Histology and histopathology Vol.30, nº5 (2015)
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- PublicationOpen AccessHorse adipose-derived mesenchymal stromal cells constitutively produce membrane vesicles: a morphological study(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Pascucci, L.; Dall’Aglio, C.; Bazzucchi, C.; Mercati, F.; Mancini, M.G.; Pessina, A.; Alessandri, G.; Giammarioli, M.; Dante, S.; Brunati, G.; Ceccarelli, P.Mesenchymal stromal cells (MSCs) are multipotent somatic cells that can differentiate into a variety of mature cell types. Over recent years, their biological in vitro and in vivo properties have elicited great expectations in the field of regenerative medicine, immunotherapy and tumour treatment. An increasing number of experimental observations suggest that their biological effects are probably related to a paracrine mechanism via the release of trophic factors and cytokines as well as through the production of membrane vesicles (MVs). These are nanometric membrane-bound structures, comprising shedding vesicles (SV) and exosomes (Ex), that enclose and transfer signalling molecules to target cells. We hypothesized that MVs may be implicated in the biological effects of MSCs from horse adipose tissue (EAdMSCs), a type of MSC that has been extensively studied in recent years for its remarkable efficacy in tissue regeneration. By means of electron microscopy, we ascertained, for the first time, that equine adipose-derived MSCs constitutively produce MVs (E-AdMSCs). The analysis of MVs separated by ultracentrifugation allowed us to describe their general morphological features. Through the examination of cell monolayers by TEM, additionally, we distinguished the different pathways of SV and Ex formation, demonstrating that both fractions are produced by E-AdMSC. The accurate description of MV heterogeneous morphological characteristics led us to emphasize the possible implications of the relationship between different morphologies versus different functions. The data presented in this paper has an additional value, as they can be noteworthy for horses as well as for other mammalian species, including humans.
- PublicationOpen AccessThe bone matrix protein secreted phosphoprotein 24 kD (Spp24): bone metabolism regulator and starting material for biotherapeutic materials(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Murray, Samuel S.; Wang, Jeffrey C.; Duarte, Maria Eugenia Leite; Zhao, Ke-Wei; Tian, Haijun; Francis, Timothy; Brochmann Murray, Elsa J.Secreted phosphoprotein 24 kD (Spp24) is a bone matrix protein that appears to be derived primarily from the liver and delivered to other tissues in a protective complex. A significant role in bone growth and turnover is suggested by genetic studies that associate the gene locus (SPP2) with bone mineral density and bone quality. The function of this protein in the normal bone environment is unknown but clues are given by the fact that Spp24, or proteolytic products of Spp24, bind cytokines of the TGF-β superfamily and also activate intracellular signaling pathways. Several potential biotherapeutics have been engineered from this protein including materials that enhance BMP-induced bone healing and, on the other hand, materials that inhibit BMPs in clinical situations where this is called for such as reducing BMP-induced inflammation and inhibiting tumors dependent on BMP autocrine systems. As understanding of the structure and function of this protein increases, more opportunities for rationally developed therapeutics will become apparent.
- PublicationOpen AccessThe diverse oncogenic and tumour suppressor roles of p63 and p73 in cancer: a review by cancer site(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Orzol, Paulina; Holcakova, Jitka; Nekulova, Marta; Nenutil, Rudolf; Vojtesek, Borivoj; Coates, Philip J.p63 and p73, the two other members of the p53 family, were identified almost 15 years ago. Here, we review their potential use for diagnosis, prognosis and prediction of response to therapy in various cancers. The two genes show distinct expression patterns in both normal and cancer tissues and each gene gives rise to multiple protein isoforms with different activities, including those with tumour-suppressor or oncogenic effects. Despite such complexity, some common themes emerge; p63 is commonly overexpressed as the ΔNp63 isoform and sometimes associated with TP63 amplification, whereas p73 is often reduced (by methylation or gene loss), or there is an increase in the ratio of ΔNp73 to TAp73. These generalisations do not apply universally; TAp63 is overexpressed in haematological malignancies, TP63 mis-sense mutations have been reported in squamous cancers and TP63 translocations occur in lymphomas and some lung adenocarcinomas. There are associations with disease prognosis and response to specific therapies in individual cancer types for both p63 and p73, making their analysis of clinical relevance. We also discuss their utility for aiding in differential diagnosis, which has been demonstrated for p63, but not yet for p73. Throughout, we highlight the discrepant nature of many studies due to the variable methodologies employed, the lack of systematic evaluation of isoforms and the problems of poor antibody characterization and crossreactions within the p63/p73 family. Finally, we emphasize the value of recently developed isoformspecific reagents that have clear advantages for the study of p63 and p73 experimentally and clinically.
- PublicationOpen AccessHuman resident CD34+ stromal cells/telocytes have progenitor capacity and are a source of αSMA+ cells during repair(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Díaz-Flores, L.; Gutiérrez, R.; García, M.P.; González, M.; Sáez, F.J.; Aparicio, F.; Díaz-Flores Jr., L.; Madrid Cuevas, Juan FranciscoWe studied the progenitor capacity of human resident CD34+ stromal cells/telocytes (SC/TCs) in the enteric wall affected by inflammatory/repair processes (appendicitis, diverticulitis of large bowel and Crohn’s disease of the terminal ileum) at different stages of evolution (inflammatory, proliferative and remodelling). In these conditions, CD34+ SC/TCs are activated, showing changes, which include the following overlapping events: 1) separation from adjacent structures (e.g., from vascular walls) and location in oedematous spaces, 2) morphological modifications (in cell shape and size) with presence of transitional cell forms between quiescent and activated CD34+ SC/TCs, 3) rapid proliferation and 4) loss of CD34 expression and gain of αSMA expression. These events mainly occur in the inflammatory and proliferative stages. During the loss of CD34 expression, the following findings are observed: a) irregular cell labelling intensity for anti-CD34, b) co-localization of CD34 and actin, c) concurrent irregular labelling intensity for αSMA and d) αSMA expression in all stromal cells, with total loss of CD34 expression. While CD34 expression was conserved, a high proliferative capacity (Ki-67 expression) was observed and vice versa. In the segments of the ileum affected by Crohn’s disease, the stromal cells around fissures were αSMA+ and, in the transitional zones with normal enteric wall, activated CD34+ SC/TCs were observed. In conclusion, human resident CD34+ SC/TCs in the enteric wall have progenitor capacity and are activated with or without differentiation into αSMA+ stromal cells during inflammatory/repair processes.
- PublicationOpen AccessLymphoid hyperplasia and lymphoma in KSHV K1 transgenic mice(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Berkova, Zuzana; Wang, Shu; Sehgal, Lalit; Pate, Keyur Pravinchandra; Prakash, Om; Samaniego, FelipeGrowing evidence supports the involvement of human herpervirus 8, Kaposi’s sarcoma associated herpesvirus (KSHV), in the pathology of primary effusion lymphoma, multicentric Castleman’s disease, and Kaposi’s sarcoma, but the exact mechanism of KSHV contribution to the oncogenic process remains elusive. We studied transgenic mice expressing the ORF K1 of KSHV, whose position in the KSHV genome corresponds to known lymphoproliferative genes of other herpesviruses. K1 protein was previously shown to contain a constitutively active ITAM domain, involved in activation of Akt and pro-survival signaling, and to inhibit Fas-mediated apoptosis by interfering with binding of FasL. All this pointed to a possible role of K1 in the pathogenesis of KSHV-associated cancers. K1 transgenic mice (80-90%) developed lymphoid hyperplasia and splenomegaly at 8 and 10 months of age, 25% had confirmed diagnosis of lymphoma, and 50% developed abdominal and/or hepatic tumors by 18 months of age. Histological examination showed loss of splenic architecture and increased cellularity. Lymph nodes showed disrupted architecture with effaced follicles and other pathological changes, including signs of angiofollicular lymphoid hyperplasia. One of the livers showed signs of angiosarcoma. In summary, our histology results revealed pathological changes in K1 transgenic mice similar to lymphoma, Castleman’s disease, and angiosarcoma, suggesting that K1 may contribute to the development of KSHV-associated cancers.
- PublicationOpen AccessAnti-inflammatory and antifibrotic effects of resveratrol in the lung(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Conte, Enrico; Fagone, Evelina; Fruciano, Mary; Gili, Elisa; Iemmolo, Maria; Vancheri, CarloResveratrol, a natural polyphenolic molecule with several biological activities, is a well recognized anti-oxidant, anti-aging and cancer chemopreventive agent. Moreover, resveratrol anti-inflammatory and antifibrotic properties have been demonstrated both in vitro and in different animal models of inflammatory pathologies, including bowel and liver diseases. We review the evidence of resveratrol protective role in respiratory diseases such as acute lung injury, asthma, chronic obstructive pulmonary disease and lung fibrosis. We conclude that resveratrol and its derivatives may act as a therapeutic agents in respiratory diseases and pertinent clinical trials should be performed.
- PublicationOpen AccessRole of miRNAs in endometrial cancer(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Li, Shuangdi; Zhang, Jiarong; Wan, XiaopingEndometrial cancer (EC) is the most common gynecologic malignancy. MicroRNAs (miRNAs) were recently associated with carcinogenesis and progression of EC. In this review, we discuss recent advances and the emerging role of miRNAs in EC and their clinical implications, with special emphasis on the differences between deregulated miRNAs in type I and type II EC, as well as the impact of this dysregulation on EC initiation and progression.
- PublicationOpen AccessSIP1 predicts progression and poor prognosis in pharyngeal squamous cell carcinoma(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Jouppila-Mättö, Anna; Mannermaa, Arto; Sironen, Reijo; Kosma, Veli-Matti; Soini, Ylermi; Pukkila, MattiObjectives: The epithelial-mesenchymal transition (EMT) is a crucial process in tumorigenesis that enables tumor cells to invade and metastasize. The transcription factors SIP1, SLUG, ZEB1, SNAI1, and TWIST are fundamental in regulating EMT. We investigated the relationships between several clinicopathological variables, prognosis, and SIP1, SLUG, or ZEB1 in a retrospective pharyngeal squamous cell carcinoma (PSCC) cohort. Study Design: Immunohistochemistry was used to evaluate the expression of SIP1, SLUG, and ZEB1 in 108 tumor samples from a retrospective cohort of patients with PSCC. Results: Tumors with positive epithelial SIP1 immunostaining were more advanced (SIII-IV, p=0.02) and had more lymph node metastases (p=0.04) than SIP1-negative tumors. Tumors with positive stromal staining of SIP1 relapsed more often than SIP1-negative tumors (p=0.007). Negative SIP1 immunoreactivity correlated significantly with better disease-specific survival (DSS) and better overall survival (OS) (p=0.012 and p=0.003 for epithelial reactivity, p=0.018 and p=0.003 for stromal reactivity, respectively). Lack of epithelial SIP1 expression remained an independent and favorable prognostic factor in a Cox proportional hazards model (p=0.046), together with high Karnofsky performance status score and low T class (p<0.001 for both). Co-expression of SNAI1, TWIST, and SIP1 in tumor epithelium predicted even shorter DSS than SIP1 expression alone (p<0.001) in the present study cohort. Conclusions: SIP1 is related to cancer progression and appears to be an independent prognostic factor in PSCC.
- PublicationOpen AccessAssessment of murine brain tissue shrinkage caused by different histological fixatives using magnetic resonance and computed tomography imaging(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Wehrl, Hans F.; Bezrukov, Ilja; Wiehr, Stefan; Lehnhoff, Mareike; Fuchs, Kerstin; Mannheim, Julia G.; Quintanilla-Martine, Leticia; Kohlhofer, Ursula; Kneilling, Manfred; Pichler, Bernd J.; Sauter, Alexander W.Especially for neuroscience and the development of new biomarkers, a direct correlation between in vivo imaging and histology is essential. However, this comparison is hampered by deformation and shrinkage of tissue samples caused by fixation, dehydration and paraffin embedding. We used magnetic resonance (MR) imaging and computed tomography (CT) imaging to analyze the degree of shrinkage on murine brains for various fixatives. After in vivo imaging using 7 T MRI, animals were sacrificed and the brains were dissected and immediately placed in different fixatives, respectively: zinc-based fixative, neutral buffered formalin (NBF), paraformaldehyde (PFA), Bouin-Holland fixative and paraformaldehyde-lysine-periodate (PLP). The degree of shrinkage based on mouse brain volumes, radiodensity in Hounsfield units (HU), as well as non-linear deformations were obtained. The highest degree of shrinkage was observed for PLP (68.1%, P<0.001), followed by PFA (60.2%, P<0.001) and NBF (58.6%, P<0.001). The zinc-based fixative revealed a low shrinkage with only 33.5% (P<0.001). Compared to NBF, the zinc-based fixative shows a slightly higher degree of deformations, but is still more homogenous than PFA. Tissue shrinkage can be monitored non-invasively with CT and MR. Zinc-based fixative causes the smallest degree of brain shrinkage and only small deformations and is therefore recommended for in vivo ex vivo comparison studies.
- PublicationOpen AccessMast cells or not? - CD117 positive cells in esophageal leiomyoma(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Ye, Ju Xiang; Liu, Yan; Qin, Yun; Ma, Xiao Long; Zhong, Hao Hao; Zhang, Yan; Shi, Xue YingThe presence of CD117 positive cells in esophageal leiomyoma may lead to a misdiagnosis of GIST. We reviewed 46 esophageal tumors which were smooth muscle tumors or GIST. Based on morphology, immunohistochemistry and mutation analysis, there were 44 (95.6%) leiomyomas, 1 (2.2%) leiomyosarcoma, and 1 (2.2%) GIST. Variable numbers of CD117 positive cells were seen in all leiomyomas. Tryptase immunostaining identified mast cells in 93.2% (41/44) of leiomyomas, and the number of mast cells per tumor decreased significantly from tumors of the upper esophagus to the esophageal-gastric junction (p<0.01). Immunofluorescence study further confirmed the presence of two types of CD117 positive spindle cells which included spindle-shaped mast cells and DOG-1- positive interstitial cells of Cajal. This is the first study to systemically review mast cells in esophageal leiomyomas and tumors which may be included in the differential diagnosis. We demonstrate that both spindled mast cells and hyperplastic interstitial cells of Cajal are present within esophageal leiomyomas. The immunoreactivity of these cells with CD117 may suggest a diagnosis of GIST, but the presence of mast cells itself supports a diagnosis of esophageal leiomyoma.
- PublicationOpen Access3D Immunofluorescence analysis of early thymic morphogenesis and medulla development(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2015) Muñoz, Juan José; Cejalvo, Teresa; Tobajas, Esther; Fanlo, Lucía; Cortés, Alfonso; Zapata, Agustín GregorioThe thymus represents an epithelial microenvironment specialized in the generation of Tcells. The mechanisms or signals that determine the initial differentiation of the two well distinguished histological compartments of the thymus, cortex and medulla, remain unknown. Here, we report a threedimensional analysis of the distribution of some established thymic epithelial markers in relation to thymic anatomical development during the first steps of thymus organogenesis. In the thymic primordium, initial lumen is lined by claudin (Cld)3/4+K5+ cells, after thymus growth and lobulation they form a continuous branched structure that increases its length and branching degree. Within it, the presence of luminal structures can be distinguished, even at E13.5. The medullary marker mouse thymic stroma 10 (MTS10) is upregulated in these Cld3/4+ lumen forming cells in a proximal-distal sequence. This structural organisation is histologically similar to that described in other epithelial organs undergoing a branching morphogenesis process. These results indicate that the thymic medulla can be evidenced as a continuous branched structure from early stages and suggest a thymic developmental program based on or containing elements of a branching morphogenesis program modified by the presence of lymphoid cells, in which medullary epithelial cell commitment is initially determined by lumen formation.