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  • 1.
    Cheddad, Abbas
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Nord, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Hörnblad, Andreas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Prunskaite-Hyyryläinen, Renata
    Oulu Center for Cell-Matrix Research, Biocenter Oulu, Laboratory of Developmental Biology and Department of Medical Biochemistry and Molecular Biology, Institute of Biomedicine, University of Oulu, Finland.
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Georgsson, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Computing Science.
    Vainio, Seppo
    Oulu Center for Cell-Matrix Research, Biocenter Oulu, Laboratory of Developmental Biology and Department of Medical Biochemistry and Molecular Biology, Institute of Biomedicine, University of Oulu, Finland.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Improving signal detection in emission optical projection tomography via single source multi-exposure image fusion2013In: Optics Express, E-ISSN 1094-4087, Vol. 21, no 14, p. 16584-16604Article in journal (Refereed)
    Abstract [en]

    We demonstrate a technique to improve structural data obtained from Optical Projection Tomography (OPT) using Image Fusion (IF) and contrast normalization. This enables the visualization of molecular expression patterns in biological specimens with highly variable contrast values. In the approach, termed IF-OPT, different exposures are fused by assigning weighted contrasts to each. When applied to projection images from mouse organs and digital phantoms our results demonstrate the capability of IF-OPT to reveal high and low signal intensity details in challenging specimens. We further provide measurements to highlight the benefits of the new algorithm in comparison to other similar methods.

  • 2.
    Eriksson, Anna U.
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Svensson, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Hörnblad, Andreas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Cheddad, Abbas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Kostromina, Elena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Norlin, Nils
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Pileggi, Antonello
    Cell Transplants Center, Diabetes Research Institute, University of Miami.
    Sharpe, James
    EMBL-CRG Systems Biology Program, Centre for Genomic Regulation, Catalan Institute of Research and Advance Studies.
    Georgsson, Fredrik
    Umeå University, Faculty of Science and Technology, Department of Computing Science.
    Alanentalo, Tomas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Near infrared optical projection tomography for assessments of beta-cell mass distribution in diabetes research2013In: Journal of Visualized Experiments, E-ISSN 1940-087X, Vol. 71, article id e50238Article in journal (Refereed)
    Abstract [en]

    By adapting OPT to include the capability of imaging in the near infrared (NIR) spectrum, we here illustrate the possibility to image larger bodies of pancreatic tissue, such as the rat pancreas, and to increase the number of channels (cell types) that may be studied in a single specimen. We further describe the implementation of a number of computational tools that provide: 1/ accurate positioning of a specimen's (in our case the pancreas) centre of mass (COM) at the axis of rotation (AR)2; 2/ improved algorithms for post-alignment tuning which prevents geometric distortions during the tomographic reconstruction2 and 3/ a protocol for intensity equalization to increase signal to noise ratios in OPT-based BCM determinations3. In addition, we describe a sample holder that minimizes the risk for unintentional movements of the specimen during image acquisition. Together, these protocols enable assessments of BCM distribution and other features, to be performed throughout the volume of intact pancreata or other organs (e.g. in studies of islet transplantation), with a resolution down to the level of individual islets of Langerhans.

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  • 3.
    Eriksson, Maria
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Litwak, Sara A.
    St Vincent's Institute of Medical Research, 9 Princes Street, Melbourne, Australia.
    Yun, Yan
    Charles Perkins Centre, Discipline of Physiology, School of Medical Sciences, University of Sydney, Johns Hopkins Dr, Sydney, Australia.
    Stanley, William J.
    St Vincent's Institute of Medical Research, 9 Princes Street, Melbourne, Australia; Department of Medicine, The University of Melbourne, Parkville, Melbourne, Australia.
    Thorn, Peter
    Charles Perkins Centre, Discipline of Physiology, School of Medical Sciences, University of Sydney, Johns Hopkins Dr, Sydney, Australia.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gurzov, Esteban N.
    Department of Medicine, The University of Melbourne, Parkville, Melbourne, Australia; Signal Transduction and Metabolism Laboratory, Laboratoire de Gastroentérologie Expérimental et Endotools, Université libre de Bruxelles, Route de Lennik 808, Brussels, Belgium.
    Insulin-Binding Peptide Probes Provide a Novel Strategy for Pancreatic β-Cell Imaging2021In: Molecular Pharmaceutics, ISSN 1543-8384, E-ISSN 1543-8392, Vol. 18, no 12, p. 4428-4436Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes develops in childhood and adolescence, with peak incidence in the early teenage years. There is an urgent need for an accurate method to detect insulin-producing β-cells in patients that is not affected by alterations in β-cell function. As part of our research program to design specific probes to measure β-cell mass, we recently developed a novel insulin-binding peptide probe (IBPP) for the detection of β-cells in vivo. Here, we applied our innovative method to show specific labeling of this IBPP to human and mouse fixed β-cells in pancreatic islets. Importantly, we showed staining of human and mouse islets in culture without any negative functional or cell viability impact. Moreover, the IBPP-stained mouse islets after tail vein injection in vivo, albeit with batch differences in staining efficiency. In conclusion, we provide evidence showing that the IBPP can be used for future accurate detection of β-cell mass in a variety of preclinical models of diabetes.

  • 4. Eter, Wael A.
    et al.
    Parween, Saba
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Joosten, Lieke
    Frielink, Cathelijne
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Brom, Maarten
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Gotthardt, Martin
    SPECT-OPT multimodal imaging enables accurate evaluation of radiotracers for beta-cell mass assessments2016In: Scientific Reports, E-ISSN 2045-2322, Vol. 6, article id 24576Article in journal (Refereed)
    Abstract [en]

    Single Photon Emission Computed Tomography (SPECT) has become a promising experimental approach to monitor changes in beta-cell mass (BCM) during diabetes progression. SPECT imaging of pancreatic islets is most commonly cross-validated by stereological analysis of histological pancreatic sections after insulin staining. Typically, stereological methods do not accurately determine the total beta-cell volume, which is inconvenient when correlating total pancreatic tracer uptake with BCM. Alternative methods are therefore warranted to cross-validate beta-cell imaging using radiotracers. In this study, we introduce multimodal SPECT - optical projection tomography (OPT) imaging as an accurate approach to cross-validate radionuclide-based imaging of beta-cells. Uptake of a promising radiotracer for beta-cell imaging by SPECT, In-111-exendin-3, was measured by ex vivo-SPECT and cross evaluated by 3D quantitative OPT imaging as well as with histology within healthy and alloxan-treated Brown Norway rat pancreata. SPECT signal was in excellent linear correlation with OPT data as compared to histology. While histological determination of islet spatial distribution was challenging, SPECT and OPT revealed similar distribution patterns of In-111-exendin-3 and insulin positive beta-cell volumes between different pancreatic lobes, both visually and quantitatively. We propose ex vivo SPECT-OPT multimodal imaging as a highly accurate strategy for validating the performance of beta-cell radiotracers.

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  • 5. Grong, Eivind
    et al.
    Kulseng, Bård
    Arbo, Ingerid Brænne
    Nord, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Mårvik, Ronald
    Sleeve gastrectomy, but not duodenojejunostomy, preserves total beta-cell mass in Goto-Kakizaki rats evaluated by three-dimensional optical projection tomography2016In: Surgical Endoscopy, ISSN 0930-2794, E-ISSN 1432-2218, Vol. 30, no 2, p. 532-542Article in journal (Refereed)
    Abstract [en]

    Background In type 2 diabetes mellitus, there is a progressive loss of beta-cell mass. Bariatric surgery has in recent investigations showed promising results in terms of diabetes remission, but little is established regarding the effect of surgery on the survival or regeneration of pancreatic beta-cells. In this study, we aim to explore how bariatric surgery with its subsequent hormonal alterations affects the islets of Langerhans.

    Methods Twenty-four Goto-Kakizaki rats were operated with duodenojejunostomy (DJ), sleeve gastrectomy (SG) or sham operation. From the 38th week after surgery, body weight, fasting blood glucose, glycosylated hemoglobin, mixed meal tolerance with repeated measures of insulin, glucagon-like peptide 1, gastrin and total ghrelin were evaluated. Forty-six weeks after surgery, the animals were euthanized and the total beta-cell mass in all animals was examined by three-dimensional volume quantification by optical projection tomography based on the signal from insulin-specific antibody staining.

    Results Body weight did not differ between groups (Pg = 0.37). SG showed lower fasting blood glucose compared to DJ and sham (Pg = 0.037); HbA1c levels in SG were lower compared to DJ only (p\0.05). GLP-1 levels were elevated for DJ compared to SG and sham (Pg = 0.001), whereas gastrin levels were higher in SG compared to the two other groups (Pg = 0.002). Beta-cell mass was significantly greater in animals operated with SG compared to both DJ and sham (p = 0.036).

    Conclusion Sleeve gastrectomy is superior to duodenojejunostomy and sham operation when comparing the preservation of beta-cell mass 46 weeks after surgery in Goto-Kakizaki rats. This could be related to both the increased gastrin levels and the long-term improvement in glycemic parameters observed after this procedure.

  • 6.
    Hahn, Max
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Nord, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Morini, Federico
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Alanentalo, Tomas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Korsgren, Olle
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    3D imaging of human organs with micrometer resolution - applied to the endocrine pancreas2021In: Communications Biology, E-ISSN 2399-3642, Vol. 4, no 1, article id 1063Article in journal (Refereed)
    Abstract [en]

    The possibility to quantitatively study specific molecular/cellular features of complete human organs with preserved spatial 3D context would have widespread implications for pre-clinical and clinical medicine. Whereas optical 3D imaging approaches have experienced a formidable revolution, they have remained limited due to current incapacities in obtaining specific labelling within large tissue volumes. We present a simple approach enabling reconstruction of antibody labeled cells within entire human organs with preserved organ context. We demonstrate the utility of the approach by providing volumetric data and 3D distribution of hundreds of thousands of islets of Langerhans within the human pancreas. By assessments of pancreata from non-diabetic and type 2 diabetic individuals, we display previously unrecognized features of the human islet mass distribution and pathology. As such, this method may contribute not only in unraveling new information of the pancreatic anatomy/pathophysiology, but it may be translated to essentially any antibody marker or organ system.

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  • 7.
    Hahn, Max
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Nord, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Franklin, Oskar
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Alanentalo, Tomas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Isaksson Mettävainio, Martin
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Morini, Federico
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Korsgren, Olle
    Sund, Malin
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery. Department of Surgical and Perioperative Sciences/Surgery, Umeå University Hospital, Umeå, Swede.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Mesoscopic 3D imaging of pancreatic cancer and Langerhans islets based on tissue autofluorescence2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 18246Article in journal (Refereed)
    Abstract [en]

    The possibility to assess pancreatic anatomy with microscopic resolution in three dimensions (3D) would significantly add to pathological analyses of disease processes. Pancreatic ductal adenocarcinoma (PDAC) has a bleak prognosis with over 90% of the patients dying within 5 years after diagnosis. Cure can be achieved by surgical resection, but the efficiency remains drearily low. Here we demonstrate a method that without prior immunohistochemical labelling provides insight into the 3D microenvironment and spread of PDAC and premalignant cysts in intact surgical biopsies. The method is based solely on the autofluorescent properties of the investigated tissues using optical projection tomography and/or light-sheet fluorescence microscopy. It does not interfere with subsequent histopathological analysis and may facilitate identification of tumor-free resection margins within hours. We further demonstrate how the developed approach can be used to assess individual volumes and numbers of the islets of Langerhans in unprecedently large biopsies of human pancreatic tissue, thus providing a new means by which remaining islet mass may be assessed in settings of diabetes. Generally, the method may provide a fast approach to provide new anatomical insight into pancreatic pathophysiology.

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  • 8.
    Hahn, Max
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    van Krieken, Pim P.
    Nord, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Alanentalo, Tomas
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Morini, Federico
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Xiong, Yan
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Mayer, Jurgen
    Kostromina, Elena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ruas, Jorge L.
    Sharpe, James
    Pereira, Teresa
    Berggren, Per-Olof
    Ilegems, Erwin
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Topologically selective islet vulnerability and self-sustained downregulation of markers for β-cell maturity in streptozotocin-induced diabetes2020In: Communications Biology, E-ISSN 2399-3642, Vol. 3, no 1, article id 541Article in journal (Refereed)
    Abstract [en]

    Mouse models of Streptozotocin (STZ) induced diabetes represent the most widely used preclinical diabetes research systems. We applied state of the art optical imaging schemes, spanning from single islet resolution to the whole organ, providing a first longitudinal, 3D-spatial and quantitative account of β-cell mass (BCM) dynamics and islet longevity in STZ-treated mice. We demonstrate that STZ-induced β-cell destruction predominantly affects large islets in the pancreatic core. Further, we show that hyperglycemic STZ-treated mice still harbor a large pool of remaining β-cells but display pancreas-wide downregulation of glucose transporter type 2 (GLUT2). Islet gene expression studies confirmed this downregulation and revealed impaired β-cell maturity. Reversing hyperglycemia by islet transplantation partially restored the expression of markers for islet function, but not BCM. Jointly our results indicate that STZ-induced hyperglycemia results from β-cell dysfunction rather than β-cell ablation and that hyperglycemia in itself sustains a negative feedback loop restraining islet function recovery.

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  • 9. Ilegems, E.
    et al.
    van Krieken, P. P.
    Edlund, P. K.
    Dicker, A.
    Alanentalo, T.
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Mandic, S.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Berggren, P. -O
    Light scattering as an intrinsic indicator for pancreatic islet cell mass and secretion2015In: Scientific Reports, E-ISSN 2045-2322, Vol. 5, article id 10740Article in journal (Refereed)
    Abstract [en]

    The pancreatic islet of Langerhans is composed of endocrine cells producing and releasing hormones from secretory granules in response to various stimuli for maintenance of blood glucose homeostasis. In order to adapt to a variation in functional demands, these islets are capable of modulating their hormone secretion by increasing the number of endocrine cells as well as the functional response of individual cells. A failure in adaptive mechanisms will lead to inadequate blood glucose regulation and thereby to the development of diabetes. It is therefore necessary to develop tools for the assessment of both pancreatic islet mass and function, with the aim of understanding cellular regulatory mechanisms and factors guiding islet plasticity. Although most of the existing techniques rely on the use of artificial indicators, we present an imaging methodology based on intrinsic optical properties originating from mature insulin secretory granules within endocrine cells that reveals both pancreatic islet mass and function. We demonstrate the advantage of using this imaging strategy by monitoring in vivo scattering signal from pancreatic islets engrafted into the anterior chamber of the mouse eye, and how this versatile and noninvasive methodology permits the characterization of islet morphology and plasticity as well as hormone secretory status.

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  • 10.
    Nord, Christoffer
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Dicker, Andrea
    Eriksson, Anna
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Grong, Eivind
    Ilegems, Erwin
    Marvik, Ronald
    Kulseng, Bard
    Berggren, Per-Olof
    Gorzsas, Andras
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Biochemical profiling of diabetes disease progression by multivariate vibrational microspectroscopy of the pancreas2017In: Scientific Reports, E-ISSN 2045-2322, Vol. 7, article id 6646Article in journal (Refereed)
    Abstract [en]

    Despite the dramatic increase in the prevalence of diabetes, techniques for in situ studies of the underlying pancreatic biochemistry are lacking. Such methods would facilitate obtaining mechanistic understanding of diabetes pathophysiology and aid in prognostic and/or diagnostic assessments. In this report we demonstrate how a multivariate imaging approach (orthogonal projections to latent structures - discriminant analysis) can be applied to generate full vibrational microspectroscopic profiles of pancreatic tissues. These profiles enable extraction of known and previously unrecorded biochemical alterations in models of diabetes, and allow for classification of the investigated tissue with regards to tissue type, strain and stage of disease progression. Most significantly, the approach provided evidence for dramatic alterations of the pancreatic biochemistry at the initial onset of immune-infiltration in the Non Obese Diabetic model for type 1 diabetes. Further, it enabled detection of a previously undocumented accumulation of collagen fibrils in the leptin deficient ob/ob mouse islets. By generating high quality spectral profiles through the tissue capsule of hydrated human pancreata and by in vivo Raman imaging of pancreatic islets transplanted to the anterior chamber of the eye, we provide critical feasibility studies for the translation of this technique to diagnostic assessments of pancreatic biochemistry in vivo.

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  • 11.
    Parween, Saba
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Nord, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Kostromina, Elena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Spatial and quantitative datasets of the pancreatic beta-cell mass distribution in lean and obese mice2017In: Scientific Data, E-ISSN 2052-4463, Vol. 4, article id 170031Article in journal (Refereed)
    Abstract [en]

    A detailed understanding of pancreatic β-cell mass distribution is a key element to fully appreciate the pathophysiology of models of diabetes and metabolic stress. Commonly, such assessments have been performed by stereological approaches that rely on the extrapolation of two-dimensional data and provide very limited topological information. We present ex vivo optical tomographic data sets of the full β-cell mass distribution in cohorts of obese ob/ob mice and their lean controls, together with information about individual islet β-cell volumes, their three-dimensional coordinates and shape throughout the volume of the pancreas between 4 and 52 weeks of age. These data sets offer the currently most comprehensive public record of the β-cell mass distribution in the mouse. As such, they may serve as a quantitative and topological reference for the planning of a variety of in vivo or ex vivo experiments including computational modelling and statistical analyses. By shedding light on intra- and inter-lobular variations in β-cell mass distribution, they further provide a powerful tool for the planning of stereological sampling assessments.

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  • 12.
    Parween, Saba
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Kostromina, Elena
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Nord, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Lindström, Per
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Intra-islet lesions and lobular variations in β-cell mass expansion in ob/ob mice revealed by 3D imaging of intact pancreas2016In: Scientific Reports, E-ISSN 2045-2322, Vol. 6, article id 34885Article in journal (Refereed)
    Abstract [en]

    The leptin deficient ob/ob mouse is a widely used model for studies on initial aspects of metabolic disturbances leading to type 2 diabetes, including insulin resistance and obesity. Although it is generally accepted that ob/ob mice display a dramatic increase in β-cell mass to compensate for increased insulin demand, the spatial and quantitative dynamics of β-cell mass distribution in this model has not been assessed by modern optical 3D imaging techniques. We applied optical projection tomography and ultramicroscopy imaging to extract information about individual islet β-cell volumes throughout the volume of ob/ob pancreas between 4 and 52 weeks of age. Our data show that cystic lesions constitute a significant volume of the hyperplastic ob/ob islets. We propose that these lesions are formed by a mechanism involving extravasation of red blood cells/plasma due to increased islet vessel blood flow and vessel instability. Further, our data indicate that the primary lobular compartments of the ob/ob pancreas have different potentials for expanding their β-cell population. Unawareness of the characteristics of β-cell expansion in ob/ob mice presented in this report may significantly influence ex vivo and in vivo assessments of this model in studies of β-cell adaptation and function.

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  • 13. Van de Casteele, M.
    et al.
    Leuckx, G.
    Baeyens, L.
    Cai, Y.
    Yuchi, Y.
    Coppens, V.
    De Groef, S.
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Svensson, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ahnfelt-Ronne, J.
    Madsen, O. D.
    Waisman, A.
    Dor, Y.
    Jensen, J. N.
    Heimberg, H.
    Neurogenin 3(+) cells contribute to beta-cell neogenesis and proliferation in injured adult mouse pancreas2013In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 4, p. e523-Article in journal (Refereed)
    Abstract [en]

    We previously showed that injury by partial duct ligation (PDL) in adult mouse pancreas activates Neurogenin 3 (Ngn3)(+) progenitor cells that can differentiate to beta cells ex vivo. Here we evaluate the role of Ngn3(+) cells in beta cell expansion in situ. PDL not only induced doubling of the beta cell volume but also increased the total number of islets. beta cells proliferated without extended delay (the so-called 'refractory' period), their proliferation potential was highest in small islets, and 86% of the beta cell expansion was attributable to proliferation of pre-existing beta cells. At sufficiently high Ngn3 expression level, upto 14% of all beta cells and 40% of small islet beta cells derived from non-beta cells. Moreover, beta cell proliferation was blunted by a selective ablation of Ngn3(+) cells but not by conditional knockout of Ngn3 in pre-existing beta cells supporting a key role for Ngn3(+) insulin(-) cells in beta cell proliferation and expansion. We conclude that Ngn3(+) cell-dependent proliferation of pre-existing and newly-formed beta cells as well as reprogramming of non-beta cells contribute to in vivo beta cell expansion in the injured pancreas of adult mice.

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  • 14.
    Witek, Barbara
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    El Wakil, Abeer
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Nord, Christoffer
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Ahlgren, Ulf
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Eriksson, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Molecular Medicine (UCMM).
    Vernersson-Lindahl, Emma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Helland, Aslaug
    Alexeyev, Oleg A.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Hallberg, Bengt
    Palmer, Ruth H.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg.
    Targeted Disruption of ALK Reveals a Potential Role in Hypogonadotropic Hypogonadism2015In: PLOS ONE, E-ISSN 1932-6203, Vol. 10, no 5, article id e0123542Article in journal (Refereed)
    Abstract [en]

    Mice lacking ALK activity have previously been reported to exhibit subtle behavioral phenotypes. In this study of ALK of loss of function mice we present data supporting a role for ALK in hypogonadotropic hypogonadism in male mice. We observed lower level of serum testosterone at P40 in ALK knock-out males, accompanied by mild disorganization of seminiferous tubules exhibiting decreased numbers of GATA4 expressing cells. These observations highlight a role for ALK in testis function and are further supported by experiments in which chemical inhibition of ALK activity with the ALK TKI crizotinib was employed. Oral administration of crizotinib resulted in a decrease of serum testosterone levels in adult wild type male mice, which reverted to normal levels after cessation of treatment. Analysis of GnRH expression in neurons of the hypothalamus revealed a significant decrease in the number of GnRH positive neurons in ALK knock-out mice at P40 when compared with control littermates. Thus, ALK appears to be involved in hypogonadotropic hypogonadism by regulating the timing of pubertal onset and testis function at the upper levels of the hypothalamic-pituitary gonadal axis.

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