Browsing by Subject "SMOOTH-MUSCLE-CELLS"

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  • Wu, Ying-Chieh; Sonninen, Tuuli-Maria; Peltonen, Sanni; Koistinaho, Jari; Lehtonen, Sarka (2021)
    The blood-brain barrier (BBB) regulates the delivery of oxygen and important nutrients to the brain through active and passive transport and prevents neurotoxins from entering the brain. It also has a clearance function and removes carbon dioxide and toxic metabolites from the central nervous system (CNS). Several drugs are unable to cross the BBB and enter the CNS, adding complexity to drug screens targeting brain disorders. A well-functioning BBB is essential for maintaining healthy brain tissue, and a malfunction of the BBB, linked to its permeability, results in toxins and immune cells entering the CNS. This impairment is associated with a variety of neurological diseases, including Alzheimer's disease and Parkinson's disease. Here, we summarize current knowledge about the BBB in neurodegenerative diseases. Furthermore, we focus on recent progress of using human-induced pluripotent stem cell (iPSC)-derived models to study the BBB. We review the potential of novel stem cell-based platforms in modeling the BBB and address advances and key challenges of using stem cell technology in modeling the human BBB. Finally, we highlight future directions in this area.
  • Tikka, Saara; Baumann, Marc; Siitonen, Maija; Pasanen, Petra; Poyhonen, Minna; Myllykangas, Liisa; Viitanen, Matti; Fukutake, Toshio; Cognat, Emmanuel; Joutel, Anne; Kalimo, Hannu (2014)
  • Magnussen, Synnove Norvoll; Hadler-Olsen, Elin; Costea, Daniela Elena; Berg, Eli; Jacobsen, Cristiane Cavalcanti; Mortensen, Bente; Salo, Tuula; Martinez-Zubiaurre, Inigo; Winberg, Jan-Olof; Uhlin-Hansen, Lars; Svineng, Gunbjorg (2017)
    Background: Urokinase plasminogen activator (uPA) receptor (uPAR) is up-regulated at the invasive tumour front of human oral squamous cell carcinoma (OSCC), indicating a role for uPAR in tumour progression. We previously observed elevated expression of uPAR at the tumour-stroma interface in a mouse model for OSCC, which was associated with increased proteolytic activity. The tumour microenvironment regulated uPAR expression, as well as its glycosylation and cleavage. Both full-length- and cleaved uPAR (uPAR (II-III)) are involved in highly regulated processes such as cell signalling, proliferation, migration, stem cell mobilization and invasion. The aim of the current study was to analyse tumour associated factors and their effect on uPAR cleavage, and the potential implications for cell proliferation, migration and invasion. Methods: Mouse uPAR was stably overexpressed in the mouse OSCC cell line AT84. The ratio of full-length versus cleaved uPAR as analysed by Western blotting and its regulation was assessed by addition of different protease inhibitors and transforming growth factor - beta 1 (TGF-beta 1). The role of uPAR cleavage in cell proliferation and migration was analysed using real- time cell analysis and invasion was assessed using the myoma invasion model. Results: We found that when uPAR was overexpressed a proportion of the receptor was cleaved, thus the cells presented both full-length uPAR and uPAR (II-III). Cleavage was mainly performed by serine proteases and urokinase plasminogen activator (uPA) in particular. When the OSCC cells were stimulated with TGF-beta 1, the production of the uPA inhibitor PAI-1 was increased, resulting in a reduction of uPAR cleavage. By inhibiting cleavage of uPAR, cell migration was reduced, and by inhibiting uPA activity, invasion was reduced. We could also show that medium containing soluble uPAR (suPAR), and cleaved soluble uPAR (suPAR (II-III)), induced migration in OSCC cells with low endogenous levels of uPAR. Conclusions: These results show that soluble factors in the tumour microenvironment, such as TGF-beta 1, PAI-1 and uPA, can influence the ratio of full length and uPAR (II-III) and thereby potentially effect cell migration and invasion. Resolving how uPAR cleavage is controlled is therefore vital for understanding how OSCC progresses and potentially provides new targets for therapy.
  • Kofler, Natalie M.; Cuervo, Henar; Uh, Minji K.; Murtomäki, Aino; Kitajewski, Jan (2015)
    Pericytes regulate vessel stability and pericyte dysfunction contributes to retinopathies, stroke, and cancer. Here we define Notch as a key regulator of pericyte function during angiogenesis. In Notch1(+/-); Notch3(-/-) mice, combined deficiency of Notch1 and Notch3 altered pericyte interaction with the endothelium and reduced pericyte coverage of the retinal vasculature. Notch1 and Notch3 were shown to cooperate to promote proper vascular basement membrane formation and contribute to endothelial cell quiescence. Accordingly, loss of pericyte function due to Notch deficiency exacerbates endothelial cell activation caused by Notch1 haploinsufficiency. Mice mutant for Notch1 and Notch3 develop arteriovenous malformations and display hallmarks of the ischemic stroke disease CADASIL. Thus, Notch deficiency compromises pericyte function and contributes to vascular pathologies.
  • Rouhiainen, Ari; Zhao, Xiang; Vanttola, Päivi; Qian, Kui; Kulesskiy, Evgeny; Kuja-Panula, Juha; Gransalke, Kathleen; Gronholm, Mikaela; Unni, Emmanual; Meistrich, Marvin; Tian, Li; Auvinen, Petri; Rauvala, Heikki (2016)
    HMGB4 is a new member in the family of HMGB proteins that has been characterized in sperm cells, but little is known about its functions in somatic cells. Here we show that HMGB4 and the highly similar rat Transition Protein 4 (HMGB4L1) are expressed in neuronal cells. Both proteins had slow mobility in nucleus of living NIH-3T3 cells. They interacted with histones and their differential expression in transformed cells of the nervous system altered the post-translational modification statuses of histones in vitro. Overexpression of HMGB4 in HEK 293T cells made cells more susceptible to cell death induced by topoisomerase inhibitors in an oncology drug screening array and altered variant composition of histone H3. HMGB4 regulated over 800 genes in HEK 293T cells with a p-value
  • Boren, Jan; Chapman, M. John; Krauss, Ronald M.; Packard, Chris J.; Bentzon, Jacob F.; Binder, Christoph J.; Daemen, Mat J.; Demer, Linda L.; Hegele, Robert A.; Nicholls, Stephen J.; Nordestgaard, Brge G.; Watts, Gerald F.; Bruckert, Eric; Fazio, Sergio; Ference, Brian A.; Graham, Ian; Horton, Jay D.; Landmesser, Ulf; Laufs, Ulrich; Masana, Luis; Pasterkamp, Gerard; Raal, Frederick J.; Ray, Kausik K.; Schunkert, Heribert; Taskinen, Marja-Riitta; van de Sluis, Bart; Wiklund, Olov; Tokgozoglu, Lale; Catapano, Alberico L.; Ginsberg, Henry N. (2020)
  • Tomasovic, Ana; Kurrle, Nina; Wempe, Frank; De-Zolt, Siike; Scheibe, Susan; Koli, Katri; Serchinger, Martin; Schnuetgen, Frank; Sueruen, Duran; Sterner-Kock, Anja; Weissmann, Norbert; von Meichner, Harald (2017)
    Latent transforming growth factor beta binding protein 4 (LTBP4) belongs to the fibrillin/LTBP family of proteins and plays an important role as a structural component of extracellular matrix (ECM) and local regulator of TGF beta signaling. We have previously reported that Ltbp4S knock out mice (Ltbp4S-/-) develop centrilobular emphysema reminiscent of late stage COPD, which could be partially rescued by inactivating the antioxidant protein Sestrin 2 (Sesn2). More recent studies showed that Sesn2 knock out mice upregulate Pdgfr beta-controlled alveolar maintenance programs that protect against cigarette smoke induced pulmonary emphysema. Based on this, we hypothesized that the emphysema of Ltbp4S-/- mice is primarily caused by defective Pdgfr beta signaling. Here we show that LTBP4 induces Pdgfr beta signaling by inhibiting the antioxidant Nr12/Keap1 pathway in a TGF beta-dependent manner. Overall, our data identified Ltbp4 as a major player in lung remodeling and injury repair. (C) 2016 The Authors. Published by Elsevier B.V.
  • Nedoszytko, Boguslaw; Wierzbicki, Piotr; Karenko, Leena; Maciejewska-Radomska, Agata; Stachewicz, Przemyslaw; Zablotna, Monika; Glen, Jolanta; Vakeva, Liisa; Nowicki, Roman J.; Sokolowska-Wojdylo, Malgorzata (2018)
    Introduction: Microbial infection and associated super antigens have been implicated in the pathogenesis of cutaneous T-cell lymphoma (CTCL), and many patients die from complicating bacterial infections. It has been postulated that Chlamydophila pneumoniae (C. pneumoniae) infection may be involved in the pathogenesis of Mycosis fungoides (MF) but published data are limited and controversial. Aim: To analyze the frequency of (C. pneumoniae) DNA presence in blood samples of lymphoma cases. Material and methods: Using Q-PCR method we analyzed the presence of DNA in the blood samples obtained from 57 patients with CTCL (55 - mycosis fungoides (MF)/Sezary syndrome (SS), one primary cutaneous anaplastic large cell lymphoma (CD30+) and one NKT cell lymphoma) and 3 patients with cutaneous B-cell lymphomas, and 120 individuals from control groups (40 patients with psoriasis, 40 patients with atopic dermatitis and 40 healthy controls). Results: Chlamydophila pneumoniae DNA was identified in 13 of 55 cases in the MF/SS group (23.6%), in 1 patient with CD30+ large cell lymphoma and in 1 of 3 patients with B-cell lymphoma. The presence of C. pneumoniae was confirmed in 1 of 40 psoriatic patients (2.5%), in 5 of 40 patients with atopic dermatitis (12.5%) and in none of 40 healthy individuals. Presence of C. pneumoniae DNA in MF patients was strongly associated with disease progression; rs = 0.756; p = 0.0123 for groups IA -> IVB, and was noted more frequently in advanced (III + IV) stages than in early (I-II) stages (p = 0.0139). There are no differences in the mean age of MF/SS patients with and without infection. Conclusions: The presence of C. pneumoniae DNA in the blood cells is a frequent event in late stages of MF/SS and may be explained by Th2 shift and suppression of the immune system during the course of the disease.
  • Marbacher, Serge; Niemelä, Mika; Hernesniemi, Juha; Frösen, Juhana (2019)
    Although endovascular therapy has been proven safe and has become in many centers the primary method of treatment for intracranial aneurysms, the long-term durability of endovascular embolization remains a concern; at least for some aneurysms despite initial good result. While healing after clipping relies on mechanical occlusion, restoration after endovascular occlusion mainly requires the induction of a biological response. Healing after embolization depends on the growth of new tissue over the thrombus formed by the embolization material, or alternatively, on the organization of thrombus into fibrous tissue. This review highlights the fundamental importance of aneurysm wall biology on the healing process and long-term occlusion after intracranial aneurysm (IA) treatment. It seems likely that the effect of luminal thrombus on the IA wall, as well as the IA wall condition at the time of thrombosis, determine if thrombus organizes into scar tissue (neointima formation by infiltration of cells originating from the IA wall) or if the wall undergoes continuous remodeling, which is primarily destructive (loss of mural cells). In the latter, intraluminal thrombus organization fails and the impaired healing increases the chance of recurrence. Mechanisms underlying IA reopening, the influence of intraluminal thrombosis on the IA wall, and clinical implications of the IA wall condition are discussed in detail, along with how knowledge of IA wall biology can offer new solutions for IA treatment and affect the patient selection for and follow-up after endovascular treatment.
  • Paukku, Kirsi; Backlund, Michael; De Boer, Rudolf A.; Kalkkinen, Nisse; Kontula, Kimmo K.; Lehtonen, Jukka Y. A. (2012)
  • Cai, Mengyin; Bompada, Pradeep; Salehi, Albert; Acosta, Juan R.; Prasad, Rashmi B.; Atac, David; Laakso, Markku; Groop, Leif; De Marinis, Yang (2018)
    Osteopontin (OPN) is involved in various physiological processes and also implicated in multiple pathological states. It has been suggested that OPN may have a role in type 2 diabetes (T2D) by protecting pancreatic islets and interaction with incretins. However, the regulation and function of OPN in islets, especially in humans, remains largely unexplored. In this study, we performed our investigations on both diabetic mouse model SUR1-E1506K+/+ and islets from human donors. We demonstrated that OPN protein, secretion and gene expression was elevated in the diabetic SUR1-E1506K+/+ islets. We also showed that high glucose and incretins simultaneously stimulated islet OPN secretion. In islets from human cadaver donors, OPN gene expression was elevated in diabetic islets, and externally added OPN significantly increased glucose-stimulated insulin secretion (GSIS) from diabetic but not normal glycemic donors. The increase in GSIS by OPN in diabetic human islets was Ca2+ dependent, which was abolished by Ca2+-channel inhibitor isradipine. Furthermore, we also confirmed that OPN promoted cell metabolic activity when challenged by high glucose. These observations provided evidence on the protective role of OPN in pancreatic islets under diabetic condition, and may point to novel therapeutic targets for islet protection in T2D. (C) 2017 Elsevier Inc. All rights reserved.