plasticity of epithelial stem cell

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Signaling in the stem cell niche: regulating cell fate, function and plasticity

Signaling in the stem cell niche: regulating cell fate, function and plasticity

liberated by delamination of a epidermal cell triggers the division of its neighboring cell (Mesa et al., 2017 preprint), which is consistent with the idea that basal cell density affects stem cell fate decisions in the epidermal layer. Interestingly, whereas in the actively stratifying embryonic epidermis cell divisions trigger crowding, in the homeostatic adult tissue cell divisions do not impact delamination but divisions occur in response to delamination (Fig. 3B). This could indicate that delamination and stem cell divisions are mechanically coupled in both the embryonic and adult epidermis, but that stem cells in the embryo are constantly cycling to provide sufficient material for the growing tissue, whereas adult stem cells divide only upon demand to replace terminally differentiated dying cells. A similar mechanism of cell density-driven homeostasis seems to operate in the Drosophila midgut (Fig. 3C), where stem cell division is triggered by removal of apoptotic cells in a process dependent on cell-cell contacts and their ability to coordinate EGF signaling (Liang et al., 2017). Another recent study in the adult Drosophila midgut further highlights the importance of mechanical signals, in particular mechanical stress in epithelial stem cell homeostasis. Here, a specific population of enteroendocrine precursor cells senses mechanical stimuli that regulate their differentiation in a process mediated by intracellular calcium increase through the stretch- activated calcium channel Piezo, allowing these cells to respond to gut compression or extension (He et al., 2018). Similarly, mechanical tension in response to injury has been shown to promote alveolar regeneration in the lung (Liu et al., 2016. Fig. 3D).

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Epithelial stem cell mutations that promote squamous cell carcinoma metastasis

Epithelial stem cell mutations that promote squamous cell carcinoma metastasis

tumors that were both benign and malignant, we only observed the outgrowth of more aggressive SCCs and BSCCs following serial passage. In addition, the transplanted tumors frequently exhibited EMT-mediated progression. These poorly differentiated SCCs, BSCCs, and SPCCs were highly metastatic. Even though we observed a dramatic increase in the population of CSC in meta- static SCCs and SPCCs, the majority of passaged tumor cells were unable to initiate secondary tumor formation. Each of the two CSC populations identified in this study can give rise to the other population after in vivo passaging, suggesting that the two popu- lations are not fixed cell types and that their plasticity is influenced by the in vivo microenvironment. These data highlight the com- plexity and heterogeneity of CSC populations. Previous studies of other highly metastatic tumors such as melanomas have suggested that the capacity of tumor cells to initiate secondary tumor forma- tion is increased when these assays are performed in more severely immune-compromised backgrounds (56). Therefore, it remains to be determined whether the tumor initiation capabilities of the dis- tinct CSC-rich and non-CSC populations identified in this study would be different if assayed in more immune-compromised mice.

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Epithelial-to-mesenchymal plasticity of cancer stem cells: therapeutic targets in hepatocellular carcinoma

Epithelial-to-mesenchymal plasticity of cancer stem cells: therapeutic targets in hepatocellular carcinoma

Recent data suggests that CSCs are indeed plastic and can be associated with both epithelial and mesenchymal states. Occurrence of two distinct populations of CSCs termed EMT-CSCs with epithelial signature and MET- CSCs with mesenchymal signature have been reported in breast cancer. These CSCs have the capacity to transi- tion between these cellular states. It has been envisioned that EMT-CSCs are located at the invasive edge of the tumor and allow the tumor to expand into new territory. On the other hand, MET-CSCs are located in the tumor interior and facilitate tumor cell growth. Furthermore, when the invasive edge becomes the interior of the tumor, the two CSCs can change cellular states [75]. It is conceivable that CSCs with distinct EMT/MET pheno- types also occur in HCC. In support for this hypothesis, CSCs with mesenchymal phenotypes were observed in the invasive front of HCC patient samples [24, 76]. In an earlier study of CSC populations defined by CD133 + /ALDH high and CD133 + /EpCAM + separated from Huh7, HepG2, and Hep3B, well-differentiated human HCC cell lines were deemed to be epithelial by expression of E-cadherin and lack of Vimentin. In contrast, poorly differentiated cell lines such as SkHep1, HLE, and HLF and double negative subpopu- lation from well-differentiated cell lines were charac- terized as mesenchymal due to the higher expression of Vimentin, Zeb1, and Snail; and transforming growth factor (TGF)-β and hedgehog pathway activation [77]. Another study examined microarray data from 238 HCC cases and found several distinct subpopulations char- acterized by expression of CD133, CD90, and EpCAM. Gene expression revealed an enriched EMT signature in CD90 + cells. Further examination of both primary tumors and HCC cell lines demonstrated that CD90 + subpopula- tion of cells were mesenchymal and overexpressed CD44, c-KIT, and TWIST1, whereas EPCAM + subpopulation were epithelial and expressed alpha-fetoprotein (AFP) and Albumin [45]. The plasticity of these distinct subpopula- tions to switch between different EMT cellular states warrants further investigation.

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Biological and clinical significance of cancer stem cell plasticity

Biological and clinical significance of cancer stem cell plasticity

LncRNA H19, together with its partner miR-675, a miRNA embedded in its first exon, were proposed to regulate EMT through multiple signaling pathways, one of them being the PI3K–AKT pathway [130]. Over-expression of H19 in lung cancer lines abolished the expression of E-cadherin by activation of Slug in a miR-675 dependent manner, suggesting a biological function of H19 in the regulation of EMT. A recent study showed that H19 can serve as a molecular sponge for the let-7 microRNA family in muscle tis- sue, suggesting an alternative function of lncRNAs in the transition between EMT to MET of CSCs through blocking microRNAs [131]. Linc-ROR was first char- acterized in induced pluripotent stem cells (iPSCs) [132] and recently it was proposed to act as a sponge for mir-145 serving to de-repress a number of mir- 145 targets, including OCT4, SOX2, and Nanog [133]. More recently, linc-ROR has been demon- strated to play an important role in the regulation of breast cancer metastasis and EMT CSCs. Overexpres- sion of linc-ROR in mammary epithelial cells resulted in an increase in the CD24 - CD44 + stem cell popula- tion with strong upregulation of the mesenchymal markers such as Vimentin, α-SMA, N-cadherin and Fibronetin, while the epithelial markers E-cadherin and Occludin were dramatically suppressed [134]. In this study, linc-ROR was suggested to have a role as a sponge for mir-205 thereby preventing the degrad- ation of its targets such as ZEB1 and ZEB2 in breast cancer to regulate CD24 - CD44 + EMT stem cells. Re- cently, lncRNA-activated by TGF-β (lncRNA-ATB) was demonstrated to competitively bind the miR-200 family and sequester them from their targets, ZEB1 and ZEB2, thereby inducing EMT and invasion in hepatocellular carcinoma. On the other hand, lncRNA-ATB also interacts with, and increases the stability of IL-11 mRNA, which results in the activation of the IL-11-STAT3 signaling pathway and enhanced colonization in hepatocellular carcinoma [135]. These findings suggest that lncRNA-ATB might act as a key regulator of TGF-β signaling by targeting both EMT and MET states of CSCs. Future studies will further elucidate the role of lncRNAs in CSC signaling and plasticity.

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Plasticity within the niche ensures the maintenance of a Sox2+ stem cell population in the mouse incisor

Plasticity within the niche ensures the maintenance of a Sox2+ stem cell population in the mouse incisor

SCs located at the proximal end of the incisor, in a structure called the labial cervical loop (laCL). The laCL arises from the dental epithelium around embryonic day (E) 14, and its various cell types are well defined prior to birth (E19) (Fig. 1A). The stellate reticulum (SR) is a pool of epithelial cells located at the core of the laCL. It is surrounded posteriorly and labially by the columnar outer enamel epithelium (OEE), and anteriorly and lingually by the columnar inner enamel epithelium (IEE). The IEE houses the early SC progeny, namely the transient-amplifying (TA) cells and the stratum intermedium (SI) cells (Harada et al., 2006). The TA cells generate pre-ameloblasts, which then differentiate into enamel-secreting ameloblasts (Fig. 1A) (Thesleff and Tummers, 2008). Initial reports suggesting that dental epithelial SCs are present in the SR (Harada et al., 1999) were followed by in vivo genetic fate mapping experiments demonstrating that Gli1 (Seidel et al., 2010), Sox2 (Juuri et al., 2012), Bmi1 (Biehs et al., 2013), Lrig1 and Igfbp5 (Seidel et al., 2017) mark SCs in the laCL; a number of potential dental SC markers that have not yet been tested through lineage tracing were recently identified using gene co-expression analysis (Seidel et al., 2017). Moreover, the expression of some genes that mark SCs in other organs, such as Lgr5 (Suomalainen and Thesleff, 2009), Abcg2, Oct3/4 (Pou5f1), Tbx1, Pitx2 and Yap (Yap1) (Cao et al., 2013; Gao et al., 2015; Hu et al., 2017; Li et al., 2011), has also been detected in the incisor SC niche.

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Concepts for a therapeutic prolongation of nephrogenesis in preterm and low-birth-weight babies must correspond to structural-functional properties in the nephrogenic zone

Concepts for a therapeutic prolongation of nephrogenesis in preterm and low-birth-weight babies must correspond to structural-functional properties in the nephrogenic zone

Numerous investigations are dealing with anlage of the mammalian kidney and primary development of nephrons. However, only few information is available about the last steps in kidney development leading at birth to a downregulation of morphogen activity in the nephrogenic zone and to a loss of stem cell niches aligned beyond the organ capsule. Surprisingly, these natural changes in the developmental program display similarities to processes occurring in the kidneys of preterm and low-birth-weight babies. Although those babies are born at a time with a principally intact nephrogenic zone and active niches, a high proportion of them suffers on impairment of nephrogenesis resulting in oligonephropathy, formation of atypical glomeruli, and immaturity of parenchyma. The setting points out that up to date not identified noxae in the nephrogenic zone hamper primary steps of parenchyma development. In this situation, a possible therapeutic aim is to prolong nephrogenesis by medications. However, actual data provide information that administration of drugs is problematic due to an unexpectedly complex microanatomy of the nephrogenic zone, in niches so far not considered textured extracellular matrix and peculiar contacts between mesenchymal cell projections and epithelial stem cells via tunneling nanotubes. Thus, it remains to be figured out whether disturbance of morphogen signaling altered synthesis of extracellular matrix, disturbed cell-to-cell contacts, or modified interstitial fluid impair nephrogenic activity. Due to most unanswered questions, search for eligible drugs prolonging nephrogenesis and their reliable administration is a special challenge for the future.

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Biomarkers for epithelial mesenchymal transitions

Biomarkers for epithelial mesenchymal transitions

Somatic cells that change from one mature phenotype to another exhibit the property of plasticity. It is increasingly clear that epithelial and endothelial cells enjoy some of this plasticity, which is easily demonstrated by studying the process of epithelial-mesenchymal transition (EMT). Published reports from the literature typically rely on ad hoc criteria for determining EMT events; consequently, there is some uncertainty as to whether the same process occurs under different experimental conditions. As we discuss in this Personal Perspective, we believe that context and various changes in plasticity biomarkers can help identify at least three types of EMT and that using a collection of criteria for EMT increases the likelihood that everyone is studying the same phenomenon — namely, the transition of epithelial and endothelial cells to a motile phenotype.

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<p>Amniotic Membrane Transplantation in Ophthalmology: An Updated Perspective</p>

<p>Amniotic Membrane Transplantation in Ophthalmology: An Updated Perspective</p>

macular holes. 169 Evidence suggests that human retinal pigmented epithelial cells seed over amnion within 24 hours of implantation. Moreover, these cells maintain epithelial features and can proliferate over epithelium-free amnion, resulting in a tight monolayer with well-de fi ned intercellular and cell – substrate interactions, secreting sev- eral growth factors important for maintaining retinal homeostasis. 170 Recently, Caporossi et al, 2019 169 studied 16 eyes of 16 patients with recurrent macular holes in a prospective case series of highly myopic eyes. All patients underwent a 23-gauge par plana vitrectomy with AMT implantation, with either 20% SF6 or air tamponade. Mean post operative BCVA was 0.94±0.24 logMAR, which improved to 0.67±0.26 logMAR post operatively . All patients experienced complete closure anatomically, although one hole reopened, requiring a repeat amniotic membrane implant two weeks post operatively.

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A clinical study on the outcome of tenoplasty in ocular chemical injuries.

A clinical study on the outcome of tenoplasty in ocular chemical injuries.

Progressive scarring of the bulbar and palpebral conjunctiva leads to mechanical abnormalities like restriction of extraocular movement, fornix foreshortening and obliteration, symblepharon formation and lid abnormalities like incomplete lid closure, cicatricial entropion, trichiasis, and lid margin keratinization. Bulbar conjunctival transplantation in unilateral cases can correct most of these abnormalities. In bilateral cases use of mucosal membrane grafts to reconstruct the fornix and restore normal lid-globe relations, prevents the above mentioned complications. But they do not restore the corneal epithelial functions following limbal stem-cell transplantation. The impaired goblet cell function of the conjunctiva can be improved by harvesting mucosal grafts from nasal mucosa.

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s-SHIP expression identifies a subset of murine basal prostate cells as neonatal stem cells

s-SHIP expression identifies a subset of murine basal prostate cells as neonatal stem cells

Dissociated prostate cells were labeled using antibodies as specified in the text, sorted by FACS, counted, and suspended in 1:1 Matrigel (BD Biosciences)/ prostate epithelial growth medium (PrEGM) (Lonza, Walkersville, MD) in a total volume of 100 μl. Samples were plated in a 6–well plate (Costar) and allowed to solidify at 37°C for 20 min, before 3 ml of PrEGM was added. Medium was replaced every 3-4 days; spheres with a double–layered appearance and a diameter >40 μm were counted at day 10, whereas small or more lucent spheroids were not counted according to the original description of the prostate sphere culture technique [31]. To passage 7 day-old spheres, medium was aspirated, and Matrigel was digested by 1 mg/ml of dispase (STEMCELL Technologies Inc, Vancouver BC, Canada) at 37°C for 30 min. Spheres were collected, pelleted, resuspended and digested by 0.05 % Trypsin/EDTA at room temperature for 5 min. Dissociated cells were passed through a 40-μm cell strainer, counted and replated.

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Ovarian cancer stem-like cells with induced translineage- differentiation capacity and are suppressed by alkaline phosphatase inhibitor

Ovarian cancer stem-like cells with induced translineage- differentiation capacity and are suppressed by alkaline phosphatase inhibitor

Our group previously characterized tumor-initiating spheroids expressing the surface markers CD44 and CD117 (c-Kit) [9]. Others have also reported that surface markers of ovarian tumor-initiating cells or ovarian CSLCs include CD133, CD24 and CD44/MyD88 [10- 12]. Surface-marker-free methods also revealed side populations and quiescent CSLCs from ovarian cancer cell lines and other human cancerous tissues [7, 13- 15]. The existence of ovarian epithelial stem cells is controversial, and there is insufficient evidence of the location of ovarian CSLCs within the abdominal cavity. A recent report has provided clues about the location of the stem cell niche for ovarian surface epithelial cells (OSEs) at the transitional area between the ovarian surface epithelium, mesothelium and tubal epithelium [16]. These OSEs from the hilum form spheroids in culture, show a dormancy-like phenotype, and display stem cell markers and long-term stem cell properties [16]. These stem-like and cancer-prone OSEs are thought to be the origin of high-grade serous type ovarian cancers. However, whether these stem-like OSEs possess translineage differentiation capability is not known, and whether the induced cancer cells retain stem-like properties has not been examined. There are insufficient data so far showing the direct transition of normal stem-like OSEs to ovarian CSLCs. In addition, the hierarchy of differentiation-related markers in CSLCs from melanomas and from colon and prostate

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Generation of CCR5-defective CD34 cells from ZFN-driven stop codon-integrated mesenchymal stem cell clones

Generation of CCR5-defective CD34 cells from ZFN-driven stop codon-integrated mesenchymal stem cell clones

Somatic stem cells are post-natal stem cells that have very high self-renewal and differential capacity. Bone marrow-derived mesenchymal stem cells (MSCs) are well-established somatic stem cells that are easily ob- tained through simple bone marrow aspiration [22,23]. The proliferation rate of MSCs is much higher than that of CD4 lymphocytes and HSCs and may be the highest among all primary cell cultures. Previous work has also shown the feasibility of ZFN-mediated exogenous gene insertion into CCR5 loci in MSCs [20]. Taken to- gether, we speculated that it might be possible to generate and enrich ZFN-mediated CCR5 -specific gene integration clones in MSCs.Recent progress in stem cell research has demonstrated that cell phenotypes are (re)programmable. In 2006, Takahashi and Yamanaka reported the successful reprogramming of somatic cells into pluripotent cells via induction with a set of transcription factors [24]. There- fore, there is great interest in the potential combination of cell reprogramming and ZFN-mediated gene editing [21,25-28]. Apart from cell reprogramming, direct conver- sion from one cell type to another is another interesting approach that may have an additional advantage of genetic stability [29]. Recently, fibroblasts were directly converted to CD45+ HSCs by overexpressing Oct4 and then main- taining the cells in defined media [30]. Collectively, these findings led us to reason that cell conversion could be a very powerful tool for future HIV treatment in conjunction with ZFN-mediated HDR. To support our speculation, we here report the generation of CD34 + /CD45 + cells that orig- inated from ZFN-mediated gene integration of MSCs.

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Activin Directed Differentiation of Human Embryonic Stem Cells Differentially  Modulates Alveolar Epithelial Wound  Repair via Paracrine Mechanism

Activin Directed Differentiation of Human Embryonic Stem Cells Differentially Modulates Alveolar Epithelial Wound Repair via Paracrine Mechanism

Idiopathic pulmonary fibrosis is a chronic progressive lung disease leading to respiratory failure and early death. Alveolar epithelial cell damage (apoptosis) and failure of re-epithelialisation underpin IPF pathogenesis. Previously, ESC has been shown to have anti-apoptotic and anti-fibrotic effects; here we demonstrate their re- epithelialisation stimulatory effect. Despite of our two consecutive approaches to identify the secretory proteins, responsible for wound healing, in the aforementioned CM and positive control by MS/MS Mass spectrometry we were unable to identify any wound-healing related human proteins, potentially, due to high KO-SR content in the media (data not shown). However, we anticipate developing a defined serum-free media to condition hESC and to test it on human primary lung epithelial cells using a more complex tissue-engineered in vitro wound-healing model and extend it to animal lung fibrosis model to reveal the detail paracrine mechanistic pro- file of ESC. Due to enormous differentiation potential, ESC has been proposed for clinical application of incur- able lungs diseases [20]. However, potential risk of teratoma formation and graft rejection in the post-transplan- tation period are the major obstacles in the ESC-mediated cell therapy. Therefore, understanding their potential paracrine healing properties could be valuable, and perhaps, adaptable as an alternative to cell therapy in rege- nerative strategies.

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Plasticity and Virus Specificity of the Airway Epithelial Cell Immune Response during Respiratory Virus Infection

Plasticity and Virus Specificity of the Airway Epithelial Cell Immune Response during Respiratory Virus Infection

When we compared RSV samples to their controls using the statistical parameters described above, we identified a total of 336 DEGs, of which 240 (71%) were upregulated and 96 (29%) were downregulated (Fig. 1C). The upregulated DEGs included type I interferon-inducible genes, such as those encoding IFI44L, IFIT2, OAS3, MX2, IFI27, OAS1, IRF7, STAT1, IFI35, and ISG20; chemokines, like CXCL10 and CCL5; cytokines, such as TNFSF13B; cell cycle-related genes (XAF1); and members of the GAGE family (see Table S1B in the supplemental material). Only two transcripts were induced more than 100-fold: CXCL10 and OASL. The number of upregulated genes in hAEC cultures ex- posed to RSV was 75% less than in influenza virus-infected cul- tures, and the number of downregulated transcripts was 96% less. In order to dissect common and unique signatures of infection in hAECs, we compared the transcripts differentially expressed between the two viral infections and their respective controls (Fig. 1D). The majority of the DEGs were unique to each infection (4,269 transcripts were unique for influenza virus and 185 were unique for RSV), and the majority of the transcripts modulated during influenza virus infection were not altered in the RSV sam- ples. We used these virus-specific DEGs to generate a gene tree signature that underscores differences in the responses of hAECs to each infection (Fig. 1E). A scatter plot of all the upregulated and downregulated transcripts for both infections is presented in Fig. 1F. Most of the transcripts in the influenza virus samples were downregulated, suggesting a global host cell transcriptional shut- off due to influenza virus replication. Interestingly, overexpres- sion of type III interferons (IL-28A, IL-28B, and IL-29) was exclu- sive to influenza virus-infected hAECs (see Table S1C in the supplemental material). Other DEGs that were specifically in-

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Multipotent stem cells in the Malpighian tubules of adult Drosophila
melanogaster

Multipotent stem cells in the Malpighian tubules of adult Drosophila melanogaster

Excretion is an essential process of an organismʼs removal of the waste products of metabolism to maintain a constant chemical composition of the body fluids despite changes in the external environment. Excretion is performed by the kidneys in vertebrates and by Malpighian tubules (MTs) in Drosophila. The kidney serves as an excellent model organ to investigate the cellular and molecular mechanisms underlying organogenesis. Mammals and Drosophila share common principles of renal development. Tissue homeostasis, which is accomplished through self-renewal or differentiation of stem cells, is critical for the maintenance of adult tissues throughout the lifetime of an animal. Growing evidence suggests that stem cell self-renewal and differentiation is controlled by both intrinsic and extrinsic factors. Deregulation of stem cell behavior results in cancer formation, tissue degeneration, and premature aging. The mammalian kidney has a low rate of cellular turnover but has a great capacity for tissue regeneration following an ischemic injury. However, there is an ongoing controversy about the source of regenerating cells in the adult kidney that repopulate injured renal tissues. Recently, we identified multipotent stem cells in the MTs of adult Drosophila and found that these stem cells are able to proliferate and differentiate in several types of cells in MTs. Furthermore, we demonstrated that an autocrine JAK-STAT (Janus kinase–signal transducers and activators of transcription) signaling regulates stem cell self-renewal or differentiation of renal stem cells. The Drosophila MTs provide an excellent in vivo system for studying the renal stem cells at cellular and molecular levels. Understanding the molecular mechanisms governing stem cell self-renewal or differentiation in vivo is not only crucial to using stem cells for future regenerative medicine and gene therapy, but it also will increase our understanding of the mechanisms underlying cancer formation, aging and degenerative diseases. Identifying and understanding the cellular processes underlying the development and repair of the mammalian kidney may enable more effective, targeted therapies for acute and chronic kidney diseases in humans.

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Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells

Notch signaling modulates proliferation and differentiation of intestinal crypt base columnar stem cells

(Jensen et al., 2000; Fre et al., 2005; Stanger et al., 2005; van Es et al., 2005; Riccio et al., 2008; Gerbe et al., 2011; Pellegrinet et al., 2011). Notch pathway inhibition of the transcription factor atonal homolog 1 (Atoh1) provides the crucial mechanism regulating cell fate choice, and Atoh1 expression appears to be both required (Yang et al., 2001; Shroyer et al., 2007) and sufficient (VanDussen and Samuelson, 2010) for the program of secretory cell differentiation. In general, disruption of Notch signaling results in increased Atoh1 expression and loss of proliferation coupled with secretory cell hyperplasia, whereas hyperactive Notch signaling results in decreased Atoh1 expression and in expansion of the proliferative zone with increased numbers of absorptive enterocytes. Accordingly, genetic depletion of Notch pathway components, including the crucial Notch DNA-binding protein RBP-J (Rbpj – Mouse Genome Informatics) (van Es et al., 2005), both Notch1 and Notch2 receptors (Riccio et al., 2008) or both delta-like (Dll) 1 and 4 ligands (Pellegrinet et al., 2011), results in decreased cellular proliferation in the intestinal crypts together with secretory cell hyperplasia. Similar phenotypes have been observed in rodents after treatment with -secretase inhibitors (GSIs) (Milano et al., 2004; Wong et al., 2004; van Es et al., 2005), which block an essential protein cleavage event in the activation of Notch signaling, or with a combination of neutralizing antibodies specific for the Notch1 and Notch2 receptors (Wu et al., 2010). Conversely, activation of constitutive Notch signaling in the mouse intestinal epithelium expands the proliferative zone and represses secretory cell differentiation (Fre et al., 2005; Stanger et al., 2005).

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Bald scalp in men with androgenetic alopecia retains hair follicle stem cells but lacks CD200 rich and CD34 positive hair follicle progenitor cells

Bald scalp in men with androgenetic alopecia retains hair follicle stem cells but lacks CD200 rich and CD34 positive hair follicle progenitor cells

Androgenetic alopecia (AGA), also known as common baldness, is characterized by a marked decrease in hair follicle size, which could be related to the loss of hair follicle stem or progenitor cells. To test this hypothesis, we analyzed bald and non-bald scalp from AGA individuals for the presence of hair follicle stem and progeni- tor cells. Cells expressing cytokeratin15 (KRT15), CD200, CD34, and integrin, α6 (ITGA6) were quantitated via flow cytometry. High levels of KRT15 expression correlated with stem cell properties of small cell size and quiescence. These KRT15 hi stem cells were maintained in bald scalp samples. However, CD200 hi ITGA6 hi and

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Integrin Rac signalling for mammary epithelial stem cell self renewal

Integrin Rac signalling for mammary epithelial stem cell self renewal

In this study, we have discovered a central role for integ- rins in stem cell maintenance and self-renewal within the mammary gland. Integrins are receptors for the ECM that contacts all mammary epithelia, and our genetic approach has revealed their requirement for stem cells. We found that β1-integrin maintains stem cells via a signalling path- way that involves both the small GTPase Rac1, as well as Wnt. These latter signalling proteins are known to deter- mine the nuclear localisation of the β-catenin. We suggest that in stem cells, integrins have a new role in specifying the activation of Wnt and β-catenin.

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Tracing anti-cancer and cancer-promoting actions of all- trans retinoic acid in breast cancer to a RAR aepigenetic mechanism of mammary epithelial cell fate

Tracing anti-cancer and cancer-promoting actions of all- trans retinoic acid in breast cancer to a RAR aepigenetic mechanism of mammary epithelial cell fate

In specific developmental contexts, the RA-RAR mechanism is connected with different upstream and downstream nuclear receptors. For example, in epithelial cells of the mammary gland, nuclear RARα (RARA), on one hand, is directly transcriptionally regulated via estrogen receptor α (ERA) [17] and, on the other hand, directly regulates the transcription of downstream RARs, including the tumor suppressor RARβ2 (RARB2) [18], thus establishing developmental-specific transcriptional cascades epigenetically regulated by hormone and RA signals. Moreover, RA controls other transcriptional signaling pathways via different nuclear receptors, such as peroxisome proliferator-activated receptor β/δ (PPARD) [19, 20] and chicken ovalbumin upstream promoter transcription factor 2 (COUP-TFII) [21]. There is compelling evidence that RA can also regulate in a non-transcriptional fashion different kinases either by direct interaction, as in the case of protein kinase C alpha (PKCA) [22, 23], or via RARA, as in the case of phosphatidyl inositide 3 kinase (PI3K) [24], thus establishing a cross-talk between different RA signaling pathways [25, 26].

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Role of microRNA in epithelial to mesenchymal transition and metastasis and clinical perspectives

Role of microRNA in epithelial to mesenchymal transition and metastasis and clinical perspectives

The dynamic nature of the EMT and MET processes along the metastatic cascade implies a finely tuned, regulated control of tumor cell plasticity that can be exerted, at least in part, through posttranscriptional modulation of the EMT- TFs, such as that mediated by miRNAs. The regulation of the miRNA expression linked to EMT and metastasis is still poorly known. Nevertheless, several mechanisms that have started to be exposed during the last years will be discussed in this section.

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