整 ,Desmin阳性肌卫星细胞数量增加 ,面密度值为 2 .52 %± 1.41% ,较生理盐水组和正常对照组无显著差异(P >0 .0 5)。③盐酸布比卡因组和盐酸布比卡因 +透明质酸酶混合液组均可见大量坏死和溶解的肌纤维 ,并伴有肌卫星细胞的激活、增殖 ,Desmin阳性肌卫星细胞显著增加 ,并有部分融合形成小肌管。面密度值分别为 19.0 1%± 4.74%和 2 2 .41%± 7.64% ,较生理盐水组显著增加 (P <0 .0 1)。结论 :局麻药盐酸布比卡因能引起在体肌卫星细胞的活化、增殖并形成肌管 ,单独透明质酸酶溶液在本实验条件下对在体肌卫星细胞无明显作用     

Differentiation of activated satellite cells in denervated muscle following single fusions in situ and in cell culture

Satellite cells represent a cellular source of regeneration in adult skeletal muscle. It remains unclear why a large pool of stem myoblasts in denervated muscle does not compensate for the loss of muscle mass during post-denervation atrophy. In this study, we present evidence that satellite cells in long-term denervated rat muscle are able to activate synthesis of contractile proteins after single fusions in situ. This process of early differentiation leads to formation of abnormally diminutive myotubes. The localization of such dwarf myotubes beneath the intact basal lamina on the surface of differentiated muscle fibers shows that they form by fusion of neighboring satellites or by the progeny of a single satellite cell following one or two mitotic divisions. We demonstrated single fusions of myoblasts using electron microscopy, immunocytochemical labeling and high resolution confocal digital imaging. Sequestration of nascent myotubes by the rapidly forming basal laminae creates a barrier that limits further fusions. The recruitment of satellite cells in the formation of new muscle fibers results in a progressive decrease in their local densities, spatial separation and ultimate exhaustion of the myogenic cell pool. To determine whether the accumulation of aberrant dwarf myotubes is explained by the intrinsic decline of myogenic properties of satellite cells, or depends on their spatial separation and the environment in the tissue, we studied the fusion of myoblasts isolated from normal and denervated muscle in cell culture. The experiments with a culture system demonstrated that the capacity of myoblasts to synthesize contractile proteins without serial fusions depended on cell density and the availability of partners for fusion. Satellite cells isolated from denervated muscle and plated at fusion-permissive densities progressed through the myogenic program and actively formed myotubes, which shows that their myogenic potential is not considerably impaired. The results of this study suggest that under conditions of denervation, progressive spatial separation and confinement of many satellite cells within the endomysial tubes of atrophic muscle fibers and progressive interstitial fibrosis are the important factors that prevent their normal differentiation. Our findings also provide an explanation of why denervated muscle partially and temporarily is able to restore its functional capacity following injury and regeneration: the release of satellite cells from their sublaminal location provides the necessary space for a more active regenerative process.