Hippo信号通路与肾病

Hippo信号通路是近年来备受关注的一条调节器官生长和组织大小的重要信号通路,其已被证实在肿瘤的发生、发展中发挥重要作用.目前Hippo信号通路与肾病的相关性研究仍处于起步阶段.在急性肾损伤(acute renal injury,AKI)方面,Hippo信号通路可能参与小管上皮细胞的凋亡、上皮-间质转化(epithelial-mesenchymal transition,EMT)以及AKI进展至慢性肾脏病(chronic kidney disease,CKD)等多个环节.此外,Hippo信号通路还参与多种慢性肾脏病,包括局灶节段性肾小球硬化症、糖尿病肾病、多囊肾等的发生和疾病进展.     

NOTCH1 is required for regeneration of Clara cells during repair of airway injury

The airways of the mammalian lung are lined with highly specialized epithelial cell types that are the targets of airborne toxicants and injury. Notch signaling plays an important role in the ontogeny of airway epithelial cells, but its contributions to recruitment, expansion or differentiation of resident progenitor/stem cells, and repair and re-establishment of the normal composition of airway epithelium following injury have not been addressed. In this study, the role of a specific Notch receptor, Notch1, was investigated by targeted inactivation in the embryonic lung epithelium using the epithelial-specific Gata5-Cre driver line. Notch1-deficient mice are viable without discernible defects in pulmonary epithelial cell-fate determination and differentiation. However, in an experimental model of airway injury, activity of Notch1 is found to be required for normal repair of the airway epithelium. Absence of Notch1 reduced the ability of a population of cells distinguished by expression of PGP9.5, otherwise a marker of pulmonary neuroendocrine cells, which appears to serve as a reservoir for regeneration of Clara cells. Hairy/enhancer of split-5 (Hes5) and paired-box-containing gene 6 (Pax6) were found to be downstream targets of Notch1. Both Hes5 and Pax6 expressions were significantly increased in association with Clara cell regeneration in wild-type lungs. Ablation of Notch1 reduced Hes5 and Pax6 and inhibited airway epithelial repair. Thus, although dispensable in developmental ontogeny of airway epithelial cells, normal activity of Notch1 is required for repair of the airway epithelium. The signaling pathway by which Notch1 regulates the repair process includes stimulation of Hes5 and Pax6 gene expression.     

The Regenerative Potential of the Kidney: What Can We Learn from Developmental Biology?

Cell turnover in the healthy adult kidney is very slow but the kidney has a strong capacity for regeneration after acute injury. Although many molecular aspects of this process have been clarified, the source of the newly-formed renal epithelial cells is still being debated. Several studies have shown, moreover, that the repair of injured renal epithelium starts from mature tubular cells, which enter into an activated proliferative state characterized by the reappearance of mesenchymal markers detectable during nephrogenesis, thus pointing to a marked plasticity of renal epithelial cells. The regenerative potential of mature epithelial cells might stem from their almost unique morphogenetic process. Unlike other tubular organs, all epithelial and mesenchymal cells in the kidney derive from the same germ layer, the mesoderm. In a fascinating view of vertebrate embryogenesis, the mesoderm might be seen as a cell layer capable of oscillating between epithelial and mesenchymal states, thus acquiring a remarkable plasticity that lends it an extended potential for innovation and a better control of three-dimensional body organization. The renal papilla contains a population of cells with the characteristic of adult stem cells. Mesenchymal stromal stem cells (MSC) have been found to reside in the connective tissue of most organs, including the kidney. Recent studies indicate that the MSC compartment extends throughout the body postnatally as a result of its perivascular location. Developmental biology suggests that this might be particularly true of the kidney and that the papilla might represent the perivascular renal stem cell niche. The perivascular niche hypothesis fits well with the evolving concept of the stem cell niche as an entity of action. It is its dynamic capability that makes the niche concept so important and essential to the feasibility of regenerative medicine.     

干细胞与胃肠道肿瘤发生关系的研究进展

目前普遍认为肿瘤起源于干细胞,是一种干细胞疾病。大量研究表明胃肠道肿瘤起源于正常胃肠黏膜的干/祖细胞,胃肠道干/祖细胞积累的突变导致了肿瘤的发生。近年来也有实验发现在慢性胃黏膜损伤的条件下,骨髓干细胞可迁移到胃参与胃黏膜损伤的修复及胃黏膜的癌变。已有研究还表明胃肠道肿瘤发生发展过程中常伴随着参与正常干细胞增殖和分化调控的信号传导通路失调,提示干细胞增殖分化调控异常与胃肠道肿瘤发生密切相关。     

Mammary Stem Cells and Breast Cancer—Role of Notch Signalling

Adult stem cells are found in numerous tissues of the body and play a role in tissue development, replacement and repair. Evidence shows that breast stem cells are multipotent and can self renew, which are key characteristics of stem cells, and a single cell enriched with cell surface markers has the ability to grow a fully functional mammary gland in vivo. Many groups have extrapolated the cancer stem cell hypothesis from the haematopoietic system to solid cancers, where using in vitro culture techniques and in vivo transplant models have established evidence of cancer stem cells in colon, pancreas, prostate, brain and breast cancers. In the report we describe the evidence for breast cancer stem cells; studies consistently show that stem cell like and breast cancer initiating populations can be enriched using cell surface makers CD44⁺/CD24⁻ and have upregulated genes which include Notch. Notch signalling has been highlighted as a pathway involved in the development of the breast and is frequently dysregulated in invasive breast cancer. We have investigated the role of Notch in a pre-invasive breast lesion, ductal carcinoma in situ (DCIS), and have found that aberrant activation of Notch signalling is an early event in breast cancer. High expression of Notch 1 intracellular domain (NICD) in DCIS also predicted a reduced time to recurrence 5 years after surgery. Using a non-adherent sphere culture technique we have grown DCIS mammospheres from primary DCIS tissue, where self-renewal capacity, measured by the number of mammosphere initiating cells, were increased from normal breast tissue. A γ-secretase inhibitor, DAPT, which inhibits all four Notch receptors and a Notch 4 neutralising antibody were shown to reduce DCIS mammosphere formation, indicating that Notch signalling and other stem cell self-renewal pathways may represent novel therapeutic targets to prevent recurrence of pre-invasive and invasive breast cancer.     

Invited lecture: activation of the epithelial mesenchymal trophic unit in the pathogenesis of asthma

BACKGROUND: A recent NIH Workshop and an ERS Task Force concluded that more work was needed to understand mechanisms of severe and chronic asthma. This report describes a series of studies that identify aberrant epithelial mesenchymal signalling in the airways as an important event in maintaining inflammation and driving remodelling in response to environmental injury. METHODS: Immunohistochemistry, genotyping and functional studies conducted on cultured asthmatic cells and mucosal biopsies were used to identify biochemical pathways involved in epithelial injury and repair in asthma and their relationship to disease severity. RESULTS: Our findings suggest that the asthmatic state results from an interaction between a susceptible epithelium and Th-2-mediated inflammation to alter the communication between the epithelium and the underlying mesenchyme - the epithelial mesenchymal trophic unit - leading to disease persistence, airway remodelling and refractoriness to corticosteroid treatment. CONCLUSIONS: Asthma is more than an inflammatory disorder, but requires engagement of important signalling pathways involved in epithelial repair and tissue remodelling. These pathways involving EGFRs and TGF-betaRs provide targets against which to develop novel therapies for chronic asthma.     

Dichotomy of Notch signalling in regulating tumour immune surveillance

Notch signalling is an evolutionarily conserved multifaceted pathway that controls diverse cellular processes. Its role in regulating development and tissue homeostasis is well established. Aberrant activation of the Notch pathway has been implicated in the initiation and progression of many types of cancers. However, although in some cancers Notch signalling acts as a tumour‐promoter, in others it is reported to suppress tumour growth and progression. Accumulating evidence suggests the involvement of both the innate and adaptive immune system in the development of various tumours. Currently, extensive studies on investigating the effects of Notch signalling in tumour immune surveillance are being carried out. Interestingly, recent literature shows how the changing expression of Notch genes in different T cell subsets like CD4 and CD8 helps in controlling anti‐tumour immune responses. In this review, we discuss in depth the roles of Notch signalling molecules and different immune cells in the context of the tumour microenvironment. We also outline how current knowledge can be exploited to develop novel therapies in order to control the propagation of cancer stem cells.     

Notch signalling in T-cell lymphoblastic leukaemia/lymphoma and other haematological malignancies

Notch receptors participate in a highly conserved signalling pathway that regulates normal development and tissue homeostasis in a context- and dose-dependent manner. Deregulated Notch signalling has been implicated in many diseases, but the clearest example of a pathogenic role is found in T-cell lymphoblastic leukaemia/lymphoma (T-LL), in which the majority of human and murine tumours have acquired mutations that lead to aberrant increases in Notch1 signalling. Remarkably, it appears that the selective pressure for Notch mutations is virtually unique among cancers to T-LL, presumably reflecting a special context-dependent role for Notch in normal T-cell progenitors. Nevertheless, there are some recent reports suggesting that Notch signalling has subtle, yet important roles in other forms of haematological malignancy as well. Here, we review the role of Notch signalling in various blood cancers, focusing on T-LL with an eye towards targeted therapeutics.     

Alterations in renal cilium length during transient complete ureteral obstruction in the mouse

The renal cilium is a non-motile sensory organelle that has been implicated in the control of epithelial phenotype in the kidney. The contribution of renal cilium defects to cystic kidney disease has been the subject of intense study. However, very little is known of the behaviour of this organelle during renal injury and repair. Here we investigate the distribution and dimensions of renal cilia in a mouse model of unilateral ureteral obstruction and reversal of ureteral obstruction. An approximate doubling in the length of renal cilia was observed throughout the nephron and collecting duct of the kidney after 10 days of unilateral ureteral obstruction. A normalization of cilium length was observed during the resolution of renal injury that occurs following the release of ureteral obstruction. Thus variations in the length of the renal cilium appear to be a previously unappreciated indicator of the status of renal injury and repair. Furthermore, increased cilium length following renal injury has implications for the specification of epithelial phenotype during repair of the renal tubule and duct.     

Differentiation of arterial and venous endothelial cells and vascular morphogenesis.

The vascular system is comprised of an organized hierarchical structure of arteries, veins, and capillaries. Recent studies in zebrafish, chick, and mouse reveal that the identity of artery and vein is governed by genetic factors as well as blood flow. The ephrin/Eph system establishes arterial and venous endothelial cell identity, and is important for structural segregation between arteries and veins. Analyses using loss- or gain-of-function mutations in zebrafish and mice show that Su(H)/RBP-J-dependent Delta/Notch signaling is a key mediator of arterial endothelial cell fate decision and vascular patterning. Vascular endothelial growth factor has also been shown to work upstream of Notch and is a key player in arteriogenesis. On the other hand, an orphan nuclear receptor, COUP-TFII, induces venous endothelial cell differentiation by suppressing the Notch signaling. Arteriovenous malformations are frequently induced by a loss of arterial and venous cell specification. These insights indicate that the balance of these genetic factors and modification by epigenetic factors such as hemodynamics and oxygen tension are important for proper endothelial cell identities in vascular morphogenesis.     

Mimicking cell-cell interactions at the biomaterial-cell interface for control of stem cell differentiation

The ability to regulate stem cell proliferation and differentiation has relevance in numerous medical applications, including medical devices, tissue engineering, and regenerative medicine. To control cellular behavior at the biomaterial or scaffold interface, many studies have employed surface modifications that mimic the extracellular matrix. Strikingly absent is the immobilization of cell-surface ligands to the biomaterial surface. One cell-to-cell signaling pathway that has been shown to regulate tissue development and stem cell fate is the Notch pathway. Recently, the Notch signaling pathway was identified as a key regulator of epithelial differentiation. Utilizing this knowledge, we applied an affinity immobilization scheme designed to attach and orient the Notch ligand, Jagged-1, in an active conformation on a biomaterial surface. When epithelial stem cells were plated on the bound ligand, the Notch/CBF-1 signaling pathway was stimulated and the cells upregulated both intermediate- and late-stage differentiation markers. In addition, the ligand promoted tight clustering and extensive stratification. Soluble Jagged-1 showed no Notch/CBF-1 signaling and very little, if any, cell differentiating activity. The high potency of bound Jagged-1 suggests that modification of a surface with a Notch ligand presents a powerful method to control stem cell differentiation at the cell-biomaterial interface.     

Notch signaling affects biliary fibrosis via transcriptional regulation of RBP-jκ in an animal model of chronic liver disease

Liver repair in patients with a chronic liver disease requires the orchestrated action of epithelial, mesenchymal, and inflammatory cells. Notch components are expressed in both the epithelial and mesenchymal compartments of the adult liver and are differentially regulated after injury. However, the functional role of Notch signaling in regulating epithelial/mesenchymal cross-talk during fibrogenic pathologic repair remains unknown. The aim of this study was to investigate how proliferation of the bile duct influences biliary fibrosis and to recognize the effect of inhibiting Notch signaling in biliary fibrotic tissue of the injured liver. We designed a synthetic decoy oligodeoxynucleotide (ODN) for recombination signal binding protein immunoglobulin kappa J (RBP-jκ), which is a common DNA-binding partner of Notch receptors. The effect of blocking RBP-jκ on fibrogenesis was assessed in the 3,5-Diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet mouse model. We observed the reduced fibrosis and decreased expression of associated signaling molecules after the RBP-jκ decoy ODN treatment. These data demonstrate that Notch signaling may play an important role in progression of ductular reaction and fibrosis. Further studies are required to unveil how ductular cells interact with other liver cell types, such as hepatic stellate cells or Kupffer cells,in patients with cholestatic liver diseases based on Notch signaling. These results suggest that controlling the ductular reaction using a synthetic ring type decoy RBP-jκ ODN will help develop a novel therapeutic approach targeting biliary fibrosis in patients with chronic liver diseases.     

miR-564在关节软骨损伤修复中作用机制的研究进展

关节软骨损伤修复一直是关节外科的热点和难点,最新研究表明,miR-564可能在关节软骨损伤修复中起着至关重要的作用。miR-564是位于第3号染色体上的非编码RNA,其功能主要是通过影响mRNA的稳定性和翻译进而参与基因表达的转录后调节,因此未来有望通过调控miR-564实现关节软骨损伤的原位修复。本文就miR-564的结构、功能及在关节软骨损伤修复中的作用机制作一综述。     

MicroRNA和雪旺细胞自噬与周围神经再生修复的研究进展

正周围神经损伤会使神经支配区域的运动、感觉机能下降和缺失,严重影响生产和生活质量。现代显微外科技术的应用已大大提高了修复效果,但由于周围神经的特殊结构和功能,目前的修复技术对于神经功能的恢复效果仍然有限,这引起了研究者们对于周围神经损伤后再生修复机制的探索。周围神经损伤后,损伤处残存雪旺细胞(Schwann cells)的数量和增殖分化能力是影响神经再生修复的关键因素[1]。在周围神经损伤后的雪旺细胞内发现大量溶     

Glucocorticoids Increase Repair Potential in a Novel in vitro Human Airway Epithelial Wounding Model

Airway epithelial damage is a cardinal feature of chronic asthma. Agents which enhance epithelial repair without triggering uncontrolled fibrosis of the mesenchyme would be predicted to be useful in the management of asthma. We have developed a repeat wound model using mucociliated human bronchial epithelial cell (HBEC) cultures to define the key pathways involved in airway epithelial repair, and to study the effects of potential therapeutic agents on epithelial repair in a chronic setting. We show that repair occurs primarily by cell migration to close a defect; this process requires activation of the EGF receptor (EGFR) and subsequent tyrosine kinase signalling. Migration is accompanied by up-regulation of CD44 in motile cells at the wound margins with proliferation of non-migrating cells adjacent to the wound area. In long-term studies β2 adrenoceptor agonists and phosphodiesterase (PDE) inhibitors have no effect on repair potential, in contrast chronic treatment with the glucocorticoid dexamethasone extends the lifespan of repeatedly wounded differentiated cultures. We suggest part of the beneficial effects of glucocorticoids in asthma is related to this ability to prolong repair potential following repeated episodes of epithelial injury.     

The role of Notch receptor expression in bile duct development and disease

Mutations in the Jagged1 gene, a ligand for the Notch signalling pathway, have been implicated in the pathogenesis of Alagille syndrome (AGS), resulting in bile duct paucity. Recently, a mouse model for AGS suggested that abnormalities of the Notch2 receptor, as well as of Jagged1, may be present. Expression patterns of Notch receptors have not been described in the developing human liver or in paediatric liver. The expression of Notch receptors and ligands was examined in fetal, paediatric normal, and diseased human liver by RT-PCR and immunohistochemistry. RT-PCR showed Notch1-4 mRNA expression to be present. In fetal liver, Notch3 protein was expressed on mesenchymal cells, closely adjacent to ductal plate cells that expressed Jagged1. In paediatric normal liver, Notch1 and Notch2 were present on mature bile duct cells. Notch expression was altered in disease, with distinct differences in AGS from extrahepatic biliary atresia (EHBA) and alpha1-anti-trypsin deficiency (alpha1AT). In AGS, where extensive ductular reaction was present, Jagged1 was expressed on ductular reactive cells (DRCs), along with marked Notch2 and Notch3 staining. Where there was ductular paucity, Notch2 and Notch3 were not expressed on remaining biliary epithelial cells. In EHBA and alpha1AT, Notch receptor expression was not seen on DRCs. Instead, Notch2 and Notch3 were expressed by stromal cells. In all diseases, Notch3 was expressed on neovessels in portal tracts and cirrhotic fibrous septa. In conclusion, Notch3 is expressed in close proximity to Jagged1 at the time of ductal plate formation, suggesting that Notch3 is important for bile duct development. The expression of both Notch2 and Notch3 in AGS on DRCs confirms that these receptors may be important in the pathogenesis of this disease. Further studies are required to investigate the presence of Notch2 and Notch3 at other periods in liver development and to clarify the role of Notch signalling in paediatric cholestases.     

Role of Notch signaling in the mammalian heart

Notch signaling is an evolutionarily ancient, highly conserved pathway important for deciding cell fate, cellular development, differentiation, proliferation, apoptosis, adhesion, and epithelial-to-mesenchymal transition. Notch signaling is also critical in mammalian cardiogenesis, as mutations in this signaling pathway are linked to human congenital heart disease. Furthermore, Notch signaling can repair myocardial injury by promoting myocardial regeneration, protecting ischemic myocardium, inducing angiogenesis, and negatively regulating cardiac fibroblast-myofibroblast transformation. This review provides an update on the known roles of Notch signaling in the mammalian heart. The goal is to assist in developing strategies to influence Notch signaling and optimize myocardial injury repair.