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J Xu  P Wan  M Wang  J Zhang  X Gao  B Hu  J Han  L Chen  K Sun  J Wu  X Wu  X Huang  J Chen 《Cell death & disease》2015,6(7):e1818
In mammals, spermatogonial stem cells (SSCs) arise from early germ cells called gonocytes, which are derived from primordial germ cells during embryogenesis and remain quiescent until birth. After birth, these germ cells migrate from the center of testicular cord, through Sertoli cells, and toward the basement membrane to form the SSC pool and establish the SSC niche architecture. However, molecular mechanisms underlying germ cell migration and niche establishment are largely unknown. Here, we show that the actin disassembly factor actin interacting protein 1 (AIP1) is required in both germ cells and Sertoli cells to regulate this process. Germ cell-specific or Sertoli cell-specific deletion of Aip1 gene each led to significant defects in germ cell migration after postnatal day 4 or 5, accompanied by elevated levels of actin filaments (F-actin) in the affected cells. Furthermore, our data demonstrated that interaction between germ cells and Sertoli cells, likely through E-cadherin-mediated cell adhesion, is critical for germ cells'' migration toward the basement membrane. At last, Aip1 deletion in Sertoli cells decreased SSC self-renewal, increased spermatogonial differentiation, but did not affect the expression and secretion levels of growth factors, suggesting that the disruption of SSC function results from architectural changes in the postnatal niche.In mammals, spermatogenesis and male fertility depend on the self-renewing and differentiating functions of spermatogonial stem cells (SSCs), which are regulated by cues from the niche microenvironment.1 During embryogenesis, the precursors of SSCs can be traced to primordial germ cells (PGCs) in the proximal epiblast at embryonic day 6.25 (E6.25), which migrate to genital ridge and together with somatic cells there to form the embryonic gonad.2 The PGCs then differentiate to gonocytes (also called prespermatogonia), proliferate for a brief period of time, and then remain mitotically quiescent until birth.3, 4, 5 After birth, these neonatal germ cells (gonocytes) located at the center of testicular cord become proliferative and relocate themselves from the center toward the basement membrane of each testicular cord.4, 6 During the migration or relocation process, germ cells associate with and move through the Sertoli cells, the sole somatic cell type within the testicular cord and the major component of the SSC niche. After reaching the basement membrane at the periphery, most of these germ cells adopt a distinct morphology and become the undifferentiated spermatogonial population, which includes SSCs and other non-stem cell progenitors,7, 8, 9 supposedly in response to cues from the supporting cells. It has been suggested that the postnatal germ cell migration is crucial for the formation of SSC pool and the establishment of the SSC niche architecture. However, the mechanisms underlying these two processes are not well understood.In neonatal mice, germ cells specifically express the cell adhesion molecule E-cadherin on the cell surface,10, 11 whereas other adhesion markers including N-cadherin and β1-integrin were found in both germ cells and Sertoli cells.12, 13, 14 However, whether these adhesion molecules have specific roles in germ cells'' outward migration and subsequent differentiation were not yet known. In Drosophila testis, the germline stem cells (GSCs) were shown to attach to the somatic hub cells (a major niche component) via membrane bound E-cadherin in both cell groups, and disruption of E-cadherin-mediated cell adhesion between GSCs and hub cells severely affected self-renewal and maintenance of GSCs.15, 16 Moreover, a recent study showed that the actin polymerization regulator profilin is required to localize and maintain E-cadherin to the GSC-hub cell interface and is thus essential for the maintenance of GSCs. This result is consistent with findings in other systems that dynamics of actin cytoskeleton directly regulate the assembly and maintenance of E-cadherin-based cell adhesion.17 Interestingly, we have previously shown that actin interacting protein 1 (AIP1), an actin disassembly factor, regulates E-cadherin distribution and dynamics during a cell rearrangement process of the Drosophila eye disc.18 AIP1 has been shown to act together with cofilin/actin-depolymerizing factors to promote actin dynamics in various cellular processes, and it is highly conserved in all eukaryotes examined so far.19, 20, 21, 22, 23, 24 Here, we utilized germ cell- or Sertoli cell-specific deletion of Aip1 (also known as Wdr1) in the murine testis to study the process of germ cell migration and SSC niche establishment.  相似文献   

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Liver fibrosis is a serious disease that is characterized by the excess deposition of extracellular matrix (ECM) components. Activated hepatic stellate cells (HSCs) are a major source of ECM and serve as a key regulator in liver fibrogenesis. Inactivation of HSCs is essential for liver fibrotic regression. The present study explores the underlying mechanisms of Schistosoma japonicum egg antigen p40 (Sjp40) promoting senescence in HSCs and antifibrosis. For the first time we report that Sjp40 inhibits the activation and proliferation of an immortalized human HSC line (LX-2 cells) and promotes cellular senescence and cell cycle arrest. Sjp40 through action on the STAT3/p53/p21 pathway triggered cellular senescence, while knockdown of p53 or STAT3 partly restored cell senescence. In addition, Sjp40-induced cellular senescence caused LX-2 cells to be more sensitive to a human NK cell line (YT cells). Together these findings provide novel insights into the mechanism of antifibrosis and may have implications for the development of antifibrosis therapies.Liver fibrosis is defined as the excess deposition of extracellular matrix (ECM) components, including fibronectin and collagen, that leads to cirrhosis, liver failure and portal hypertension in advanced hepatic fibrosis.1, 2 It is widely accepted that activated hepatic stellate cells (HSCs) are a major source of the ECM and play a central role in liver fibrogenesis. HSCs undergo a transformation from a quiescent cell to a myofibroblast that can produce a great deal of ECM and secrete large amounts of pro-inflammatory and pro-fibrogenic cytokines.3, 4 Therefore, the inhibition of HSC activation and the removal of activated HSCs have been effective strategies used to combat hepatic fibrosis.5, 6 In recent years, the role of senescence in activated HSCs has been explored, and studies have found that HSCs that underwent cellular senescence resulted in liver fibrosis regression.7 These data suggest that the induction of senescence in activated HSCs may be a promising approach for treating hepatic fibrosis.Schistosomiasis is a parasitic disease characterized by egg deposition, a granulomatous inflammatory reaction and subsequent hepatic fibrosis formation.8, 9 However, the antifibrotic effect of Schistosoma eggs and soluble egg antigens (SEA) on activated HSCs has been demonstrated in both Schistosoma mansoni eggs and Schistosoma japonicum eggs. These eggs could restrict the activation of HSCs during hepatic fibrogenesis.10, 11 Our previous research demonstrated that SEA from S. japonicum induced suppression of activated human HSC cell lines (LX-2) and primary mice HSCs through the TGFβ and PPARγ signaling pathways.12 SEA-treated LX-2 and primary HSCs exhibited cell cycle arrest, cell growth inhibition, and both caspase-12 and p53/DR5-dependent apoptosis.13SEA is a complex mixture that is composed of a number of egg antigens. Some laboratories have isolated multiple antigens from SEAs, including Smp40 (S. mansoni egg antigen p40) and Sjp40 (S. japonicum egg antigen p40). Smp40 has been cloned, sequenced and shown to have high immunogenicity in humans.14 The Sjp40 antigen may be a promising target for prevention and control of the disease following its discovery as a marker for early schistosomiasis diagnosis.15 Sjp40 has also been observed to markedly increase IL-10 and significantly reduce IL-5 in Smp40-treated peripheral blood mononuclear cells from patients infected with S. japonicum.16 In addition, other studies have been carried out that support a role for IL-10 and IL-5 in hepatic fibrosis. Research has demonstrated that IL-10 could reverse hepatic fibrosis by attenuating the expression of matrix metalloproteinase and collagen.17, 18 More work also showcased the ability of IL-5 to promote the progression of hepatic fibrosis by regulating IL-13 activity.19 Together, these observations support a model in which Sjp40 might modulate liver fibrosis and exert an antifibrosis effect.In previous research by our laboratory we expressed and purified Sjp40 and used this antigen to stimulate LX-2 cells in vitro.20 Our results confirmed that Sjp40 potently inhibited the activation of HSCs and combated liver fibrosis. We also demonstrated, for the first time, that Sjp40 could induce cellular senescence in LX-2 cells. In this work we set out to clarify the role of Sjp40-induced senescence in LX-2 cells and elucidate the underlying molecular mechanism.  相似文献   

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The erythropoietin receptor (EpoR) was discovered and described in red blood cells (RBCs), stimulating its proliferation and survival. The target in humans for EpoR agonists drugs appears clear—to treat anemia. However, there is evidence of the pleitropic actions of erythropoietin (Epo). For that reason, rhEpo therapy was suggested as a reliable approach for treating a broad range of pathologies, including heart and cardiovascular diseases, neurodegenerative disorders (Parkinson’s and Alzheimer’s disease), spinal cord injury, stroke, diabetic retinopathy and rare diseases (Friedreich ataxia). Unfortunately, the side effects of rhEpo are also evident. A new generation of nonhematopoietic EpoR agonists drugs (asialoEpo, Cepo and ARA 290) have been investigated and further developed. These EpoR agonists, without the erythropoietic activity of Epo, while preserving its tissue-protective properties, will provide better outcomes in ongoing clinical trials. Nonhematopoietic EpoR agonists represent safer and more effective surrogates for the treatment of several diseases such as brain and peripheral nerve injury, diabetic complications, renal ischemia, rare diseases, myocardial infarction, chronic heart disease and others.In principle, the erythropoietin receptor (EpoR) was discovered and described in red blood cell (RBC) progenitors, stimulating its proliferation and survival. Erythropoietin (Epo) is mainly synthesized in fetal liver and adult kidneys (13). Therefore, it was hypothesized that Epo act exclusively on erythroid progenitor cells. Accordingly, the target in humans for EpoR agonists drugs (such as recombinant erythropoietin [rhEpo], in general, called erythropoiesis-simulating agents) appears clear (that is, to treat anemia). However, evidence of a kaleidoscope of pleitropic actions of Epo has been provided (4,5). The Epo/EpoR axis research involved an initial journey from laboratory basic research to clinical therapeutics. However, as a consequence of clinical observations, basic research on Epo/EpoR comes back to expand its clinical therapeutic applicability.Although kidney and liver have long been considered the major sources of synthesis, Epo mRNA expression has also been detected in the brain (neurons and glial cells), lung, heart, bone marrow, spleen, hair follicles, reproductive tract and osteoblasts (617). Accordingly, EpoR was detected in other cells, such as neurons, astrocytes, microglia, immune cells, cancer cell lines, endothelial cells, bone marrow stromal cells and cells of heart, reproductive system, gastrointestinal tract, kidney, pancreas and skeletal muscle (1827). Conversely, Sinclair et al.(28) reported data questioning the presence or function of EpoR on nonhematopoietic cells (endothelial, neuronal and cardiac cells), suggesting that further studies are needed to confirm the diversity of EpoR. Elliott et al.(29) also showed that EpoR is virtually undetectable in human renal cells and other tissues with no detectable EpoR on cell surfaces. These results have raised doubts about the preclinical basis for studies exploring pleiotropic actions of rhEpo (30).For the above-mentioned data, a return to basic research studies has become necessary, and many studies in animal models have been initiated or have already been performed. The effect of rhEpo administration on angiogenesis, myogenesis, shift in muscle fiber types and oxidative enzyme activities in skeletal muscle (4,31), cardiac muscle mitochondrial biogenesis (32), cognitive effects (31), antiapoptotic and antiinflammatory actions (3337) and plasma glucose concentrations (38) has been extensively studied. Neuro- and cardioprotection properties have been mainly described. Accordingly, rhEpo therapy was suggested as a reliable approach for treating a broad range of pathologies, including heart and cardiovascular diseases, neurodegenerative disorders (Parkinson’s and Alzheimer’s disease), spinal cord injury, stroke, diabetic retinopathy and rare diseases (Friedreich ataxia).Unfortunately, the side effects of rhEpo are also evident. Epo is involved in regulating tumor angiogenesis (39) and probably in the survival and growth of tumor cells (25,40,41). rhEpo administration also induces serious side effects such as hypertension, polycythemia, myocardial infarction, stroke and seizures, platelet activation and increased thromboembolic risk, and immunogenicity (4246), with the most common being hypertension (47,48). A new generation of nonhematopoietic EpoR agonists drugs have hence been investigated and further developed in animals models. These compounds, namely asialoerythropoietin (asialoEpo) and carbamylated Epo (Cepo), were developed for preserving tissue-protective properties but reducing the erythropoietic activity of native Epo (49,50). These drugs will provide better outcome in ongoing clinical trials. The advantage of using nonhematopoietic Epo analogs is to avoid the stimulation of hematopoiesis and thereby the prevention of an increased hematocrit with a subsequent procoagulant status or increased blood pressure. In this regard, a new study by van Rijt et al. has shed new light on this topic (51). A new nonhematopoietic EpoR agonist analog named ARA 290 has been developed, promising cytoprotective capacities to prevent renal ischemia/reperfusion injury (51). ARA 290 is a short peptide that has shown no safety concerns in preclinical and human studies. In addition, ARA 290 has proven efficacious in cardiac disorders (52,53), neuropathic pain (54) and sarcoidosis-induced chronic neuropathic pain (55). Thus, ARA 290 is a novel nonhematopoietic EpoR agonist with promising therapeutic options in treating a wide range of pathologies and without increased risks of cardiovascular events.Overall, this new generation of EpoR agonists without the erythropoietic activity of Epo while preserving tissue-protective properties of Epo will provide better outcomes in ongoing clinical trials (49,50). Nonhematopoietic EpoR agonists represent safer and more effective surrogates for the treatment of several diseases, such as brain and peripheral nerve injury, diabetic complications, renal ischemia, rare diseases, myocardial infarction, chronic heart disease and others.  相似文献   

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V Horsley 《The EMBO journal》2012,31(18):3653-3654
Science advance online publication July192012; doi:10.1126/science.1218835The maintenance and regeneration of continually shedding epithelial tissues that make up the linings and barriers of our bodies requires rapid and continual input of proliferative progenitor cells for tissue homeostasis. The mechanisms by which epithelial progenitors cells maintain tissues remain controversial. In a recent Science paper, Doupé et al (2012) demonstrate that a population of equivalent progenitor cells support tissue homeostasis of the oesophagus without the need for slow cycling cells as described in other rapidly dividing epithelia.In tissues such as blood and skin in which differentiated cells constantly turnover, proliferative progenitor populations are required to continually produce lost differentiated cells. Several models have been proposed to explain mechanisms by which progenitor cells contribute to tissue maintenance (Figure 1). A hierarchical model has been suggested in which longer lived stem cells, which may also cycle slowly, produce highly proliferative cells with less self-renewal potential that differentiate into a restricted number of cells. Following proliferative cells in pulse-chase experiments and genetic lineage tracing has supported a hierarchical model in the blood, epidermis and intestine (Fuchs, 2009). Alternatively, an equivalency model has been proposed in which all proliferative progenitor cells are equally able to produce proliferative and differentiated progeny in a stochastic manner. Analysis of labelled clones has supported an equivalency model for progenitors in the interfollicular epidermis and intestine (Clayton et al, 2007; Doupé et al, 2010; Snippert et al, 2010).Open in a separate windowFigure 1Two types of models have been put forward to describe the pattern of progenitor behaviour within mammalian tissues. In the hierarchical model, a stem cell can produce proliferative progenitors with less self-renewal potential that differentiate into lineage-specific cells. Alternatively, an equivalency model has been proposed that assumes equal behaviour of progenitor cells to maintain tissue homeostasis.An elevated interest in understanding the dynamics of oesophageal epithelium has resulted, in part, from the rapid increase in the incidence of oesophageal adenocarcinoma (Devesa et al, 1998). The oesophagus is a stratified epithelium that lacks any appendages or glands, and thus consists of a basal layer of proliferative keratinocytes and several suprabasal layers of differentiated cells, which are continually shed. Previously, labelling of proliferative cells with DNA analogues has demonstrated that proliferation is restricted to the basal cells, which all proliferate in 5 days seemingly stochastically, supporting an equivalency model (Marques-Periera and Leblond, 1965). In contrast, studies using chimeric mice have suggested that proliferation of labelled progenitor cells occurs in a hierarchical manner (Thomas et al, 1988; Croagh et al, 2008).To address this controversy, a recent study in Science uses several genetic mouse models to define the contribution of proliferative basal cells to oesophageal homeostasis (Doupé et al, 2012). In one mouse model, the authors utilized a genetic pulse-chase system based on the tetracycline-regulated expression of the histone H2B-GFP (Tumbar et al, 2004). They find that the rapidly dividing epithelial cells of the oesophagus lose H2B-GFP expression after 4 weeks. These data suggest that either H2B-GFP is degraded (Waghmare et al, 2008) or oesophageal progenitor cells proliferate faster than their counterparts in skin epithelial appendages or blood lineages, which retain H2B-GFP after 4 weeks (Tumbar et al, 2004; Foudi et al, 2009).To analyse the properties of oesophageal progenitor cells in more detail, the authors label single cells using an inducible cre-lox genetic system and followed clones for a year. Similar to their results with this system in the tail and ear epidermis (Clayton et al, 2007; Doupé et al, 2010), the authors find that the size of the persistent clones is linear with time. Statistical analysis of the clone size data supports the ability of the cells to contribute to proliferative and non-proliferative (i.e., differentiated) progeny with equal probability. Thus, these data support a model in which all of the labelled cells are equivalent.In addition to homeostasis, the authors explore how proliferative progenitors contribute to alterations in tissue homeostasis. After inflicting wounds by biopsy, marked clones span both proliferative and non-proliferative zones of the healing oesophageal epithelium, suggesting that they maintain a progenitor fate with distinct phenotypes. With atRA treatment, the authors show that suprabasal cell formation increases, which is consistent with the known effect of atRA on the oesophagus (Lasnitzki, 1963). Statistical analysis reveals that the probability of forming basal and suprabasal cells was not altered with atRA administration. However, since proliferative cells exist in suprabasal layers during epithelial hyperplasia, additional analyses of cell state are required to determine if atRA maintains stochastic fate decisions of progenitor cells. Furthermore, the progenitor response to atRA treatment might be limited by niche space along the basement membrane like in intestinal crypt progenitor cells (Snippert et al, 2010).In summary, this study together with the authors'' previous work provides additional support for the existence of equivalent progenitor cells within stratified epithelium in several tissues. Additional studies revealing how epithelial progenitor cells behave when proliferation and differentiation are altered in the oesophagus could shed light on mechanisms for the pathogenesis of oesophageal tumours or diseases such as Barrett''s oesophagus.  相似文献   

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EMBO J (2013) 32 23, 3017–3028 10.1038/emboj.2013.224; published online October182013Commensal gut bacteria benefit their host in many ways, for instance by aiding digestion and producing vitamins. In a new study in The EMBO Journal, Jones et al (2013) report that commensal bacteria can also promote intestinal epithelial renewal in both flies and mice. Interestingly, among commensals this effect is most specific to Lactobacilli, the friendly bacteria we use to produce cheese and yogurt. Lactobacilli stimulate NADPH oxidase (dNox/Nox1)-dependent ROS production by intestinal enterocytes and thereby activate intestinal stem cells.The human gut contains huge numbers of bacteria (∼1014/person) that play beneficial roles for our health, including digestion, building our immune system and competing with harmful microbes (Sommer and Backhed, 2013). Both commensal and pathogenic bacteria can elicit antimicrobial responses in the intestinal epithelium and also stimulate epithelial turnover (Buchon et al, 2013; Sommer and Backhed, 2013). In contrast to gut pathogens, relatively little is known about how commensal bacteria influence intestinal turnover. In a simple yet elegant study reported recently in The EMBO Journal, Jones et al (2013) show that among several different commensal bacteria tested, only Lactobacilli promoted much intestinal stem cell (ISC) proliferation, and it did so by stimulating reactive oxygen species (ROS) production. Interestingly, the specific effect of Lactobacilli was similar in both Drosophila and mice. In addition to distinguishing functional differences between species of commensals, this work suggests how the ingestion of Lactobacillus-containing probiotic supplements or food (e.g., yogurt) might support epithelial turnover and health.In both mammals and insects, ISCs give rise to intestinal enterocytes, which not only absorb nutrients from the diet but must also interact with the gut microbiota (Jiang and Edgar, 2012). The metazoan intestinal epithelium has developed conserved responses to enteric bacteria, for instance the expression of antimicrobial peptides (AMPs; Gallo and Hooper, 2012; Buchon et al, 2013), presumably to kill harmful bacteria while allowing symbiotic commensals to flourish. In addition to AMPs, intestinal epithelial cells use NADPH family oxidases to generate ROS that are used as microbicides (Lambeth and Neish, 2013). High ROS levels during enteric infections likely act non-discriminately against both commensals and pathogens, but controlled, low-level ROS can act as signalling molecules that regulate various cellular processes including proliferation (Lambeth and Neish, 2013). In flies, exposure to pathogenic Gram-negative bacteria has been reported to result in ROS (H2O2) production by an enzyme called dual oxidase (Duox; Ha et al, 2005). Duox activity in the fly intestine (and likely also the mammalian one) has recently been discovered to be stimulated by uracil secretion by pathogenic bacteria (Lee et al, 2013). In the mammalian intestine another enzyme, NADPH oxidase (Nox), has also been shown to produce ROS in the form of superoxide (O2), in this case in response to formylated bacterial peptides (Lambeth and Neish, 2013). A conserved role for Nox in the Drosophila intestinal epithelium had not until now been explored.Jones et al (2013) checked seven different commensal bacterial to see which would stimulate ROS production by the fly''s intestinal epithelium, and found that only one species, a Gram-positive Lactobacillus, could stimulate significant production of ROS in intestinal enterocytes. Five bacterial species were checked in mice or cultured intestinal cells, and again it was a Lactobacillus that generated the strongest ROS response. Although not all of the most prevalent enteric bacteria were assayed, those others that were—such as E. coli—induced only mild, barely detectable levels of ROS in enterocytes. Surprisingly, although bacteria pathogenic to Drosophila, like Erwinia caratovora, were expected to stimulate ROS production via Duox, Jones et al (2013) did not observe this using the ROS detecting dye hydrocyanine-Cy3, or a ROS-sensitive transgene reporter, Glutatione S-transferase-GFP, in flies. Further, Jones et al (2013) found that genetically suppressing Nox in either Drosophila or mice decreased ROS production after Lactobacillus ingestion. Consistent with the important role of Nox, Duox appeared not to be required for ROS production after Lactobacillus ingestion. In addition, Jones et al (2013) found that Lactobacilli also promoted DNA replication—a metric of cell proliferation and epithelial renewal—in the fly''s intestine, and that this was also ROS- and Nox-dependent. Again, the same relationship was found in the mouse small intestine. Together, these results suggest a conserved mechanism by which Lactobacilli can stimulate Nox-dependent ROS production in intestinal enterocytes and thereby promote ISC proliferation and enhance gut epithelial renewal.In the fly midgut, uracil produced by pathogenic bacteria can stimulate Duox-dependent ROS production, which is thought to act as a microbicide (Lee et al, 2013), and can also promote ISC proliferation (Buchon et al, 2009). However, Duox-produced ROS may also damage the intestinal epithelium itself and thereby promote epithelial regeneration indirectly through stress responses. In this disease scenario, ROS appears to be sensed by the stress-activated Jun N-terminal Kinase (JNK; Figure 1A), which can induce pro-proliferative cytokines of the Leptin/IL-6 family (Unpaireds, Upd1–3) (Buchon et al, 2009; Jiang et al, 2009). These cytokines activate JAK/STAT signalling in the ISCs, promoting their growth and proliferation, and accelerating regenerative repair of the gut epithelium (Buchon et al, 2009; Jiang et al, 2009). It is also possible, however, that low-level ROS, or specific types of ROS (e.g., H2O2) might induce ISC proliferation directly by acting as a signal between enterocytes and ISCs. Since commensal Lactobacillus stimulates ROS production via Nox rather than Duox, this might be a case in which a non-damaging ROS signal promotes intestinal epithelial renewal without stress signalling or a microbicidal effect (Figure 1B). However, Jones et al (2013) stopped short of ruling out a role for oxidative damage, cell death or stress signalling in the intestinal epithelium following colonization by Lactobacilli, and so these parameters must be checked in future studies. Perhaps even the friendliest symbiotes cause a bit of ‘healthy'' damage to the gut lining, stimulating it to refresh and renew. Whether damage-dependent or not, the stimulation of Drosophila ISC proliferation by commensals and pathogens alike appears to involve the same cytokine (Upd3; Buchon et al, 2009), and so some of the differences between truly pathogenic and ‘friendly'' gut microbes might be ascribed more to matters of degree than qualitative distinctions. Future studies exploring exactly how different types of ROS signals stimulate JNK activity, gut cytokine expression and epithelial renewal should be able to sort this out, and perhaps help us learn how to better manage the ecosystems in our own bellies. From the lovely examples reported by Jones et al (2013), an experimental back-and-forth between the Drosophila and mouse intestine seems an informative way to go.Open in a separate windowFigure 1Metazoan intestinal epithelial responses to commensal and pathogenic bacteria. (A) High reactive oxygen species (ROS) levels generated by dual oxidase (Duox) in response to uracil secretion by pathogenic bacteria. (B) Low ROS levels generated by NADPH oxidase (Nox) in response to commensal bacteria. In addition to acting as a microbiocide, ROS in flies may stimulate JNK signaling and cytokine (Upd 1–3) expression in enterocytes, thereby stimulating ISC proliferation and epithelial turnover or regeneration. Whether this stimulation required damage to or loss of enterocytes has yet to be explored.  相似文献   

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Background:

The gut microbiota is essential to human health throughout life, yet the acquisition and development of this microbial community during infancy remains poorly understood. Meanwhile, there is increasing concern over rising rates of cesarean delivery and insufficient exclusive breastfeeding of infants in developed countries. In this article, we characterize the gut microbiota of healthy Canadian infants and describe the influence of cesarean delivery and formula feeding.

Methods:

We included a subset of 24 term infants from the Canadian Healthy Infant Longitudinal Development (CHILD) birth cohort. Mode of delivery was obtained from medical records, and mothers were asked to report on infant diet and medication use. Fecal samples were collected at 4 months of age, and we characterized the microbiota composition using high-throughput DNA sequencing.

Results:

We observed high variability in the profiles of fecal microbiota among the infants. The profiles were generally dominated by Actinobacteria (mainly the genus Bifidobacterium) and Firmicutes (with diverse representation from numerous genera). Compared with breastfed infants, formula-fed infants had increased richness of species, with overrepresentation of Clostridium difficile. Escherichia–Shigella and Bacteroides species were underrepresented in infants born by cesarean delivery. Infants born by elective cesarean delivery had particularly low bacterial richness and diversity.

Interpretation:

These findings advance our understanding of the gut microbiota in healthy infants. They also provide new evidence for the effects of delivery mode and infant diet as determinants of this essential microbial community in early life.The human body harbours trillions of microbes, known collectively as the “human microbiome.” By far the highest density of commensal bacteria is found in the digestive tract, where resident microbes outnumber host cells by at least 10 to 1. Gut bacteria play a fundamental role in human health by promoting intestinal homeostasis, stimulating development of the immune system, providing protection against pathogens, and contributing to the processing of nutrients and harvesting of energy.1,2 The disruption of the gut microbiota has been linked to an increasing number of diseases, including inflammatory bowel disease, necrotizing enterocolitis, diabetes, obesity, cancer, allergies and asthma.1 Despite this evidence and a growing appreciation for the integral role of the gut microbiota in lifelong health, relatively little is known about the acquisition and development of this complex microbial community during infancy.3Two of the best-studied determinants of the gut microbiota during infancy are mode of delivery and exposure to breast milk.4,5 Cesarean delivery perturbs normal colonization of the infant gut by preventing exposure to maternal microbes, whereas breastfeeding promotes a “healthy” gut microbiota by providing selective metabolic substrates for beneficial bacteria.3,5 Despite recommendations from the World Health Organization,6 the rate of cesarean delivery has continued to rise in developed countries and rates of breastfeeding decrease substantially within the first few months of life.7,8 In Canada, more than 1 in 4 newborns are born by cesarean delivery, and less than 15% of infants are exclusively breastfed for the recommended duration of 6 months.9,10 In some parts of the world, elective cesarean deliveries are performed by maternal request, often because of apprehension about pain during childbirth, and sometimes for patient–physician convenience.11The potential long-term consequences of decisions regarding mode of delivery and infant diet are not to be underestimated. Infants born by cesarean delivery are at increased risk of asthma, obesity and type 1 diabetes,12 whereas breastfeeding is variably protective against these and other disorders.13 These long-term health consequences may be partially attributable to disruption of the gut microbiota.12,14Historically, the gut microbiota has been studied with the use of culture-based methodologies to examine individual organisms. However, up to 80% of intestinal microbes cannot be grown in culture.3,15 New technology using culture-independent DNA sequencing enables comprehensive detection of intestinal microbes and permits simultaneous characterization of entire microbial communities. Multinational consortia have been established to characterize the “normal” adult microbiome using these exciting new methods;16 however, these methods have been underused in infant studies. Because early colonization may have long-lasting effects on health, infant studies are vital.3,4 Among the few studies of infant gut microbiota using DNA sequencing, most were conducted in restricted populations, such as infants delivered vaginally,17 infants born by cesarean delivery who were formula-fed18 or preterm infants with necrotizing enterocolitis.19Thus, the gut microbiota is essential to human health, yet the acquisition and development of this microbial community during infancy remains poorly understood.3 In the current study, we address this gap in knowledge using new sequencing technology and detailed exposure assessments20 of healthy Canadian infants selected from a national birth cohort to provide representative, comprehensive profiles of gut microbiota according to mode of delivery and infant diet.  相似文献   

11.
Elucidating the temporal order of silencing   总被引:1,自引:0,他引:1  
Izaurralde E 《EMBO reports》2012,13(8):662-663
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12.
EMBO J 32: 2905–2919 10.1038/emboj.2013.199; published online September032013Some B cells of the adaptive immune system secrete polyreactive immunoglobulin G (IgG) in the absence of immunization or infection. Owing to its limited affinity and specificity, this natural IgG is thought to play a modest protective role. In this issue, a report reveals that natural IgG binds to microbes following their opsonization by ficolin and mannan-binding lectin (MBL), two carbohydrate receptors of the innate immune system. The interaction of natural IgG with ficolins and MBL protects against pathogenic bacteria via a complement-independent mechanism that involves IgG receptor FcγRI expressing macrophages. Thus, natural IgG enhances immunity by adopting a defensive strategy that crossovers the conventional boundaries between innate and adaptive microbial recognition systems.The adaptive immune system generates protective somatically recombined antibodies through a T cell-dependent (TD) pathway that involves follicular B cells. After recognizing antigen through the B-cell receptor (BCR), follicular B cells establish a cognate interaction with CD4+ T follicular helper (TFH) cells and thereafter either rapidly differentiate into short-lived IgM-secreting plasmablasts or enter the germinal centre (GC) of lymphoid follicles to complete class switch recombination (CSR) and somatic hypermutation (SHM) (Victora and Nussenzweig, 2012). CSR from IgM to IgG, IgA and IgE generates antibodies with novel effector functions, whereas SHM provides the structural correlate for the induction of affinity maturation (Victora and Nussenzweig, 2012). Eventually, this canonical TD pathway generates long-lived bone marrow plasma cells and circulating memory B cells that produce protective class-switched antibodies capable to recognize specific antigens with high affinity (Victora and Nussenzweig, 2012).In addition to post-immune monoreactive antibodies, B cells produce pre-immune polyreactive antibodies in the absence of conventional antigenic stimulation (Ehrenstein and Notley, 2010). These natural antibodies form a vast and stable repertoire that recognizes both non-protein and protein antigens with low affinity (Ehrenstein and Notley, 2010). Natural antibodies usually emerge from a T cell-independent (TI) pathway that involves innate-like B-1 and marginal zone (MZ) B cells. These are extrafollicular B-cell subsets that rapidly differentiate into short-lived antibody-secreting plasmablasts after detecting highly conserved microbial and autologus antigens through polyreactive BCRs and nonspecific germline-encoded pattern recognition receptors (Pone et al, 2012; Cerutti et al, 2013).The most studied natural antibody is IgM, a pentameric complement-activating molecule with high avidity but low affinity for antigen (Ehrenstein and Notley, 2010). In addition to promoting the initial clearance of intruding microbes, natural IgM regulates tissue homeostasis, immunological tolerance and tumour surveillance (Ochsenbein et al, 1999; Zhou et al, 2007; Ehrenstein and Notley, 2010). Besides secreting IgM, B-1 and MZ B cells produce IgG and IgA after receiving CSR-inducing signals from dendritic cells (DCs), macrophages and neutrophils of the innate immune system (Cohen and Norins, 1966; Cerutti et al, 2013). In humans, certain natural IgG and IgA are moderately mutated and show some specificity, which may reflect the ability of human MZ B cells to undergo SHM (Cerutti et al, 2013). Yet, natural IgG and IgA are generally perceived as functionally quiescent.In this issue, Panda et al show that natural IgG bound to a broad spectrum of bacteria with high affinity by cooperating with ficolin and MBL (Panda et al, 2013), two ancestral soluble lectins of the innate immune system (Holmskov et al, 2003). This binding involved some degree of specificity, because it required the presence of ficolin or MBL on the microbial surface as well as lower pH and decreased calcium concentration in the extracellular environment as a result of infection or inflammation (see Figure 1).Open in a separate windowFigure 1Ficolins and MBL are produced by hepatocytes and various cells of the innate immune system and opsonize bacteria after recognizing conserved carbohydrates. Low pH and calcium concentrations present under infection-inflammation conditions promote the interaction of ficolin or MBL with natural IgG on the surface of bacteria. The resulting immunocomplex is efficiently phagocytosed by macrophages through FcγR1 independently of the complement protein C3, leading to the clearance of bacteria.Ficolins and MBL are soluble pattern recognition receptors that opsonize microbes after binding to glycoconjugates through distinct carbohydrate recognition domain (CRD) structures (Holmskov et al, 2003). While ficolins use a fibrinogen domain, MBL and other members of the collectin family use a C-type lectin domain attached to a collagen-like region (Holmskov et al, 2003). Similar to pentraxins, ficolins and MBL are released by innate effector cells and hepatocytes, and thus may have served as ancestral antibody-like molecules prior to the inception of the adaptive immune system (Holmskov et al, 2003; Bottazzi et al, 2010). Of note, MBL and the MBL-like complement protein C1q are recruited by natural IgM to mediate complement-dependent clearance of autologous apoptotic cells and microbes (Holmskov et al, 2003; Ehrenstein and Notley, 2010). Panda et al found that a similar lectin-dependent co-optation strategy enhances the protective properties of natural IgG (Panda et al, 2013).By using bacteria and the bacterial glycan N-acetylglicosamine, Panda et al show that natural IgG isolated from human serum or T cell-deficient mice interacted with the fibrinogen domain of microbe-associated ficolins (Panda et al, 2013). The resulting immunocomplex was phagocytosed by macrophages via the IgG receptor FcγRI in a complement-independent manner (Panda et al, 2013). The additional involvement of MBL was demonstrated by experiments showing that natural IgG retained some bacteria-binding activity in the absence of ficolins (Panda et al, 2013).Surface plasmon resonance provided some clues regarding the molecular requirements of the ficolin–IgG interaction (Panda et al, 2013), but the conformational changes required by ficolin to interact with natural IgG remain to be addressed. In particular, it is unclear what segment of the effector Fc domain of natural IgG binds to ficolins and whether Fc-associated glycans are involved in this binding. Specific glycans have been recently shown to mitigate the inflammatory properties of IgG emerging from TI responses (Hess et al, 2013) and this process could implicate ficolins and MBL. Moreover, it would be important to elucidate whether and how the antigen-binding Fab portion of natural IgG regulates its interaction with ficolins and MBL.The in vivo protective role of natural IgG was elegantly demonstrated by showing that reconstitution of IgG-deficient mice lacking the CSR-enzyme activation-induced cytidine deaminase with natural IgG from T cell-insufficient animals enhanced resistance to pathogenic Pseudomonas aeruginosa (Panda et al, 2013). This protective effect was associated with reduced production of proinflammatory cytokines, occurred independently of the complement protein C3 and was impaired by peptides capable to inhibit the binding of natural IgG to ficolin (Panda et al, 2013). Additional in vivo studies will be needed to determine whether natural IgG exerts protective activity in mice lacking ficolin, MBL or FcγRI, and to ascertain whether these molecules also enhance the protective properties of canonical or natural IgG and IgA released by bone marrow plasma cells and mucosal plasma cells, respectively.In conclusion, the findings by Panda et al show that natural IgG adopts ‘crossover'' defensive strategies that blur the conventional boundaries between the innate and adaptive immune systems. The sophisticated integration of somatically recombined and germline-encoded antigen recognition systems described in this new study shall stimulate immunologists to further explore the often underestimated protective virtues of our vast natural antibody repertoire. This effort may lead to the development of novel therapies against infections.  相似文献   

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Schultz AS  Finegan B  Nykiforuk CI  Kvern MA 《CMAJ》2011,183(18):E1334-E1344

Background:

Many hospitals have adopted smoke-free policies on their property. We examined the consequences of such polices at two Canadian tertiary acute-care hospitals.

Methods:

We conducted a qualitative study using ethnographic techniques over a six-month period. Participants (n = 186) shared their perspectives on and experiences with tobacco dependence and managing the use of tobacco, as well as their impressions of the smoke-free policy. We interviewed inpatients individually from eight wards (n = 82), key policy-makers (n = 9) and support staff (n = 14) and held 16 focus groups with health care providers and ward staff (n = 81). We also reviewed ward documents relating to tobacco dependence and looked at smoking-related activities on hospital property.

Results:

Noncompliance with the policy and exposure to secondhand smoke were ongoing concerns. Peoples’ impressions of the use of tobacco varied, including divergent opinions as to whether such use was a bad habit or an addiction. Treatment for tobacco dependence and the management of symptoms of withdrawal were offered inconsistently. Participants voiced concerns over patient safety and leaving the ward to smoke.

Interpretation:

Policies mandating smoke-free hospital property have important consequences beyond noncompliance, including concerns over patient safety and disruptions to care. Without adequately available and accessible support for withdrawal from tobacco, patients will continue to face personal risk when they leave hospital property to smoke.Canadian cities and provinces have passed smoking bans with the goal of reducing people’s exposure to secondhand smoke in workplaces, public spaces and on the property adjacent to public buildings.1,2 In response, Canadian health authorities and hospitals began implementing policies mandating smoke-free hospital property, with the goals of reducing the exposure of workers, patients and visitors to tobacco smoke while delivering a public health message about the dangers of smoking.25 An additional anticipated outcome was the reduced use of tobacco among patients and staff. The impetuses for adopting smoke-free policies include public support for such legislation and the potential for litigation for exposure to second-hand smoke.2,4Tobacco use is a modifiable risk factor associated with a variety of cancers, cardiovascular diseases and respiratory conditions.611 Patients in hospital who use tobacco tend to have more surgical complications and exacerbations of acute and chronic health conditions than patients who do not use tobacco.611 Any policy aimed at reducing exposure to tobacco in hospitals is well supported by evidence, as is the integration of interventions targetting tobacco dependence.12 Unfortunately, most of the nearly five million Canadians who smoke will receive suboptimal treatment,13 as the routine provision of interventions for tobacco dependence in hospital settings is not a practice norm.1416 In smoke-free hospitals, two studies suggest minimal support is offered for withdrawal, 17,18 and one reports an increased use of nicotine-replacement therapy after the implementation of the smoke-free policy.19Assessments of the effectiveness of smoke-free policies for hospital property tend to focus on noncompliance and related issues of enforcement.17,20,21 Although evidence of noncompliance and litter on hospital property2,17,20 implies ongoing exposure to tobacco smoke, half of the participating hospital sites in one study reported less exposure to tobacco smoke within hospital buildings and on the property.18 In addition, there is evidence to suggest some decline in smoking among staff.18,19,21,22We sought to determine the consequences of policies mandating smoke-free hospital property in two Canadian acute-care hospitals by eliciting lived experiences of the people faced with enacting the policies: patients and health care providers. In addition, we elicited stories from hospital support staff and administrators regarding the policies.  相似文献   

18.
EMBO J (2013) 32 2, 219–230 doi:10.1038/emboj.2012.308; published online November272012The identification of distinct bone marrow microenvironments that support haematopoietic stem cell (HSC) survival and function is one of the most significant recent advances in our understanding of HSC biology. While the intricate organization of these structures and their effect on HSC is on its own a fascinating biological question, solving this puzzle remains a key step in the development of more efficient stem cell therapies through improved in vitro HSC culture systems. In this issue, a study conducted by Wang and colleagues describes a novel structure within the bone marrow and provides evidence for an additional layer of complexity and compartmentalisation within the bone marrow microenvironment, suggesting the presence of specialised structures that support clonal HSC expansion.The bone marrow is a complex tissue, containing stem and progenitor cells for the haematopoietic, endothelial and osteogenic lineages. Surrounded by compact bone, the marrow is perfused by a complex network of vessels. Small arteries reach the marrow through the bone and branch into increasingly smaller arterioles. These in turn feed into intricate slow flowing sinusoidal capillaries, drained by venules, which eventually flow into a relatively large central sinus. The architecture of the bone marrow and the relationship between these structural building blocks and the haematopoietic stem cells (HSC) residing there is currently a topic of great interest. Specifically, an understanding of how elements of the endothelium, stromal cells and haematopoietic tissue interact to regulate steady state haematopoiesis is critical for the development and improvement of stem cell therapies based on HSC manipulation and administration.The close connection between vascular tissue and bone development and remodelling have been documented and studied for a number of years (Wang et al, 2007). The initial discovery that functional alterations in osteoblastic cells in spongy bones had consequences on HSC function and number attracted the interest of researchers in the HSC field (Calvi et al, 2003; Visnjic et al, 2004; Zhang et al, 2003). A growing number of studies have subsequently implicated endothelial cells and bone marrow vasculature in the support of HSC survival and function. HSC were consistently found residing in the proximity of bone marrow vessels in histological studies (Kiel et al, 2005) and it is now clear that endothelial cells can be used to support HSC culture in vitro (reviewed in Butler et al (2010)). Moreover, manipulation of the vascular bone marrow compartment can affect haematopoiesis (Ding et al, 2012). It has been proposed by multiple groups that while the osteoblastic niche favours HSC quiescence and maintenance, perivascular niches are associated with HSC expansion (Li and Li, 2006).In this issue, a study conducted by Wang et al (2012) presents an in depth histological analysis of distinct bone marrow microenvironments identified using a combination of genetic labelling and traditional immunohistochemistry. Using this approach, they document a functional unit composed of vasculature, bone and HSC, which they name ‘haemosphere''. Structurally, the haemosphere is a cyst-like protrusion of sinusoidal epithelial cells encased by an inner shell of stroma cells and, finally, mineralized bone. The most interesting aspect of haemospheres is that single or multiple, tightly packed CD45+ haematopoietic cells are often found enclosed within this structure. (Figure 1 depicts the proposed stages of development of a haemosphere). Using in situ SLAM marker labelling and cell cycle analysis, the authors identify the cells within the haemosphere as clonal, highly proliferative pockets of haematopoietic cells enriched for primitive HSC, suggesting that this vascular structure has a particularly important role in HSC expansion. Additionally, in lethally irradiated mice, haemospheres were shown to preferentially host the engraftment of transplanted bone marrow cells, adding further weight to the idea that they play a specialised role in the support of stem cell proliferation and expansion. The studies described here provide another step towards dissecting the composition of bone marrow microenvironments and indicate a topological location for expanding HSC clones.Open in a separate windowFigure 1Haemospheres likely initiate as an invagination of bone, mediated by bone remodelling around a vessel branch and eventually providing space for a growing clone of haematopoietic stem/progenitor cells. Larger cavities, such as the main femur diaphysis marrow space, allow mixing of haematopoietic clones. The maintenance of haemospheres depends on signalling through VEGF receptor 2.Interestingly, haemospheres were shown to be dependent on vascular endothelial growth factor (VEGF) signalling, suggesting they may be dynamic structures. This is consistent with recent findings implicating a role for angiocrine factors released by endothelial cells in vivo in the replenishment of the HSC pool and the negative effect on reconstitution efficiency when VEGF2 signalling is inhibited (Hooper et al, 2009; Butler et al, 2010). The results presented here suggest an additional layer of complexity as they indicate that VEGFR2 might mediate significant vascular and bone remodelling, that could potentially generate new microenvironments supportive of HSC.As with most novel findings, the work from Wang et al. opens a handful of new questions whose answer will considerably increase our understanding of the connection between HSC and bone marrow stroma. Most notably, which came first, haemosphere or HSC? And how plastic is this relationship? The studies here demonstrate that active remodelling of bone marrow microenvironments via VEGF signalling is necessary for haemosphere formation. However, it is still unclear how formation of these structures recruits and maintains HSC. Additionally, does the structure of the haemosphere create a unique combination of growth factors and ligands compared with other microenvironments that specifically supports HSC engraftment as well as homoeostatic proliferation? Conversely, could single HSC migrate to these perivascular sites and initiate remodelling of the local environment to their own advantage? And if this is the case, how does an HSC initiate such drastic remodelling and how can we use these factors to address clinical problems in stem cell transplantation therapy? Further studies are needed to obtain temporal information on the generation, maintenance and stability of haemospheres and to functionally compare haematopoiesis in haemospheres and in diaphyseal marrow. It is possible that the two locations may be functionally identical even though anatomically different, with the physical constraint of the encasing bone forcing haematopoietic clones to remain cohesive within haemospheres, while clones outside this environment can readily mix in the central, more fluid marrow.The findings presented by Wang et al. challenge current paradigms of the plasticity of the niche and its composition. Technological and experimental advances allowing full bone imaging and isolation of live cells from specific bone regions will be critical to obtain a complete picture of the function and dynamics of anatomically distinct bone marrow microenvironment and their relationship with HSC. In the mean time, the haemospheres are a new type of bone marrow structure that deserves further attention and guarantees further insights in our understanding of the HSC niche.  相似文献   

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Alzheimer''s disease (AD) is characterized by neuronal loss in several regions of the brain. Recent studies have suggested that stem cell transplantation could serve as a potential therapeutic strategy to halt or ameliorate the inexorable disease progression. However, the optimal stage of the disease for stem cell transplantation to have a therapeutic effect has yet to be determined. Here, we demonstrated that transplantation of neural stem cells into 12-month-old Tg2576 brains markedly improved both cognitive impairments and neuropathological features by reducing β-amyloid processing and upregulating clearance of β-amyloid, secretion of anti-inflammatory cytokines, endogenous neurogenesis, as well as synapse formation. In contrast, the stem cell transplantation did not recover cognitive dysfunction and β-amyloid neuropathology in Tg2576 mice aged 15 months when the memory loss is manifest. Overall, this study underscores that stem cell therapy at optimal time frame is crucial to obtain maximal therapeutic effects that can restore functional deficits or stop the progression of AD.Alzheimer''s disease (AD) is the most common neurodegenerative disorder, and is characterized by progressive cognitive dysfunction and memory loss that are caused by the death of nerve cells in several brain regions, including the cortex and hippocampus. Pathologically, senile plaques, including amyloid beta (Aβ) and carboxy-terminal fragments (CTFs) are derived via amyloid precursor protein (APP) proteolysis, and neurofibrillary tangles, including hyperphosphorylated tau, are two representative hallmarks of AD.1, 2, 3 Together with the accumulation of Aβ, local inflammation, altered hippocampal neurogenesis and synaptic loss have been correlated with cognitive deficits in AD patients.4, 5 However, no treatment has yet been developed that can cure or prevent the progression of dementia.Accumulating evidence indicates that the transplantation of neural stem cells (NSCs) or bone marrow stem cells (BMSCs) into the hippocampus improves cognitive functions in AD animal models.6, 7, 8, 9, 10, 11, 12 The stem cell-induced functional recovery seems to be mediated by either neurotrophic factors and/or neuroprotective cytokines. For instance, genetically engineered stem cells that secrete nerve growth factor (NGF),11, 12 the co-administration of stem cells with brain-derived neurotrophic factor (BDNF) or grafting encapsulated vascular endothelial growth factor (VEGF) secreting cells substantially improved behavioral outcomes of AD animal models.9, 13 Thus, the functional effects of stem cell grafts involve the increase of several neurotrophic factors, such as BDNF, FGF2, insulin-like growth factor 1 (IGF1), NGF and VEGF.10, 14, 15 In contrast, BMSCs or adipose-derived stem cells (ASCs) transplantation induces microglial activation16, 17, 18 and the secretion of neuroprotective cytokines, leading to a decline of Aβ deposits and the restoration of memory deficits in AD mice.18, 19 However, the optimal stage of the disease for stem cell transplantation in AD models has yet to be determined.In this study, we have investigated whether the transplantation of NSCs at two distinguished stages in the disease development could have different beneficial effects in AD model mice, Tg2576 mice.20 In this model, the over-production of Aβ begins at 6–7 months of age, and neuritic plaques with amyloid cores are formed from 9 to 12 months after birth followed by the onset of memory deficits at 12 months of age.21, 22, 23 NSCs were bilaterally transplanted into the dentate gyrus (DG) of the hippocampus and the third ventricle of 12-month-old (early stage) or 15-month-old (advanced stage) Tg2576 and age-matched wild-type (WT) mice. We determined whether the engrafted NSCs at two stages of the disease rescued cognitive deficits and the neuropathology of the mice.  相似文献   

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